BioPAX pathway converted from "G2/M Checkpoints" in the Reactome database. G2/M Checkpoints G2/M Checkpoints G2/M checkpoints include the checks for damaged DNA, unreplicated DNA, and checks that ensure that the genome is replicated once and only once per cell cycle. If cells pass these checkpoints, they follow normal transition to the M phase. However, if any of these checkpoints fail, mitotic entry is prevented by specific G2/M checkpoint events.<p>The G2/M checkpoints can fail due to the presence of unreplicated DNA or damaged DNA. In such instances, the cyclin-dependent kinase, Cdc2(Cdk1), is maintained in its inactive, phosphorylated state, and mitotic entry is prevented. Events that ensure that origins of DNA replication fire once and only once per cell cycle are also an example of a G2/M checkpoint.<p>In the event of high levels of DNA damage, the cells may also be directed to undergo apopotosis (not covered). G2/M DNA damage checkpoint G2/M DNA damage checkpoint Throughout the cell cycle, the genome is constantly monitored for damage, resulting either from errors of replication, by-products of metabolism or through extrinsic sources such as ultra-violet or ionizing radiation. The different DNA damage checkpoints act to inhibit or maintain the inhibition of the relevant CDK that will control the next cell cycle transition. The G2 DNA damage checkpoint prevents mitotic entry solely through T14Y15 phosphorylation of Cdc2 (Cdk1). Failure of the G2 DNA damage checkpoint leads to catastrophic attempts to segregate unrepaired chromosomes. 2.7.11.1 Recruitment and activation of Chk1 Recruitment and activation of Chk1 Chk1 is a checkpoint kinase activated during genotoxic stress. Like ATR, Chk1 is essential for viability in mammals. Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. While the ATR and ATM pathways are distinct, there is interplay between the two. For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. The ATR and ATM pathways also have mechanistic similarities. Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53). Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 113826 1 nucleoplasm GO 0005654 UniProt:O14757 CHEK1 CHEK1 CHK1 CHEK1 FUNCTION Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047, PubMed:32357935). May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Binds to and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889, PubMed:14559997). Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C (PubMed:9278511). Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889). Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A (PubMed:9278511, PubMed:19734889, PubMed:20090422). Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression (PubMed:9278511). Also phosphorylates NEK6 (PubMed:18728393). Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination (PubMed:15665856). Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation (PubMed:10673501, PubMed:15659650, PubMed:16511572). Also promotes repair of DNA cross-links through phosphorylation of FANCE (PubMed:17296736). Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A (PubMed:12660173, PubMed:12955071). This may enhance chromatin assembly both in the presence or absence of DNA damage (PubMed:12660173, PubMed:12955071). May also play a role in replication fork maintenance through regulation of PCNA (PubMed:18451105). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones (By similarity). Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (By similarity). May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest (PubMed:17380128). Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (PubMed:31316063). Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (PubMed:33108758).ACTIVITY REGULATION Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication (PubMed:11390642, PubMed:12588868, PubMed:12676583, PubMed:12676962, PubMed:15665856, PubMed:19716789). Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B (PubMed:11836499, PubMed:12766152, PubMed:16963448, PubMed:19330022). Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity (PubMed:31316063).SUBUNIT Interacts (phosphorylated by ATR) with RAD51 (PubMed:15665856). Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1 (PubMed:16963448). Interacts with BRCA1 (PubMed:11836499). Interacts with and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511). Interacts with FBXO6, which regulates CHEK1 (PubMed:19716789). Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (PubMed:15870257). Interacts with TIMELESS; DNA damage-dependent (PubMed:15798197). Interacts with FEM1B; activates CHEK1 in response to stress (PubMed:19330022). Interacts with TLK1 (PubMed:12660173). Interacts with XPO1 and YWHAZ (PubMed:12676962). Interacts with CDK5RAP3; antagonizes CHEK1 (PubMed:19223857).TISSUE SPECIFICITY Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.DOMAIN The autoinhibitory region (AIR) inhibits the activity of the kinase domain.PTM Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.PTM Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (PubMed:32357935).PTM Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt O14757 Chain Coordinates 1 EQUAL 476 EQUAL Reactome DB_ID: 29358 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 113582 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 113838 1 O-phospho-L-serine at 317 317 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 345 345 EQUAL 1 EQUAL 476 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 176269 ATR:ATRIP [nucleoplasm] ATR:ATRIP ATM- and rad3-related (ATR) ATR-interacting protein (ATRIP) ATR-ATRIP Reactome DB_ID: 176231 1 UniProt:Q8WXE1 ATRIP ATRIP AGS1 ATRIP FUNCTION Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein.SUBUNIT Interacts with ATR (By similarity). Heterodimer with ATR. The heterodimer binds the RPA complex and is then recruited to single-stranded DNA. Interacts with CEP164 (via N-terminus). Interacts with CINP.TISSUE SPECIFICITY Ubiquitous.DOMAIN The EEXXXDDL motif is required for the interaction with catalytic subunit PRKDC and its recruitment to sites of DNA damage.PTM Phosphorylated by ATR.SIMILARITY Belongs to the ATRIP family.CAUTION The gene for this protein is either identical to or adjacent to that of TREX1. Some of the mRNAs that encode ATRIP also encode TREX1 in another reading frame. UniProt Q8WXE1 1 EQUAL 791 EQUAL Reactome DB_ID: 912443 1 UniProt:Q13535 ATR ATR FRP1 ATR FUNCTION Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex (By similarity).ACTIVITY REGULATION Serine/threonine-protein kinase activity is directly stimulated by TOPBP1 (PubMed:16530042). ATR kinase activity is also directly activated by ETAA1, independently of TOPBP1 (PubMed:27723720, PubMed:27723717). Activated by DNA and inhibited by BCR-ABL oncogene (PubMed:10597277). Slightly activated by ATRIP (PubMed:14729973). Inhibited by caffeine, wortmannin and LY294002 (PubMed:9766667).SUBUNIT Forms a heterodimer with ATRIP.(PubMed:11721054). Binds to DNA, and to UV-damaged DNA with higher affinity. Interacts with RAD17, MSH2 and HDAC2. Present in a complex containing ATRIP and RPA-coated single-stranded DNA. Present in a complex containing CHD4 and HDAC2. Interacts with EEF1E1, the interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1. Interacts with BCR-ABL after genotoxic stress. Interacts with UHRF2; this interaction promotes ATR activation.TISSUE SPECIFICITY Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.PTM Phosphorylated; autophosphorylates in vitro.SIMILARITY Belongs to the PI3/PI4-kinase family. ATM subfamily. UniProt Q13535 1 EQUAL 2644 EQUAL Reactome Database ID Release 82 176269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176269 Reactome R-HSA-176269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176269.1 GO 0004674 GO molecular function Reactome Database ID Release 82 176203 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176203 Reactome Database ID Release 82 176116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176116 Reactome R-HSA-176116 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176116.2 11390642 Pubmed 2001 ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1 Zhao, H Piwnica-Worms, H Mol Cell Biol 21:4129-39 12781359 Pubmed 2003 Chk1 and Chk2 kinases in checkpoint control and cancer Bartek, J Lukas, J Cancer Cell 3:421-9 16431910 Pubmed 2006 Rapid activation of ATR by ionizing radiation requires ATM and Mre11 Myers, JS Cortez, D J Biol Chem 11090622 Pubmed 2000 Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts Kumagai, A Dunphy, WG Mol Cell 6:839-49 12766152 Pubmed 2003 Human claspin is required for replication checkpoint control Chini, CC Chen, J J Biol Chem 278:30057-62 15190204 Pubmed 2004 ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage Sorensen, CS Syljuasen, RG Lukas, J Bartek, J Cell Cycle 3:941-5 10859164 Pubmed 2000 Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Liu, Q Guntuku, S Cui, XS Matsuoka, S Cortez, D Tamai, K Luo, G Carattini-Rivera, S DeMayo, F Bradley, A Donehower, LA Elledge, SJ Genes Dev 14:1448-59 15272308 Pubmed 2004 Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism Uto, K Inoue, D Shimuta, K Nakajo, N Sagata, N EMBO J 23:3386-96 15279789 Pubmed 2004 Chk1 in the DNA damage response: conserved roles from yeasts to mammals Chen, Y Sanchez, Y DNA Repair (Amst) 3:1025-32 16360315 Pubmed 2006 Rapid PIKK-Dependent Release of Chk1 from Chromatin Promotes the DNA-Damage Checkpoint Response Smits, VA Reaper, PM Jackson, SP Curr Biol 16:150-9 10859163 Pubmed 2000 Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice Takai, H Tominaga, K Motoyama, N Minamishima, YA Nagahama, H Tsukiyama, T Ikeda, K Nakayama, Keiko Nakanishi, M Nakayama, Ken-ichi Genes Dev 14:1439-47 GO 0006260 GO biological process CHEK2 is recruited to DNA DSBs CHEK2 is recruited to DNA DSBs CHEK2 (CHK2, Cds1) is recruited to DNA double-strand breaks (DSBs) mainly through its interaction with TP53BP1 (53BP1) (Wang et al. 2002), but BRCA1 also contributes to CHEK2 recruitment (Wilson and Stern 2008). Authored: Orlic-Milacic, Marija, 2015-05-12 Reviewed: Borowiec, James A, 2015-06-12 Edited: Orlic-Milacic, Marija, 2015-05-12 Reactome DB_ID: 5683605 1 DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex [nucleoplasm] DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex Reactome DB_ID: 5683417 1 DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1 [nucleoplasm] DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1 Reactome DB_ID: 5683418 1 UniProt:Q12888 TP53BP1 TP53BP1 TP53BP1 FUNCTION Double-strand break (DSB) repair protein involved in response to DNA damage, telomere dynamics and class-switch recombination (CSR) during antibody genesis (PubMed:12364621, PubMed:22553214, PubMed:23333306, PubMed:17190600, PubMed:21144835, PubMed:27153538, PubMed:28241136). Plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs and specifically counteracting the function of the homologous recombination (HR) repair protein BRCA1 (PubMed:22553214, PubMed:23727112, PubMed:23333306, PubMed:27153538). In response to DSBs, phosphorylation by ATM promotes interaction with RIF1 and dissociation from NUDT16L1/TIRR, leading to recruitment to DSBs sites (PubMed:28241136). Recruited to DSBs sites by recognizing and binding histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) and histone H4 dimethylated at 'Lys-20' (H4K20me2), two histone marks that are present at DSBs sites (PubMed:23760478, PubMed:27153538, PubMed:28241136, PubMed:17190600). Required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs (PubMed:23345425). Participates in the repair and the orientation of the broken DNA ends during CSR (By similarity). In contrast, it is not required for classic NHEJ and V(D)J recombination (By similarity). Promotes NHEJ of dysfunctional telomeres via interaction with PAXIP1 (PubMed:23727112).SUBUNIT Homoligomer (PubMed:16294047, PubMed:23760478, PubMed:23345425). Interacts with p53/TP53 (via the central domain) (PubMed:12110597, PubMed:11877378). Interacts with DCLRE1C (PubMed:15574327). Interacts with histone H2AX and this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12607005). Interacts with histone H4 that has been dimethylated at 'Lys-20' (H4K20me2) (PubMed:17190600). Has low affinity for histone H4 containing monomethylated 'Lys-20' (H4K20me1) (PubMed:17190600). Does not bind histone H4 containing unmethylated or trimethylated 'Lys-20' (H4K20me3) (PubMed:17190600). Has low affinity for histone H3 that has been dimethylated on 'Lys-79' (PubMed:15525939). Has very low affinity for histone H3 that has been monomethylated on 'Lys-79' (in vitro) (PubMed:15525939). Does not bind unmethylated histone H3 (PubMed:15525939). Interacts with histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) (PubMed:23760478). Interacts with PWWP3A/EXPAND1 (PubMed:20347427). Interacts with CHEK2; modulates CHEK2 phosphorylation at 'Thr-68' in response to infrared (PubMed:12364621). Interacts with MSL1; this interaction may be required for MSL1 DNA repair activity, but not for histone acetyltransferase activity (PubMed:19650074). Interacts (when phosphorylated by ATM) with RIF1 (PubMed:23727112, PubMed:23333306, PubMed:28241136). Interacts (via the Tudor-like domain) with NUDT16L1/TIRR; interaction masks the Tudor-like domain and prevents recruitment to chromatin (PubMed:28241136). Interacts with PAXIP1 (PubMed:23727112). Interacts with IFI202A (By similarity). Interacts with SHLD2 (PubMed:29789392).DOMAIN The Tudor-like region mediates binding to histone H4 dimethylated at 'Lys-20' (H4K20me2) (PubMed:17190600). Interaction with NUDT16L1/TIRR masks the Tudor-like domain and prevents recruitment to chromatin (PubMed:28241136).DOMAIN The UDR (ubiquitin-dependent recruitment) motif specifically recognizes and binds histone H2A monoubiquitinated at 'Lys-15' (H2AK15ub) (PubMed:23760478, PubMed:24703952). Phosphorylation of the UDR blocks interaction with H2AK15ub (PubMed:24703952).PTM Asymmetrically dimethylated on Arg residues by PRMT1. Methylation is required for DNA binding.PTM Phosphorylated at basal level in the absence of DNA damage (PubMed:11042216, PubMed:11331310). Phosphorylated by ATM in response to DNA damage: phosphorylation at different sites promotes interaction with different set of proteins: phosphorylation at the N-terminus by ATM (residues from 6-178) promotes interaction with PAXIP1 and non-homologous end joining (NHEJ) of dysfunctional telomeres (PubMed:23727112). Phosphorylation by ATM at residues that are located more C-terminus (residues 300-650) leads to promote interaction with RIF1 (PubMed:23727112, PubMed:23333306, PubMed:28241136). Interaction with RIF1 leads to disrupt interaction with NUDT16L1/TIRR (PubMed:28241136). Phosphorylation at Thr-1609 and Ser-1618 in the UDR motif blocks interaction with H2AK15ub (PubMed:24703952). Dephosphorylated by PPP4C (PubMed:24703952). Hyperphosphorylation during mitosis correlates with its exclusion from chromatin and DNA lesions. Hyperphosphorylated in an ATR-dependent manner in response to DNA damage induced by UV irradiation (PubMed:17553757, PubMed:21144835). Dephosphorylated by PPP5C (PubMed:19176521).DISEASE A chromosomal aberration involving TP53BP1 is found in a form of myeloproliferative disorder chronic with eosinophilia. Translocation t(5;15)(q33;q22) with PDGFRB creating a TP53BP1-PDGFRB fusion protein. UniProt Q12888 O-phospho-L-serine at 25 25 EQUAL O-phospho-L-serine at 1778 1778 EQUAL 1 EQUAL 1972 EQUAL Reactome DB_ID: 5683079 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4 [nucleoplasm] DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4 Reactome DB_ID: 5682996 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1 [nucleoplasm] DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1 Reactome DB_ID: 5682997 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1 [nucleoplasm] DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1 Reactome DB_ID: 5682525 1 p-5T-MDC1 [nucleoplasm] p-5T-MDC1 p-5T-MDC1 homodimer Reactome DB_ID: 75236 2 UniProt:Q14676 MDC1 MDC1 MDC1 KIAA0170 NFBD1 FUNCTION Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.SUBUNIT Homodimer. Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AX, which requires phosphorylation of H2AX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain).TISSUE SPECIFICITY Highly expressed in testis.DOMAIN Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AX.PTM Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain.PTM Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation.PTM Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination. UniProt Q14676 O-phospho-L-threonine at 4 4 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 699 699 EQUAL O-phospho-L-threonine at 719 719 EQUAL O-phospho-L-threonine at 752 752 EQUAL O-phospho-L-threonine at 765 765 EQUAL 1 EQUAL 2089 EQUAL Reactome Database ID Release 82 5682525 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682525 Reactome R-HSA-5682525 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682525.1 Reactome DB_ID: 5682995 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome [nucleoplasm] DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome Reactome DB_ID: 5682998 1 K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome [nucleoplasm] K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome Nucleosome with Histone K63PolyUb,gamma-H2A.x and H4K20Me2 Reactome DB_ID: 5682847 2 UniProt:P16104 H2AX H2AX H2AX H2AFX FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (Probable). Interacts with numerous proteins required for DNA damage signaling and repair when phosphorylated on Ser-140 (PubMed:12419185, PubMed:12607005, PubMed:15201865). These include MDC1, TP53BP1, BRCA1 and the MRN complex, composed of MRE11, RAD50, and NBN (PubMed:12419185, PubMed:12607005, PubMed:15201865). Interaction with the MRN complex is mediated at least in part by NBN (PubMed:12419185). Also interacts with DHX9/NDHII when phosphorylated on Ser-140 and MCPH1 when phosphorylated at Ser-140 or Tyr-143 (PubMed:15613478). Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation (PubMed:16820410). Interacts with WRAP53/TCAB1 (PubMed:26734725, PubMed:27715493). Interacts with HDGFL2 (PubMed:26721387).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein EBNA6.DEVELOPMENTAL STAGE Synthesized in G1 as well as in S-phase.DOMAIN The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.PTM Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents and by stalled replication forks, and may also occur during meiotic recombination events and immunoglobulin class switching in lymphocytes. Phosphorylation can extend up to several thousand nucleosomes from the actual site of the DSB and may mark the surrounding chromatin for recruitment of proteins required for DNA damage signaling and repair. Widespread phosphorylation may also serve to amplify the damage signal or aid repair of persistent lesions. Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing radiation is mediated by both ATM and PRKDC while defects in DNA replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to activation of ATR and PRKDC. Dephosphorylation of Ser-140 by PP2A is required for DNA DSB repair. In meiosis, Ser-140 phosphorylation (H2AX139ph) may occur at synaptonemal complexes during leptotene as an ATM-dependent response to the formation of programmed DSBs by SPO11. Ser-140 phosphorylation (H2AX139ph) may subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene, downstream of ATR and BRCA1 activation. Ser-140 phosphorylation (H2AX139ph) may also be required for transcriptional repression of unsynapsed chromatin and meiotic sex chromosome inactivation (MSCI), whereby the X and Y chromosomes condense in pachytene to form the heterochromatic XY-body. During immunoglobulin class switch recombination in lymphocytes, Ser-140 phosphorylation (H2AX139ph) may occur at sites of DNA-recombination subsequent to activation of the activation-induced cytidine deaminase AICDA. Phosphorylation at Tyr-143 (H2AXY142ph) by BAZ1B/WSTF determines the relative recruitment of either DNA repair or pro-apoptotic factors. Phosphorylation at Tyr-143 (H2AXY142ph) favors the recruitment of APBB1/FE65 and pro-apoptosis factors such as MAPK8/JNK1, triggering apoptosis. In contrast, dephosphorylation of Tyr-143 by EYA proteins (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph).PTM Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression (By similarity). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Acetylation at Lys-6 (H2AXK5ac) by KAT5 component of the NuA4 histone acetyltransferase complex promotes NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). Acetylation at Lys-37 increases in S and G2 phases. This modification has been proposed to play a role in DNA double-strand break repair (By similarity).SIMILARITY Belongs to the histone H2A family. UniProt P16104 O-phospho-L-serine at 140 140 EQUAL ubiquitinylated lysine (K63polyUb [nucleoplasm]) at 14 14 EQUAL ubiquitinylated lysine [MOD:01148] ubiquitinylated lysine (K63polyUb [nucleoplasm]) at 16 16 EQUAL 2 EQUAL 143 EQUAL Reactome DB_ID: 181914 2 UniProt:Q16695 H3-4 H3-4 H3-4 HIST3H3 H3FT FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with TONSL; CHAF1A and CHAF1B (PubMed:33857403).TISSUE SPECIFICITY Expressed in testicular cells.DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability (By similarity).PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters (By similarity).PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication (By similarity).PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin (By similarity).PTM Ubiquitinated.PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression (By similarity).PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes. It gives a specific tag for epigenetic transcription activation. Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair.PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac).SIMILARITY Belongs to the histone H3 family. UniProt Q16695 2 EQUAL 136 EQUAL Reactome DB_ID: 5651652 2 UniProt:P62805 H4C1 H4C1 H4FA H4FC H4FB H4FE H4FD H4FG H4FI H4FH H4FK H4FJ H4FM H4FO H4FN H4C2 H4C1 H4C4 H4C3 H4C6 H4C5 H4-16 H4C15 H4C14 HIST4H4 H4C13 H4C12 HIST2H4 H4C11 H4F2 H4/D H4/C H4/E H4/H H4/G H4/J H4/I H4/K H4/N H4/M H4/O HIST2H4A HIST2H4B H4C8 H4C9 HIST1H4K HIST1H4L HIST1H4A HIST1H4B HIST1H4H HIST1H4I HIST1H4J HIST1H4C HIST1H4D H4/B HIST1H4E H4/A HIST1H4F FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (By similarity). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (PubMed:33857403). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (PubMed:33857403).PTM Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin.PTM Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation.PTM Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3) (PubMed:12086618, PubMed:15964846, PubMed:17967882). Monomethylation is performed by KMT5A/SET8 (PubMed:15964846). Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing (By similarity). Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators (PubMed:31061526).PTM Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4.PTM Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me).PTM Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage.PTM Sumoylated, which is associated with transcriptional repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation.PTM Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.SIMILARITY Belongs to the histone H4 family. UniProt P62805 N6,N6-dimethyl-L-lysine at 21 21 EQUAL N6,N6-dimethyl-L-lysine [MOD:00084] 2 EQUAL 103 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 181911 2 Histone H2B [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 5682998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682998 Reactome R-HSA-5682998 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682998.2 Reactome DB_ID: 5682162 1 DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 [nucleoplasm] DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 Reactome DB_ID: 5693527 1 UniProt:Q13315 ATM ATM ATM FUNCTION Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FBXW7, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:9843217, PubMed:9733515, PubMed:10550055, PubMed:10766245, PubMed:10839545, PubMed:10910365, PubMed:10802669, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:30612738, PubMed:30886146, PubMed:26774286). May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Phosphorylates TTC5/STRAP at 'Ser-203' in the cytoplasm in response to DNA damage, which promotes TTC5/STRAP nuclear localization (PubMed:15448695).ACTIVITY REGULATION Inhibited by wortmannin.SUBUNIT Homodimer (PubMed:28508083). Dimers or tetramers in inactive state. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active. Binds p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RAD17; DNA damage promotes the association. Interacts with EEF1E1; the interaction, induced on DNA damage, up-regulates TP53. Interacts with DCLRE1C, KAT8, KAT5, NABP2, ATMIN and CEP164. Interacts with AP2B1 and AP3B2; the interaction occurs in cytoplasmic vesicles (By similarity). Interacts with TELO2 and TTI1. Interacts with DDX1. Interacts with BRAT1. Interacts with CYREN (via XLF motif) (By similarity).TISSUE SPECIFICITY Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.INDUCTION By ionizing radiation.DOMAIN The FATC domain is required for interaction with KAT5.PTM Phosphorylated by NUAK1/ARK5 (PubMed:12409306). Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:21144835, PubMed:27664052). During the late stages of DNA damage response, dephosphorylated following deacetylation by SIRT7, leading to ATM deactivation (PubMed:30944854).PTM Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981 (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:17923702, PubMed:21144835). Acetylated in vitro by KAT5/TIP60 (PubMed:16141325). Deacetylated by SIRT7 during the late stages of DNA damage response, promoting ATM dephosphorylation and subsequent deactivation (PubMed:30944854).DISEASE Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.DISEASE Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).DISEASE Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.SIMILARITY Belongs to the PI3/PI4-kinase family. ATM subfamily. UniProt Q13315 O-phospho-L-serine at 1981 1981 EQUAL N6-acetyl-L-lysine at 3016 3016 EQUAL N6-acetyl-L-lysine [MOD:00064] 1 EQUAL 3056 EQUAL Reactome DB_ID: 3321979 1 UniProt:Q92993 KAT5 KAT5 KAT5 TIP60 HTATIP FUNCTION Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4 (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:16387653, PubMed:19909775, PubMed:25865756, PubMed:27153538, PubMed:29335245, PubMed:29174981, PubMed:33076429, PubMed:32822602). Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270). The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:17709392, PubMed:19783983, PubMed:32832608). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks (PubMed:27153538, PubMed:32832608). Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes (By similarity). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as ARNTL/BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17360565, PubMed:17996965, PubMed:24835996, PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:30704899, PubMed:32034146, PubMed:32817552, PubMed:34077757). Directly acetylates and activates ATM (PubMed:16141325). Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex (PubMed:32034146). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity (PubMed:17360565, PubMed:24835996). Involved in skeletal myoblast differentiation by mediating acetylation of SOX4 (PubMed:26291311). Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity (PubMed:33938178). Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of ARNTL/BMAL1, promoting elongation of circadian transcripts (By similarity). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation (PubMed:32817552). Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1 (PubMed:34077757). Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase (PubMed:34077757). Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol (PubMed:29765047). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation and 2-hydroxyisobutyrylation, respectively (PubMed:29192674, PubMed:34608293). Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins (PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:34608293). Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis (PubMed:26829474). Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes (PubMed:29040603). Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293).ACTIVITY REGULATION Acyltransferase and acetyltransferase activities are activated by phosphorylation and autoacetylation (PubMed:20100829, PubMed:30704899). Autoacetylation activates the histone acetyltransferase activity (PubMed:20100829, PubMed:25865756, PubMed:30704899).SUBUNIT Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270, PubMed:29174981). KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC (PubMed:12776177). Interacts with ATM (PubMed:16141325). Interacts with JADE1 (PubMed:15502158). Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7 (PubMed:11416127, PubMed:11262386, PubMed:12551922). Interacts with the cytoplasmic tail of APP and APBB1/FE65 (PubMed:33938178). Interacts with TRIM24 and TRIM68 (PubMed:18451177, PubMed:19909775). Forms a complex with SENP6 and UBE2I in response to UV irradiation. Identified in a complex with HINT1 (PubMed:16835243). Interacts with ATF2 and CUL3 (PubMed:18397884). Interacts with NR1D2 (via N-terminus) (PubMed:17996965). Component of a SWR1-like complex (PubMed:24463511). Interacts with FOXP3 (PubMed:17360565, PubMed:24835996). Interacts with ZBTB49 (PubMed:25245946). Interacts with SRF (By similarity). Interacts with ATF3; promoting autoacetylation and deubiquitination by USP7 (PubMed:25865756). Interacts with EP300/p300; interaction promotes KAT5 autoacetylation (PubMed:24835996). Interacts with PRKDC; interaction is impaired following KAT5 sumoylation (PubMed:32832608).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT.PTM Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase (PubMed:12468530, PubMed:26829474, PubMed:29335245). The phosphorylated form has a higher activity (PubMed:12468530, PubMed:29335245). Phosphorylation at Ser-90 by CDK1 or CDK9 is a prerequisite for phosphorylation at Ser-86 by GSK3 (PubMed:26829474, PubMed:30704899). Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase and acyltransferase activities (PubMed:30704899). Phosphorylation at Ser-90 by CDK9 promotes KAT5 recruitment to chromatin (PubMed:29335245). Phosphorylation by VRK1 following DNA damage promotes KAT5 association with chromatin and histone acetyltransferase activity (PubMed:33076429).PTM Autoacetylated (PubMed:20100829, PubMed:24835996, PubMed:25301942, PubMed:26291311, PubMed:33938178). Autoacetylation is required for histone acetyltransferase activity (PubMed:20100829, PubMed:25865756). Autoacetylation at Lys-327 is facilitated by interaction with EP300/p300: it prevents ubiquitination and subsequent degradation by the proteasome and promotes acetylation of target proteins (PubMed:24835996). Deacetylated by HDAC3 and SIRT1 (PubMed:20100829, PubMed:25301942). Deacetylation by HDAC3 promotes its ubiquitination and cytoplasmic localization (PubMed:25301942).PTM Sumoylated by UBE2I at Lys-430 and Lys-451, leading to increase of its histone acetyltransferase activity in UV-induced DNA damage response, as well as its translocation to nuclear bodies (PubMed:17704809). Sumoylation with SUMO2 by PIAS4 at Lys-430 promotes repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:32832608). Sumoylation by PIAS4 impairs interaction with PRKDC, inhibiting non-homologous end joining (NHEJ)-mediated repair of DSBs, thereby facilitating HR (PubMed:32832608). Desumoylated by SENP3 (PubMed:32832608).PTM Ubiquitinated by MDM2, leading to its proteasome-dependent degradation (PubMed:11927554, PubMed:24835996). Ubiquitination is prevented by autoacetylation at Lys-327 (PubMed:24835996). Ubiquitinated following deacetylation by HDAC3, leading to cytoplasmic localization (PubMed:25301942). Deubiquitinated by USP7 following interaction with ATF3, promoting its stabilization (PubMed:25865756).PTM (Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.SIMILARITY Belongs to the MYST (SAS/MOZ) family.CAUTION The role of the Tudor-knot domain, also named chromo barrel or chromodomain, is unclear. Based on its similarity with some chromo domains, it was first reported to bind histone H3 trimethylated on 'Lys-4' and/or 'Lys-9' (H3K4me3 and/or H3K9me3, respectively) (PubMed:19783983, PubMed:25560918). However, another group was not able to see any binding to methylated histones (PubMed:29494751). The 3D structure of the domain suggests that the inability to bind histones is caused by occlusion of the putative peptide-binding site by a basic amino acid side chain within a unique beta hairpin (PubMed:29494751). UniProt Q92993 1 EQUAL 513 EQUAL Reactome DB_ID: 5682175 1 DNA DSBs:p-MRN [nucleoplasm] DNA DSBs:p-MRN DNA DSBs:MRE11:RAD50:p-S343-NBN Reactome DB_ID: 75165 1 DNA double-strand break ends [nucleoplasm] DNA double-strand break ends Reactome DB_ID: 5682166 1 p-MRN [nucleoplasm] p-MRN MRE11:RAD50:p-S343-NBN MRE11:RAD50:p-S343-NBS1 Reactome DB_ID: 59544 1 UniProt:P49959 MRE11 MRE11 MRE11 HNGS1 MRE11A FUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11 (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). RAD50 may be required to bind DNA ends and hold them in close proximity (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289, PubMed:30612738). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).ACTIVITY REGULATION Interaction with SAMHD1 stimulates the double-strand-specific 3'-5' exonuclease activity.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo (PubMed:15456891, PubMed:15723659, PubMed:18469862). Interacts with ATF2 (PubMed:15916964). Interacts with EXD2 (PubMed:26807646). Interacts with MRNIP (PubMed:27568553). Interacts with SAMHD1; leading to stimulate 3'-5' exonuclease activity (PubMed:28834754, PubMed:29670289). Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain) (PubMed:30612738). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).PTM Ubiquitinated following DNA damage. Ubiquitination triggers interaction with UBQLN4, leading to MRE11 removal from chromatin and degradation by the proteasome.DISEASE Defects in MRE11 can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11 has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the MRE11/RAD32 family. UniProt P49959 1 EQUAL 708 EQUAL Reactome DB_ID: 75237 1 UniProt:O60934 NBN NBN NBS1 NBN P95 NBS FUNCTION Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:26215093, PubMed:9590181, PubMed:9705271, PubMed:11238951). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Interacts with histone H2AX this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12419185). Interacts with HJURP (PubMed:17823411). Interacts with INTS3 (PubMed:19683501). Interacts with KPNA2 (PubMed:16188882). Interacts with TERF2 (PubMed:10888888). Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection (PubMed:19759395). Interacts with SP100; recruits NBN to PML bodies (PubMed:12470659). Interacts with ATF2 (PubMed:15916964). Interacts with MTOR, MAPKAP1 isoform 2 and RICTOR; indicative for an association with the mTORC2 complex (PubMed:23762398). Interacts with MRNIP (PubMed:27568553). Interacts with UFL1; promoting UFL1 recruitment to double-strand breaks following DNA damage (PubMed:30886146). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.TISSUE SPECIFICITY Ubiquitous (PubMed:9590180). Expressed at high levels in testis (PubMed:9590180).INDUCTION Up-regulated by ionizing radiation (IR).DOMAIN The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage.DOMAIN The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex.DOMAIN The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response.PTM Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.DISEASE Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells. UniProt O60934 O-phospho-L-serine at 343 343 EQUAL 1 EQUAL 754 EQUAL Reactome DB_ID: 75160 1 UniProt:Q92878 RAD50 RAD50 RAD50 FUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:11741547, PubMed:9590181, PubMed:9705271, PubMed:9651580). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:8756642, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM8 and MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with RINT1 (PubMed:11096100). Interacts with BRCA1 via its N-terminal domain (PubMed:10426999). Interacts with DCLRE1C/Artemis (PubMed:15456891, PubMed:15723659). Interacts with MRNIP (PubMed:27568553). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).TISSUE SPECIFICITY Expressed at very low level in most tissues, except in testis where it is expressed at higher level. Expressed in fibroblasts.DOMAIN The zinc-hook, which separates the large intramolecular coiled coil regions, contains 2 Cys residues that coordinate one molecule of zinc with the help of the 2 Cys residues of the zinc-hook of another RAD50 molecule, thereby forming a V-shaped homodimer. The two heads of the homodimer, which constitute the ATP-binding domain, interact with the MRE11 homodimer (By similarity).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the SMC family. RAD50 subfamily. UniProt Q92878 1 EQUAL 1312 EQUAL Reactome Database ID Release 82 5682166 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682166 Reactome R-HSA-5682166 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682166.1 Reactome Database ID Release 82 5682175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682175 Reactome R-HSA-5682175 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682175.1 Reactome Database ID Release 82 5682162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682162 Reactome R-HSA-5682162 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682162.1 Reactome Database ID Release 82 5682995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682995 Reactome R-HSA-5682995 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682995.1 Reactome Database ID Release 82 5682997 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682997 Reactome R-HSA-5682997 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682997.1 Reactome DB_ID: 5682984 1 UniProt:O96028 NSD2 NSD2 KIAA1090 MMSET NSD2 WHSC1 TRX5 FUNCTION Histone methyltransferase which specifically dimethylates nucleosomal histone H3 at 'Lys-36' (H3K36me2) (PubMed:27571355, PubMed:22099308, PubMed:19808676, PubMed:29728617). Also monomethylates nucleosomal histone H3 at 'Lys-36' (H3K36me) in vitro (PubMed:22099308). Does not trimethylate nucleosomal histone H3 at 'Lys-36' (H3K36me3) (PubMed:22099308). However, specifically trimethylates histone H3 at 'Lys-36' (H3K36me3) at euchromatic regions in embryonic stem (ES) cells (By similarity). By methylating histone H3 at 'Lys-36', involved in the regulation of gene transcription during various biological processes (PubMed:16115125, PubMed:22099308, PubMed:29728617). In ES cells, associates with developmental transcription factors such as SALL1 and represses inappropriate gene transcription mediated by histone deacetylation (By similarity). During heart development, associates with transcription factor NKX2-5 to repress transcription of NKX2-5 target genes (By similarity). Plays an essential role in adipogenesis, by regulating expression of genes involved in pre-adipocyte differentiation (PubMed:29728617). During T-cell receptor (TCR) and CD28-mediated T-cell activation, promotes the transcription of transcription factor BCL6 which is required for follicular helper T (Tfh) cell differentiation (By similarity). During B-cell development, required for the generation of the B1 lineage (By similarity). During B2 cell activation, may contribute to the control of isotype class switch recombination (CRS), splenic germinal center formation, and the humoral immune response (By similarity). Plays a role in class switch recombination of the immunoglobulin heavy chain (IgH) locus during B-cell activation (By similarity). By regulating the methylation of histone H3 at 'Lys-36' and histone H4 at 'Lys-20' at the IgH locus, involved in TP53BP1 recruitment to the IgH switch region and promotes the transcription of IgA (By similarity).SUBUNIT Interacts with HDAC1. Interacts (via PHD-type zinc fingers 1, 2 and 3) with SALL1. Interacts (via PHD-type 1, 2 and 3) with SALL4. Interacts with NANOG. Interacts with OGT. Interacts (via HMG box) with NKX2-5.TISSUE SPECIFICITY Widely expressed (PubMed:9618163, PubMed:18172012). Predominantly expressed in thymus and testis (PubMed:9787135, PubMed:18172012).DISEASE A chromosomal aberration involving NSD2 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH.DISEASE NSD2 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. NSD2 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily.CAUTION Depending on the experimental set up and substrate used, NSD2 has been shown to mono-, di- or tri-methylate 'Lys-27', 'Lys-36' or 'Lys-79' of histone H3 and 'Lys-20' or 'Lys-44' of histone H4 (PubMed:19808676). However, dimethylation of nucleosomal histone H3 at 'Lys-36' (H3K36me2) is likely to be the physiological reaction catalyzed by NSD2 (PubMed:19808676, PubMed:22099308). UniProt O96028 O-phospho-L-serine at 102 102 EQUAL 1 EQUAL 1365 EQUAL Reactome Database ID Release 82 5682996 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682996 Reactome R-HSA-5682996 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682996.1 Reactome DB_ID: 5682631 1 RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2 [nucleoplasm] RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2 Reactome DB_ID: 5682542 1 UBE2N:UBE2V2 [nucleoplasm] UBE2N:UBE2V2 UBC13:MMS2 Reactome DB_ID: 5682541 1 UniProt:P61088 UBE2N UBE2N UBE2N BLU FUNCTION The UBE2V1-UBE2N and UBE2V2-UBE2N heterodimers catalyze the synthesis of non-canonical 'Lys-63'-linked polyubiquitin chains. This type of polyubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage. Acts together with the E3 ligases, HLTF and SHPRH, in the 'Lys-63'-linked poly-ubiquitination of PCNA upon genotoxic stress, which is required for DNA repair. Appears to act together with E3 ligase RNF5 in the 'Lys-63'-linked polyubiquitination of JKAMP thereby regulating JKAMP function by decreasing its association with components of the proteasome and ERAD. Promotes TRIM5 capsid-specific restriction activity and the UBE2V1-UBE2N heterodimer acts in concert with TRIM5 to generate 'Lys-63'-linked polyubiquitin chains which activate the MAP3K7/TAK1 complex which in turn results in the induction and expression of NF-kappa-B and MAPK-responsive inflammatory genes. Together with RNF135 and UB2V1, catalyzes the viral RNA-dependent 'Lys-63'-linked polyubiquitination of RIG-I/DDX58 to activate the downstream signaling pathway that leads to interferon beta production (PubMed:28469175, PubMed:31006531). UBE2V1-UBE2N together with TRAF3IP2 E3 ubiquitin ligase mediate 'Lys-63'-linked polyubiquitination of TRAF6, a component of IL17A-mediated signaling pathway.ACTIVITY REGULATION Activity is inhibited by binding to OTUB1, which prevents 'Lys-63'-linked polyubiquitination (PubMed:20725033, PubMed:22325355, PubMed:22367539). Activity is inhibited by GPS2, leading to prevent 'Lys-63'-linked polyubiquitination (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with UBE2V2 (PubMed:10089880, PubMed:11473255, PubMed:14562038, PubMed:16307917, PubMed:16307917). Interacts (UBE2V2-UBE2N heterodimer) with the E3 ligase STUB1 (via the U-box domain); the complex has a specific 'Lys-63'-linked polyubiquitination activity (PubMed:16307917). Interacts with RNF8 and RNF168 (PubMed:16215985, PubMed:19203578). Interacts with RNF11 (PubMed:18615712). Interacts with the E3 ligases, HLTF and SHPRH; the interactions promote the 'Lys-63'-linked polyubiquitination of PCNA upon genotoxic stress and lead to DNA repair (PubMed:17108083, PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with ARIH2 (via RING-type 2) (PubMed:19340006). Interacts with OTUB1; leading to inhibit E2-conjugating activity (PubMed:20725033, PubMed:22325355, PubMed:22367539). Interacts with GPS2; leading to inhibit E2-conjugating activity (By similarity). Interacts with DDX58 and RNF135; involved in DDX58 ubiquitination and activation (PubMed:28469175).PTM Conjugation to ISG15 impairs formation of the thioester bond with ubiquitin but not interaction with UBE2V2.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt P61088 1 EQUAL 152 EQUAL Reactome DB_ID: 5682543 1 UniProt:Q15819 UBE2V2 UBE2V2 UBE2V2 MMS2 UEV2 FUNCTION Has no ubiquitin ligase activity on its own. The UBE2V2/UBE2N heterodimer catalyzes the synthesis of non-canonical poly-ubiquitin chains that are linked through 'Lys-63'. This type of poly-ubiquitination does not lead to protein degradation by the proteasome. Mediates transcriptional activation of target genes. Plays a role in the control of progress through the cell cycle and differentiation. Plays a role in the error-free DNA repair pathway and contributes to the survival of cells after DNA damage.SUBUNIT Heterodimer with UBE2N. Binds CHFR.TISSUE SPECIFICITY Detected in placenta, colon, liver and skin. Detected at very low levels in most tissues.INDUCTION Up-regulated in cultured fresh blood cells upon treatment with vitamin D3.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family. UniProt Q15819 2 EQUAL 145 EQUAL Reactome Database ID Release 82 5682542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682542 Reactome R-HSA-5682542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682542.1 Reactome DB_ID: 5682608 1 RNF8:Zn2+:SUMO1:p-T4827-HERC2 [nucleoplasm] RNF8:Zn2+:SUMO1:p-T4827-HERC2 Reactome DB_ID: 5682540 1 RNF8:Zn2+ [nucleoplasm] RNF8:Zn2+ RNF8 homodimer Reactome DB_ID: 5682539 2 UniProt:O76064 RNF8 RNF8 KIAA0646 RNF8 FUNCTION E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the 'Lys-63'-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand breaks (DSBs) sites, and by catalyzing 'Lys-48'-linked ubiquitination to remove target proteins from DNA damage sites. Following DNA DSBs, it is recruited to the sites of damage by ATM-phosphorylated MDC1 and catalyzes the 'Lys-63'-linked ubiquitination of histones H2A and H2AX, thereby promoting the formation of TP53BP1 and BRCA1 ionizing radiation-induced foci (IRIF). Also controls the recruitment of UIMC1-BRCC3 (RAP80-BRCC36) and PAXIP1/PTIP to DNA damage sites. Also recruited at DNA interstrand cross-links (ICLs) sites and catalyzes 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Promotes the formation of 'Lys-63'-linked polyubiquitin chains via interactions with the specific ubiquitin-conjugating UBE2N/UBC13 and ubiquitinates non-histone substrates such as PCNA. Substrates that are polyubiquitinated at 'Lys-63' are usually not targeted for degradation. Also catalyzes the formation of 'Lys-48'-linked polyubiquitin chains via interaction with the ubiquitin-conjugating UBE2L6/UBCH8, leading to degradation of substrate proteins such as CHEK2, JMJD2A/KDM4A and KU80/XRCC5: it is still unclear how the preference toward 'Lys-48'- versus 'Lys-63'-linked ubiquitination is regulated but it could be due to RNF8 ability to interact with specific E2 specific ligases. For instance, interaction with phosphorylated HERC2 promotes the association between RNF8 and UBE2N/UBC13 and favors the specific formation of 'Lys-63'-linked ubiquitin chains. Promotes non-homologous end joining (NHEJ) by promoting the 'Lys-48'-linked ubiquitination and degradation the of KU80/XRCC5. Following DNA damage, mediates the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF168, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979). Following DNA damage, mediates the ubiquitination and degradation of POLD4/p12, a subunit of DNA polymerase delta. In the absence of POLD4, DNA polymerase delta complex exhibits higher proofreading activity (PubMed:23233665). In addition to its function in damage signaling, also plays a role in higher-order chromatin structure by mediating extensive chromatin decondensation. Involved in the activation of ATM by promoting histone H2B ubiquitination, which indirectly triggers histone H4 'Lys-16' acetylation (H4K16ac), establishing a chromatin environment that promotes efficient activation of ATM kinase. Required in the testis, where it plays a role in the replacement of histones during spermatogenesis. At uncapped telomeres, promotes the joining of deprotected chromosome ends by inducing H2A ubiquitination and TP53BP1 recruitment, suggesting that it may enhance cancer development by aggravating telomere-induced genome instability in case of telomeric crisis. Promotes the assembly of RAD51 at DNA DSBs in the absence of BRCA1 and TP53BP1 Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. May be required for proper exit from mitosis after spindle checkpoint activation and may regulate cytokinesis. May play a role in the regulation of RXRA-mediated transcriptional activity. Not involved in RXRA ubiquitination by UBE2E2 (PubMed:11322894, PubMed:14981089, PubMed:17724460, PubMed:18001824, PubMed:18001825, PubMed:18006705, PubMed:18077395, PubMed:18337245, PubMed:18948756, PubMed:19015238, PubMed:19124460, PubMed:19202061, PubMed:19203578, PubMed:19203579, PubMed:20550933, PubMed:21558560, PubMed:21857671, PubMed:21911360, PubMed:22266820, PubMed:22373579, PubMed:22531782, PubMed:22705371, PubMed:22865450, PubMed:22980979).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. Forms a E2-E3 ubiquitin ligase complex composed of the RNF8 homodimer and a E2 heterodimer of UBE2N and UBE2V2. Interacts with class III E2s, including UBE2E1, UBE2E2, and UBE2E3 and with UBE2N. Interacts with RXRA. Interacts (via FHA domain) with ATM-phosphorylated MDC1. Interacts (via FHA domain) with 'Thr-4827' phosphorylated HERC2 (via C-terminus). Interacts with PIWIL1; leading to sequester RNF8 in the cytoplasm (By similarity). Interacts with WRAP53/TCAB1 (PubMed:25512560).SUBUNIT (Microbial infection) Interacts (via FHA domain) with phosphorylated human herpesvirus 1 ICP0 protein; leading to RNF8 degradation by the proteasome.TISSUE SPECIFICITY Ubiquitous. In fetal tissues, highest expression in brain, thymus and liver. In adult tissues, highest levels in brain and testis, lowest levels in peripheral blood cells.DEVELOPMENTAL STAGE Low levels at the G1-S boundary increase in intensity during S phase and until the end of the G2 phase. Abruptly decreases in late mitosis (at protein level). Barely detectable in anaphase.DOMAIN The FHA domain specifically recognizes and binds ATM-phosphorylated MDC1 and 'Thr-4827' phosphorylated HERC2 (PubMed:18001824). This domain is required for proper recruitment to DNA damage sites after UV irradiation, ionizing radiation, or treatment with an alkylating agent (PubMed:23233665).PTM Autoubiquitinated through 'Lys-48' and 'Lys-63' of ubiquitin. 'Lys-63' polyubiquitination is mediated by UBE2N. 'Lys-29'-type polyubiquitination is also observed, but it doesn't require its own functional RING-type zinc finger.SIMILARITY Belongs to the RNF8 family.CAUTION According to a well-established model, RNF8 initiate H2A 'Lys-63'-linked ubiquitination leading to recruitment of RNF168 to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data. UniProt O76064 1 EQUAL 485 EQUAL Reactome DB_ID: 200493 2 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome Database ID Release 82 5682540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682540 Reactome R-HSA-5682540 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682540.1 Reactome DB_ID: 5682615 1 UniProt:O95714 HERC2 HERC2 HERC2 FUNCTION E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts (when phosphorylated at Thr-4827 and sumoylated) with RNF8 (via FHA domain); this interaction increases after ionizing radiation (IR) treatment. Interacts with XPA. Interacts with NEURL4. Via its interaction with NEURL4, may indirectly interact with CCP110 and CEP97.DOMAIN The ZZ-type zinc finger mediates binding to SUMO1, and at low level SUMO2.DOMAIN The RCC1 repeats are grouped into three seven-bladed beta-propeller regions.PTM Phosphorylation at Thr-4827 is required for interaction with RNF8.PTM Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs), promoting the interaction with RNF8.POLYMORPHISM Genetic variants in HERC2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair color type 3 (HCL3). Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.MISCELLANEOUS A regulatory element withinin an intron of the HERC2 gene inhibits OCA2 promoter. There are several single nucleotide polymorphisms within the OCA2 gene and within the HERC2 gene that have a statistical association with human eye color. UniProt O95714 sumoylated lysine (monoSUMO1 [nucleoplasm]) at unknown position sumoylated lysine O-phospho-L-threonine at 4827 4827 EQUAL 1 EQUAL 4834 EQUAL Reactome Database ID Release 82 5682608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682608 Reactome R-HSA-5682608 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682608.2 Reactome Database ID Release 82 5682631 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5682631 Reactome R-HSA-5682631 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5682631.1 Reactome DB_ID: 2993789 1 UniProt:Q8N2W9 PIAS4 PIAS4 PIAS4 PIASG FUNCTION Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor (PubMed:12511558, PubMed:12631292, PubMed:12727872, PubMed:15831457, PubMed:15976810, PubMed:22508508, PubMed:32832608). Mediates sumoylation of CEBPA, PARK7, HERC2, MYB, TCF4 and RNF168 (PubMed:12511558, PubMed:12631292, PubMed:12727872, PubMed:15831457, PubMed:15976810, PubMed:22508508). Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling pathway (PubMed:11388671). Involved in gene silencing (PubMed:11248056). In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations (PubMed:12727872, PubMed:15831457). Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation (PubMed:21965678). Binds to AT-rich DNA sequences, known as matrix or scaffold attachment regions (MARs/SARs) (By similarity). Catalyzes conjugation of SUMO2 to KAT5 in response to DNA damage, facilitating repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:32832608).PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with AR, AXIN1, GATA2, LEF1, TP53 and STAT1 (IFNG-induced) (PubMed:11248056, PubMed:11388671, PubMed:11439351, PubMed:12223491, PubMed:12750312). Interacts with TICAM1 (PubMed:15251447). Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase (PubMed:16617055). Interacts with MTA1 (PubMed:21965678). Interacts with PRDM1/Blimp-1 (PubMed:28842558). Interacts with TRIM32 upon treatment with UVB and TNF-alpha (By similarity).TISSUE SPECIFICITY Highly expressed in testis and, at lower levels, in spleen, prostate, ovary, colon and peripheral blood leukocytes.DOMAIN The LXXLL motif is a coregulator signature that is essential for transcriptional corepression.PTM Sumoylated. Lys-35 is the main site of sumoylation. Sumoylation is required for TCF4 sumoylation and transcriptional activation. Represses LEF1 transcriptional activity. SUMO1 is the preferred conjugate.SIMILARITY Belongs to the PIAS family. UniProt Q8N2W9 2 EQUAL 510 EQUAL Reactome DB_ID: 4551605 1 UniProt:Q8IYW5 RNF168 RNF168 RNF168 FUNCTION E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer. Interacts with UBE2N/UBC13.DOMAIN The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).PTM Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs).PTM Ubiquitinated.SIMILARITY Belongs to the RNF168 family.CAUTION According to a well-established model, RNF168 cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19500350, PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data. UniProt Q8IYW5 1 EQUAL 571 EQUAL Reactome Database ID Release 82 5683079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683079 Reactome R-HSA-5683079 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683079.1 Reactome Database ID Release 82 5683417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683417 Reactome R-HSA-5683417 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683417.1 Reactome DB_ID: 5683606 1 p-4S,2T-BRCA1-A Complex [nucleoplasm] p-4S,2T-BRCA1-A Complex p-S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1:BRCC3:BRE:BABAM1:UIMC1:p-S406-FAM175A Reactome DB_ID: 5682575 1 UniProt:Q6UWZ7 ABRAXAS1 ABRAXAS1 ABRA1 UNQ496/PRO1013 ABRAXAS1 FAM175A CCDC98 FUNCTION Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX.SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the complex, interacts directly with UIMC1/RAP80, BRCC3/BRCC36 and BABAM2. Interacts directly (when phosphorylated at Ser-406) with BRCA1. Homodimer. The homodimer interacts directly (when phosphorylated at Ser-404 and Ser-406) with two BRCA1 chains, giving rise to a heterotetramer. Binds polyubiquitin.PTM Phosphorylation of Ser-406 of the pSXXF motif by ATM or ATR constitutes a specific recognition motif for the BRCT domain of BRCA1 (PubMed:17643121, PubMed:17525340, PubMed:17643122). Ionizing radiation promotes rapid phosphorylation at Ser-404 and Ser-406 by ATM; this promotes recruitment of BRCA1 to sites of DNA damage (PubMed:26778126).SIMILARITY Belongs to the FAM175 family. Abraxas subfamily. UniProt Q6UWZ7 O-phospho-L-serine at 406 406 EQUAL 1 EQUAL 409 EQUAL Reactome DB_ID: 5682582 1 UniProt:Q9NWV8 BABAM1 BABAM1 BABAM1 NBA1 C19orf62 MERIT40 HSPC142 FUNCTION Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it is required for the complex integrity and its localization at DSBs. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:24075985, PubMed:26195665). In these 2 complexes, it is probably required to maintain the stability of BABAM2 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261749, PubMed:19261748, PubMed:21282113). In the BRCA1-A complex, interacts directly with ABRAXAS1 and BABAM2 (PubMed:19261749, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985).DOMAIN The VWFA-like region is similar to the VWFA domain. Its presence reveals similarities between the structure of the 19S proteasome and the BRCA1-A complexes.SIMILARITY Belongs to the BABAM1 family. UniProt Q9NWV8 1 EQUAL 329 EQUAL Reactome DB_ID: 5682579 1 UniProt:Q9NXR7 BABAM2 BABAM2 BABAM2 BRCC45 BRE FUNCTION Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX (PubMed:17525341, PubMed:19261746, PubMed:19261749, PubMed:19261748). In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer (PubMed:21282113, PubMed:19261748). Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:19214193, PubMed:24075985, PubMed:25283148, PubMed:26195665). Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity (PubMed:21282113). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect (PubMed:15465831).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:21282113, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1, BRCC3/BRCC36 and BABAM1/NBA1. Binds polyubiquitin. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BRCC3/BRCC36 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. May interact with FAS and TNFRSF1A (PubMed:15465831).TISSUE SPECIFICITY Expressed in all cell lines examined. Highly expressed in placenta.INDUCTION Down-regulated by DNA-damaging agents in fibroblasts, by retinoic acid in brain glioma U-251MG and promyelocytic HL-60 cell lines, and by bacterial lipopolysaccharides (LPS) in peripheral blood mononuclear cells (PBMC).DOMAIN Contains 2 ubiquitin-conjugating enzyme family-like (UEV-like) regions. These regions lack the critical Cys residues required for ubiquitination but retain the ability to bind ubiquitin.SIMILARITY Belongs to the BABAM2 family. UniProt Q9NXR7 1 EQUAL 383 EQUAL Reactome DB_ID: 5682577 1 UniProt:P46736 BRCC3 BRCC3 BRCC36 CXorf53 C6.1A BRCC3 FUNCTION Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Deubiquitinates HDAC1 and PWWP2B leading to their stabilization (By similarity).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:20656690, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, babam2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1 and babam2 (PubMed:18077395, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985, PubMed:25283148, PubMed:26344097). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). In the BRISC complex, interacts directly with ABRAXAS2 (PubMed:20656690, PubMed:26344097). Identified in a complex with ABRAXAS2 and NUMA1 (PubMed:26195665). The BRISC complex interacts with the CSN complex. Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BABAM2 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. Interacts with BRCA1. Binds polyubiquitin. Interacts with PWWP2B (By similarity). Interacts with HDAC1; this interaction is enhanced in the presence of PWWP2B (By similarity).TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.DISEASE A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.SIMILARITY Belongs to the peptidase M67A family. BRCC36 subfamily. UniProt P46736 2 EQUAL 316 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9707287 1 p-S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 5682574 1 UniProt:Q96RL1 UIMC1 UIMC1 RXRIP110 UIMC1 RAP80 FUNCTION Ubiquitin-binding protein (PubMed:24627472). Specifically recognizes and binds 'Lys-63'-linked ubiquitin (PubMed:19328070, Ref.38). Plays a central role in the BRCA1-A complex by specifically binding 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:17525341, PubMed:17525342, PubMed:19261746, PubMed:19261749). In the BRCA1-A complex, interacts directly with ABRAXAS1 (PubMed:17643121, PubMed:17643122, PubMed:19261749, PubMed:19261748, PubMed:18077395). Interacts with UBE2I (PubMed:17698038). Interacts with NR6A1 (PubMed:12080054). Interacts with ESR1 (PubMed:17311814). Interacts with TSP57 (By similarity). Interacts with TRAIP (PubMed:26781088).TISSUE SPECIFICITY Expressed in testis, ovary, thymus and heart. Expressed in germ cells of the testis.DOMAIN The tandem UIM domains form a continuous 60 Angstrom-long alpha-helix and mediate binding to 'Lys-63'-linked ubiquitins. UIM1 and UIM2 bind to the proximal and distal ubiquitin moieties and recognize an 'Ile-44'-centered hydrophobic patch. Since UIMs don't interact with the 'Lys-63' isopeptide bond the UIM-linker region between the 2 UIM domains determines the selectivity for 'Lys-63'-linkage, and its length is very important for specificity.DOMAIN The Abraxas-interacting region (AIR) mediates the interaction with ABRAXAS1.PTM Sumoylated.PTM Phosphorylated upon DNA damage by ATM or ATR.SIMILARITY Belongs to the RAP80 family. UniProt Q96RL1 1 EQUAL 719 EQUAL Reactome Database ID Release 82 5683606 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683606 Reactome R-HSA-5683606 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683606.2 Reactome Database ID Release 82 5683605 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683605 Reactome R-HSA-5683605 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683605.1 Reactome DB_ID: 113824 1 UniProt:O96017 CHEK2 CHEK2 CDS1 RAD53 CHK2 CHEK2 FUNCTION Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978).FUNCTION (Microbial infection) Phosphorylates herpes simplex virus 1/HHV-1 protein ICP0 and thus activates its SUMO-targeted ubiquitin ligase activity.ACTIVITY REGULATION Activated through phosphorylation at Thr-68 by ATM in response to DNA double-strand breaks. Activation is modulated by several mediators including MDC1 and TP53BP1. Induces homodimerization with exchange of the T-loop/activation segment between protomers and transphosphorylation of the protomers. The autophosphorylated kinase dimer is fully active. Negatively regulated by PPM1D through dephosphorylation of Thr-68.SUBUNIT Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-terminus). Interacts with SIRT1.TISSUE SPECIFICITY High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.PTM Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response to DNA damage, promoting phosphorylation at Thr-68 by ATM and the G2/M transition checkpoint. Phosphorylation at Thr-68 induces homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-loop/activation segment upon dimerization to become fully active and phosphorylate its substrates like for instance CDC25C. DNA damage-induced autophosphorylation at Ser-379 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-456 also regulates ubiquitination. Phosphorylated by PLK4.PTM Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability. Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily. UniProt O96017 1 EQUAL 543 EQUAL Reactome DB_ID: 5683737 1 DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2 [nucleoplasm] DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex:CHEK2 Reactome DB_ID: 5683605 1 Reactome DB_ID: 113824 1 1 EQUAL 543 EQUAL Reactome Database ID Release 82 5683737 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683737 Reactome R-HSA-5683737 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683737.1 Reactome Database ID Release 82 5683735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683735 Reactome R-HSA-5683735 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683735.2 12364621 Pubmed 2002 53BP1, a mediator of the DNA damage checkpoint. Wang, B Matsuoka, S Carpenter, PB Elledge, SJ Science 298:1435-8 19001859 Pubmed 2008 NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway Wilson, Kathleen A Stern, David F Cell Cycle 7:3584-94 2.7.11.1 Phosphorylation and activation of CHEK2 by ATM Phosphorylation and activation of CHEK2 by ATM Activated ATM phosphorylates CHEK2 (CHK2, Cds1) on threonine residue T68 (Matsuoka et al. 2000, Melchionna et al. 2000). The presence of BRCA1 and TP53BP1 positively regulates ATM-mediated phosphorylation of CHEK2 (Wang et al. 2002, Foray et al. 2003). ATM-mediated phosphorylation causes formation of CHEK2 dimers and dissociation of CHEK2 from chromatin (Li and Stern 2005). Authored: Orlic-Milacic, Marija, 2015-05-12 Reviewed: Borowiec, James A, 2015-06-12 Edited: Orlic-Milacic, Marija, 2015-05-12 Reactome DB_ID: 5683737 1 Reactome DB_ID: 29358 1 Reactome DB_ID: 5683605 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 113825 1 O-phospho-L-threonine at 68 68 EQUAL 1 EQUAL 543 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5683737 Reactome Database ID Release 82 5683600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683600 Reactome Database ID Release 82 69891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69891 Reactome R-HSA-69891 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69891.1 10973490 Pubmed 2000 Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro Matsuoka, S Rotman, G Ogawa, A Shiloh, Y Tamai, K Elledge, SJ Proc Natl Acad Sci U S A 97:10389-94 11025670 Pubmed 2000 Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1 Melchionna, R Chen, X B Blasina, A McGowan, CH Nat. Cell Biol. 2:762-5 12773400 Pubmed 2003 A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Foray, N Marot, D Gabriel, A Randrianarison, V Perricaudet, M Ashworth, A Jeggo, P EMBO J 22:2860-71 16150728 Pubmed 2005 DNA damage regulates Chk2 association with chromatin Li, Jia Stern, David F J. Biol. Chem. 280:37948-56 p-T68-CHEK2 dimerizes p-T68-CHEK2 dimerizes ATM-mediated phosphorylation of CHEK2 (CHK2, Cds1) on threonine residue T68 promotes formation of transitional CHEK2 homodimers primarily through intermolecular interactions of FHA domains and phospho-T68 residues of two CHEK2 protomers (Cai et al. 2009). Authored: Orlic-Milacic, Marija, 2015-05-12 Reviewed: Borowiec, James A, 2015-06-12 Edited: Orlic-Milacic, Marija, 2015-05-12 Reactome DB_ID: 113825 2 O-phospho-L-threonine at 68 68 EQUAL 1 EQUAL 543 EQUAL Reactome DB_ID: 5683773 1 p-T68-CHEK2 dimer [nucleoplasm] p-T68-CHEK2 dimer Reactome DB_ID: 113825 2 O-phospho-L-threonine at 68 68 EQUAL 1 EQUAL 543 EQUAL Reactome Database ID Release 82 5683773 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683773 Reactome R-HSA-5683773 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683773.1 Reactome Database ID Release 82 5683774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683774 Reactome R-HSA-5683774 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683774.2 19782031 Pubmed 2009 Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase Cai, Zhenjian Chehab, Nabil H Pavletich, Nikola P Mol. Cell 35:818-29 2.7.11.1 p-T68-CHEK2 autophosphorylates p-T68-CHEK2 autophosphorylates Upon dimerization, p-T68-CHEK2 protomers trans-autophosphorylate on serine residue S379 (Lovly et al. 2008) and threonine residues T383 and T387 (Lee et al. 2001). Autophosphorylation leads to dissociation of CHEK2 dimers into active CHEK2 monomers (Cai et al. 2009). Authored: Orlic-Milacic, Marija, 2015-05-12 Reviewed: Borowiec, James A, 2015-06-12 Edited: Orlic-Milacic, Marija, 2015-05-12 Reactome DB_ID: 5683773 1 Reactome DB_ID: 29358 3 Reactome DB_ID: 113582 3 Reactome DB_ID: 5683784 2 O-phospho-L-threonine at 68 68 EQUAL O-phospho-L-serine at 379 379 EQUAL O-phospho-L-threonine at 383 383 EQUAL O-phospho-L-threonine at 387 387 EQUAL 1 EQUAL 543 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5683773 Reactome Database ID Release 82 5683789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683789 Reactome Database ID Release 82 5683792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5683792 Reactome R-HSA-5683792 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5683792.1 11390408 Pubmed 2001 The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation Lee, C H Chung, J H J. Biol. Chem. 276:30537-41 18644861 Pubmed 2008 Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379 Lovly, Christine M Yan, Ling Ryan, Christine E Takada, Saeko Piwnica-Worms, Helen Mol. Cell. Biol. 28:5874-85 Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex DNA damage induced activation of the checkpoint kinases Chk1/Chk2(Cds1) results in the conversion and/or maintenance of CyclinB:Cdc2 complex in its Tyrosine 15 phosphorylated (inactive) state. Cdc2 activity is regulated by a balance between the phosphorylation and dephosphorylation by the Wee1/Myt1 kinase and Cdc25 phosphatase. Inactivation of the Cyclin B:Cdc2 complex likely involves both inactivation of Cdc25 and/or stimulation of Wee1/Myt1 kinase activity. Authored: Matthews, L, 2003-08-05 01:10:00 2.7.11.1 Phosphorylation of Cdc25C at Ser216 by CHEK2 Phosphorylation of Cdc25C at Ser216 by CHEK2 Cdc25C is negatively regulated by phosphorylation on Ser 216, the 14-3-3-binding site. This is an important regulatory mechanism used by cells to block mitotic entry under normal conditions and after DNA damage (Chaturvedi et al, 1999; Bulavin et al., 2003). Authored: Sanchez, Y, 2004-02-10 21:59:11 Reviewed: Manfredi, James J Edited: Matthews, L, 2004-03-22 22:00:00 Reactome DB_ID: 69741 1 UniProt:P30307 CDC25C CDC25C CDC25C FUNCTION Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle. When phosphorylated, highly effective in activating G2 cells into prophase. Directly dephosphorylates CDK1 and activates its kinase activity.SUBUNIT Interacts with MAPK14 and 14-3-3 proteins. When phosphorylated on Ser-129 and/or Thr-130, interacts with PLK1.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpr; this interaction inactivates CDC25C phosphatase activity.DEVELOPMENTAL STAGE Expressed predominantly in G2 phase.PTM Phosphorylated by CHEK1 and MAPK14 at Ser-216. This phosphorylation creates a binding site for 14-3-3 protein and inhibits the phosphatase. Phosphorylated by PLK4. Phosphorylated by PLK1, leading to activate the phosphatase activity. Phosphorylation by PLK3 at Ser-191 promotes nuclear translocation. Ser-198 is a minor phosphorylation site. Was initially reported to be phosphorylated by PLK3 at Ser-216 (PubMed:10557092). However, such phosphorylation by PLK3 was not confirmed by other groups. Phosphorylation at Thr-48, Thr-67, Ser-122, Thr-130, Ser-168 and Ser-214 occurs at G2 and G2-M transition and is probably catalyzed by CDK1. Ser-168 phosphorylation levels are lower than those at the other 5 CDK1 sites. Phosphorylation by CDK1 leads to increased activity.SIMILARITY Belongs to the MPI phosphatase family. UniProt P30307 1 EQUAL 473 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 156496 1 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5683784 O-phospho-L-threonine at 68 68 EQUAL O-phospho-L-serine at 379 379 EQUAL O-phospho-L-threonine at 383 383 EQUAL O-phospho-L-threonine at 387 387 EQUAL 1 EQUAL 543 EQUAL Reactome Database ID Release 82 75808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75808 Reactome Database ID Release 82 75809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75809 Reactome R-HSA-75809 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75809.5 12766774 Pubmed 2003 Dual phosphorylation controls Cdc25 phosphatases and mitotic entry Bulavin, DV Higashimoto, Y Demidenko, ZN Meek, S Graves, P Phillips, C Zhao, H Moody, SA Appella, E Piwnica-Worms, H Fornace AJ, Jr Nat Cell Biol 5:545-51 10435585 Pubmed 1999 Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway Chaturvedi, P Eng, W K Zhu, Y Mattern, M R Mishra, R Hurle, M R Zhang, X Annan, R S Lu, Q Faucette, L F Scott, G F Li, X Carr, S A Johnson, R K Winkler, J D Zhou, B B Oncogene 18:4047-54 p-S216-CDC25C translocates to the cytosol p-S216-CDC25C translocates to the cytosol Phosphorylated CDC25C translocates to the cytoplasm. Phosphorylation at serine residue S216 is not a prerequisite for translocation to the cytoplasm (Dalal et al., 1999). Authored: Matthews, L, 2003-08-05 01:10:00 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 156496 1 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL Reactome DB_ID: 75003 1 cytosol GO 0005829 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL Reactome Database ID Release 82 9029987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9029987 Reactome R-HSA-9029987 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9029987.1 10330186 Pubmed 1999 Cytoplasmic localization of human cdc25C during interphase requires an intact 14-3-3 binding site. Dalal, SN Schweitzer, CM Gan, J DeCaprio, JA Mol Cell Biol 19:4465-79 Association of p-S216-CDC25C with 14-3-3 proteins Association of p-S216-CDC25C with 14-3-3 proteins CDC25C is phosphorylated by CHK1 at ser-216 (Blasina et al.,1999 ) resulting in both inhibition of the CDC25 phosphatase activity and creation of a 14-3-3 docking site (Peng et al., 1997). Association of 14-3-3 proteins with phosphorylated CDC25C (p-S216-CDC25C) is thought to result in retention of this complex within the cytoplasm (Dalal et al., 1999; Graves et al, 2001). Authored: Matthews, L, 2003-08-05 01:10:00 Edited: Orlic-Milacic, Marija, 2015-02-02 Converted from EntitySet in Reactome Reactome DB_ID: 1445138 1 14-3-3 dimer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 75003 1 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL Reactome DB_ID: 75005 1 p-S216-CDC25C:14-3-3 protein complex [cytosol] p-S216-CDC25C:14-3-3 protein complex Converted from EntitySet in Reactome Reactome DB_ID: 1445138 1 Reactome DB_ID: 75003 1 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL Reactome Database ID Release 82 75005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75005 Reactome R-HSA-75005 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75005.1 Reactome Database ID Release 82 75016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75016 Reactome R-HSA-75016 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75016.5 9889122 Pubmed 1999 A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase Blasina, A de Weyer, IV Laus, MC Luyten, WH Parker, AE McGowan, CH Curr Biol 9:1-10 9278512 Pubmed 1997 Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Peng, CY Graves, PR Thoma, RS Wu, Z Shaw, AS Piwnica-Worms, H Science 277:1501-5 11313932 Pubmed 2001 Localization of human Cdc25C is regulated both by nuclear export and 14-3-3 protein binding. Graves, PR Lovly, CM Uy, GL Piwnica-Worms, H Oncogene 20:1839-51 2.7.11.1 Phosphorylation of Wee1 kinase by Chk1 Phosphorylation of Wee1 kinase by Chk1 Phosphorylation of Wee1 by Chk1 stimulates Wee1 kinase activity. Authored: Matthews, L, 2003-08-08 02:54:00 Reactome DB_ID: 69253 1 UniProt:P30291 WEE1 WEE1 WEE1 FUNCTION Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation.ACTIVITY REGULATION Synthesis is increased during S and G2 phases, presumably by an increase in transcription; activity is decreased by phosphorylation during m phase. Protein levels fall in M phase as a result of decreased synthesis combined with degradation. Activity seems to be negatively regulated by phosphorylation upon entry into mitosis, although N-terminal phosphorylation might also regulate the protein stability via protection from proteolysis or might regulate the subcellular location.PTM Phosphorylated during M and G1 phases. Also autophosphorylated. Phosphorylation at Ser-642 by BRSK1 and BRSK2 in post-mitotic neurons, leads to down-regulate WEE1 activity in polarized neurons. Phosphorylated at Ser-53 and Ser-123 by PLK1 and CDK1, respectively, generating an signal for degradation that can be recognized by the SCF(BTRC) complex, leading to its ubiquitination and degradation at the onset of G2/M phase.PTM Dephosphorylated at Thr-239 by CTDP1 (PubMed:22692537). Dephosphorylated at Ser-53 and Ser-123 by the serine/threonine-protein phosphatase 2A preventing its ubiquitin-mediated degradation (PubMed:33108758).PTM Ubiquitinated and degraded at the onset of G2/M phase.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WEE1 subfamily. UniProt P30291 1 EQUAL 646 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 156491 1 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 646 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 113838 O-phospho-L-serine at 317 317 EQUAL O-phospho-L-serine at 345 345 EQUAL 1 EQUAL 476 EQUAL Reactome Database ID Release 82 143490 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=143490 Reactome Database ID Release 82 75028 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75028 Reactome R-HSA-75028 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75028.5 2.7.10.2 Wee1-mediated phosphorylation of Cyclin B1:phospho-Cdc2 complexes Wee1-mediated phosphorylation of Cyclin B1:phospho-Cdc2 complexes WEE1, a nuclear kinase, phosphorylates cyclin B1:Cdc2 (CCNB1:CDK1) on tyrosine 15 (Y15), inactivating the complex (Parker and Piwnica-Worms 1992, McGowan and Russell 1993). The complex of cyclin B2 and Cdc2 (CCNB2:CDK1) is also phosphorylated on Y15 (Galaktionov and Beach 1991). Reactome DB_ID: 170073 1 CCNB1:p-T14,T161-CDK1 [nucleoplasm] CCNB1:p-T14,T161-CDK1 Cyclin B1:phospho-Cdc2 (Thr 14, Thr 161) Reactome DB_ID: 170078 1 UniProt:P06493 CDK1 CDK1 P34CDC2 CDK1 CDC28A CDKN1 CDC2 FUNCTION Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:26829474, PubMed:30704899). Required in higher cells for entry into S-phase and mitosis (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658). Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, KAT5, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2, CGAS and RUNX2 (PubMed:16407259, PubMed:17459720, PubMed:16933150, PubMed:18356527, PubMed:19509060, PubMed:20171170, PubMed:19917720, PubMed:20937773, PubMed:20935635, PubMed:21063390, PubMed:23355470, PubMed:23601106, PubMed:23602554, PubMed:25556658, PubMed:32351706, PubMed:26829474, PubMed:30704899). CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs (PubMed:18480403, PubMed:20360007). Essential for early stages of embryonic development (PubMed:18480403, PubMed:20360007). During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation (PubMed:18480403, PubMed:20360007). Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis (PubMed:18480403, PubMed:20360007). Phosphorylates KRT5 during prometaphase and metaphase (By similarity). Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair (PubMed:20360007). Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression (PubMed:20395957). In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons (PubMed:18356527). The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis (PubMed:16371510). NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation (PubMed:19509060). In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis (PubMed:20171170). The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis (PubMed:19917720). In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis (PubMed:20937773). This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes (PubMed:20937773). EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing (PubMed:20935635). CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration (By similarity). CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (PubMed:26549230). Regulates the amplitude of the cyclic expression of the core clock gene ARNTL/BMAL1 by phosphorylating its transcriptional repressor NR1D1, and this phosphorylation is necessary for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1 (PubMed:27238018). Phosphorylates EML3 at 'Thr-881' which is essential for its interaction with HAUS augmin-like complex and TUBG1 (PubMed:30723163). Phosphorylates CGAS during mitosis, leading to its inhibition, thereby preventing CGAS activation by self DNA during mitosis (PubMed:32351706).FUNCTION (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry.ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-161 activates it. Activated through a multistep process; binding to cyclin-B is required for relocation of cyclin-kinase complexes to the nucleus, activated by CAK/CDK7-mediated phosphorylation on Thr-161, and CDC25-mediated dephosphorylation of inhibitory phosphorylation on Thr-14 and Tyr-15. Inhibited by flavopiridol and derivatives, pyrimidine derivatives, pyridine derivatives, purine derivatives, staurosporine, paullones, oxoindoles, indazole analogs, indolin-2-ones, pyrazolo[3,4-b]pyridines, imidazo[1,2-a]pyridine (AZ703), thiazolinone analogs(RO-3306), thiazol urea, macrocyclic quinoxalin-2-one, pyrrolo[2,3-a]carbazole, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine (Dinaciclib, SCH 727965), 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), olomoucine, AG-024322, AT-7519, P276-00, R547/Ro-4584820 and SNS-032/BMS-387032. Repressed by the CDK inhibitors CDKN1A/p21 and CDKN1B/p27 during the G1 phase and by CDKN1A/p21 at the G1-S checkpoint upon DNA damage. Transient activation by rapid and transient dephosphorylation at Tyr-15 triggered by TGFB1.SUBUNIT Forms a stable but non-covalent complex with a regulatory subunit and with a cyclin. Interacts with cyclins-B (CCNB1, CCNB2 and CCNB3) to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Can also form CDK1-cylin-D and CDK1-cyclin-E complexes that phosphorylate RB1 in vitro. Binds to RB1 and other transcription factors such as FOXO1 and RUNX2. Promotes G2-M transition when in complex with a cyclin-B. Interacts with DLGAP5. Binds to the CDK inhibitors CDKN1A/p21 and CDKN1B/p27. Isoform 2 is unable to complex with cyclin-B1 and also fails to bind to CDKN1A/p21. Interacts with catalytically active CCNB1 and RALBP1 during mitosis to form an endocytotic complex during interphase. Associates with cyclins-A and B1 during S-phase in regenerating hepatocytes. Interacts with FANCC. Interacts with CEP63; this interaction recruits CDK1 to centrosomes. Interacts with CENPA (PubMed:25556658). Interacts with NR1D1 (PubMed:27238018). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).SUBUNIT (Microbial infection) Interacts with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs; this interaction is inclusion body dependent, it inhibits the formation and nuclear import of the cyclin B1-CDK1 complex and leads to cell cycle arrest.TISSUE SPECIFICITY Isoform 2 is found in breast cancer tissues.INDUCTION Follows a cyclic expression; during interphase, accumulates gradually following G1, S to reach a critical threshold at the end of G2, which promotes self-activation and triggers onset of mitosis. Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis, but later repressed. Triggered by CKS1B during mitotic entry in breast cancer cells. Down-regulated under genotoxic stresses triggered by PKR/EIF2AK2-mediated phosphorylation.PTM Phosphorylation at Thr-161 by CAK/CDK7 activates kinase activity. Phosphorylation at Thr-14 and Tyr-15 by PKMYT1 prevents nuclear translocation. Phosphorylation at Tyr-15 by WEE1 and WEE2 inhibits the protein kinase activity and acts as a negative regulator of entry into mitosis (G2 to M transition). Phosphorylation by PKMYT1 and WEE1 takes place during mitosis to keep CDK1-cyclin-B complexes inactive until the end of G2. By the end of G2, PKMYT1 and WEE1 are inactivated, but CDC25A and CDC25B are activated. Dephosphorylation by active CDC25A and CDC25B at Thr-14 and Tyr-15, leads to CDK1 activation at the G2-M transition. Phosphorylation at Tyr-15 by WEE2 during oogenesis is required to maintain meiotic arrest in oocytes during the germinal vesicle (GV) stage, a long period of quiescence at dictyate prophase I, leading to prevent meiotic reentry. Phosphorylation by WEE2 is also required for metaphase II exit during egg activation to ensure exit from meiosis in oocytes and promote pronuclear formation. Phosphorylated at Tyr-4 by PKR/EIF2AK2 upon genotoxic stress. This phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest. In response to UV irradiation, phosphorylation at Tyr-15 by PRKCD activates the G2/M DNA damage checkpoint.PTM Polyubiquitinated upon genotoxic stress.MISCELLANEOUS As a key regulator of the cell cycle, CDK1 is a potent therapeutic target for inhibitors in cancer treatment.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P06493 O-phospho-L-threonine at 14 14 EQUAL O-phospho-L-threonine at 161 161 EQUAL 1 EQUAL 297 EQUAL Reactome DB_ID: 68901 1 UniProt:P14635 CCNB1 CCNB1 CCNB1 CCNB FUNCTION Essential for the control of the cell cycle at the G2/M (mitosis) transition.SUBUNIT Interacts with the CDC2 protein kinase to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Binds HEI10. Interacts with catalytically active RALBP1 and CDC2 during mitosis to form an endocytotic complex during interphase. Interacts with CCNF; interaction is required for nuclear localization. Interacts with CDK5RAP3 (PubMed:15790566). Interacts with RFPL4A and UBE2A (By similarity). Interacts with INCA1 (PubMed:21540187).DEVELOPMENTAL STAGE Accumulates steadily during G2 and is abruptly destroyed at mitosis.PTM Ubiquitinated by the SCF(NIPA) complex during interphase, leading to its destruction. Not ubiquitinated during G2/M phases.PTM Phosphorylated by PLK1 at Ser-133 on centrosomes during prophase: phosphorylation by PLK1 does not cause nuclear import. Phosphorylation at Ser-147 was also reported to be mediated by PLK1 but Ser-133 seems to be the primary phosphorylation site.SIMILARITY Belongs to the cyclin family. Cyclin AB subfamily. UniProt P14635 1 EQUAL 433 EQUAL Reactome Database ID Release 82 170073 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170073 Reactome R-HSA-170073 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170073.1 Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 170065 1 CCNB1:p-T14,Y15,T161-CDK1 [nucleoplasm] CCNB1:p-T14,Y15,T161-CDK1 Cyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15) Reactome DB_ID: 68901 1 1 EQUAL 433 EQUAL Reactome DB_ID: 170074 1 O-phospho-L-threonine at 161 161 EQUAL O-phospho-L-threonine at 14 14 EQUAL O4'-phospho-L-tyrosine at 15 15 EQUAL O4'-phospho-L-tyrosine [MOD:00048] 1 EQUAL 297 EQUAL Reactome Database ID Release 82 170065 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170065 Reactome R-HSA-170065 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170065.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 69253 1 EQUAL 646 EQUAL GO 0004713 GO molecular function Reactome Database ID Release 82 69254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69254 Reactome Database ID Release 82 170070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170070 Reactome R-HSA-170070 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170070.3 1836978 Pubmed 1991 Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins Galaktionov, K Beach, D Cell 67:1181-94 8428596 Pubmed 1993 Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15 McGowan, CH Russell, P EMBO J. 12:75-85 1384126 Pubmed 1992 Inactivation of the p34cdc2-cyclin B complex by the human WEE1 tyrosine kinase Parker, LL Piwnica-Worms, H Science 257:1955-7 Reactome Database ID Release 82 75035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75035 Reactome R-HSA-75035 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75035.4 2.7.11.1 ATR phosphorylates TP53 ATR phosphorylates TP53 ATR, bound to DNA damage sites, phosphorylates TP53 (p53) at serine residue S15. S15 phosphorylation stabilizes TP53 by inhibiting the binding of TP53 to the ubiquitin ligase MDM2 (Tibbetts et al. 1999, Lakin et al. 1999). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 Reactome DB_ID: 3209194 1 TP53 Tetramer [nucleoplasm] TP53 Tetramer Reactome DB_ID: 69488 4 UniProt:P04637 TP53 TP53 TP53 P53 FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process (PubMed:11025664, PubMed:12524540, PubMed:12810724, PubMed:15186775, PubMed:15340061, PubMed:17317671, PubMed:17349958, PubMed:19556538, PubMed:20673990, PubMed:20959462, PubMed:22726440, PubMed:24051492, PubMed:9840937, PubMed:24652652). One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is TTC5/STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243). Interacts with NQO1; this interaction is NADH-dependent, stabilizes TP53 in response to oxidative stress and protects it from ubiquitin-independent degradation by the 20S proteasome.SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.SUBUNIT (Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylation of Lys-382 by CREBBP enhances transcriptional activity (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Acetylation of Lys-382 by EP300 (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner (PubMed:10656795, PubMed:15448695, PubMed:20228809, PubMed:23431171). Acetylation at Lys-381 increases stability (PubMed:29474172). Deacetylation at Lys-381 by SIRT6 decreases its stability, thereby regulating cell senescence (PubMed:29474172).PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.CAUTION Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965). UniProt P04637 1 EQUAL 393 EQUAL Reactome Database ID Release 82 3209194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3209194 Reactome R-HSA-3209194 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3209194.1 Reactome DB_ID: 29358 4 Reactome DB_ID: 113582 4 Reactome DB_ID: 349474 1 p-S15-TP53 Tetramer [nucleoplasm] p-S15-TP53 Tetramer Reactome DB_ID: 69507 4 O-phospho-L-serine at 15 15 EQUAL 1 EQUAL 393 EQUAL Reactome Database ID Release 82 349474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=349474 Reactome R-HSA-349474 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-349474.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5685039 ATR:ATRIP:RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1 [nucleoplasm] ATR:ATRIP:RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1 Reactome DB_ID: 5684874 1 ATR:ATRIP:RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 [nucleoplasm] ATR:ATRIP:RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 Reactome DB_ID: 176269 1 Reactome DB_ID: 5693552 1 RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 [nucleoplasm] RPA:3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 Reactome DB_ID: 68462 1 RPA heterotrimer [nucleoplasm] RPA heterotrimer Reactome DB_ID: 68457 1 UniProt:P15927 RPA2 RPA2 RPA2 REPA2 RPA32 RPA34 FUNCTION As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Also plays a role in base excision repair (BER) probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance.SUBUNIT Component of the replication protein A complex (RPA/RP-A), a heterotrimeric complex composed of RPA1, RPA2 and RPA3 (PubMed:2406247, PubMed:19116208, PubMed:10449415). Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA) (PubMed:24332808). Interacts with SERTAD3 (PubMed:10982866). Interacts with TIPIN (PubMed:17141802, PubMed:17296725). Interacts with TIMELESS (PubMed:17141802). Interacts with PPP4R2; the interaction is direct, DNA damage-dependent and mediates the recruitment of the PP4 catalytic subunit PPP4C (PubMed:20154705). Interacts (hyperphosphorylated) with RAD51 (PubMed:20154705). Interacts with SMARCAL1; the interaction is direct and mediates the recruitment to the RPA complex of SMARCAL1 (PubMed:19793861, PubMed:19793862, PubMed:19793863). Interacts with RAD52 and XPA; those interactions are direct and associate RAD52 and XPA to the RPA complex (PubMed:7700386, PubMed:8702565, PubMed:17765923, PubMed:11081631). Interacts with FBH1 (PubMed:23319600). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RFWD3 (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657). Interacts with DDI2 (PubMed:29290612).INDUCTION Translationally up-regulated in response to DNA damage (at protein level).PTM Differentially phosphorylated throughout the cell cycle, becoming phosphorylated at the G1-S transition and dephosphorylated in late mitosis. Mainly phosphorylated at Ser-23 and Ser-29, by cyclin A-CDK2 and cyclin B-CDK1, respectively during DNA replication and mitosis. Dephosphorylation may require the serine/threonine-protein phosphatase 4. Phosphorylation at Ser-23 and Ser-29 is a prerequisite for further phosphorylation. Becomes hyperphosphorylated on additional residues including Ser-4, Ser-8, Thr-21 and Ser-33 in response to DNA damage. Hyperphosphorylation is mediated by ATM, ATR and PRKDC. Primarily recruited to DNA repair nuclear foci as a hypophosphorylated form it undergoes subsequent hyperphosphorylation, catalyzed by ATR. Hyperphosphorylation is required for RAD51 recruitment to chromatin and efficient DNA repair. Phosphorylation at Thr-21 depends upon RFWD3 presence.PTM DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).SIMILARITY Belongs to the replication factor A protein 2 family. UniProt P15927 1 EQUAL 270 EQUAL Reactome DB_ID: 68459 1 UniProt:P35244 RPA3 RPA3 RPA3 REPA3 RPA14 FUNCTION As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin, in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Also plays a role in base excision repair (BER), probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance. RPA3 has its own single-stranded DNA-binding activity and may be responsible for polarity of the binding of the complex to DNA (PubMed:19010961). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105).SUBUNIT Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3. Also a component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2.PTM Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).SIMILARITY Belongs to the replication factor A protein 3 family. UniProt P35244 1 EQUAL 121 EQUAL Reactome DB_ID: 68461 1 UniProt:P27694 RPA1 RPA1 RPA70 RPA1 REPA1 FUNCTION As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism (PubMed:27723720, PubMed:27723717). Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage (PubMed:17765923). Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Also plays a role in base excision repair (BER) probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance (PubMed:17959650). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105).SUBUNIT Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3 (PubMed:27723720, PubMed:27723717). Also a component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2 (PubMed:7760808, PubMed:19116208). The DNA-binding activity may reside exclusively on the RPA1 subunit. Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA) (PubMed:24332808). Interacts with RIPK1 (PubMed:16135809). Interacts with the polymerase alpha subunit POLA1/p180; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288). Interacts with RAD51 and SENP6 to regulate DNA repair (PubMed:20705237). Interacts with HELB; this interaction promotes HELB recruitment to chromatin following DNA damage (PubMed:22194613, PubMed:26774285). Interacts with PRIMPOL; leading to recruit PRIMPOL on chromatin and stimulate its DNA primase activity (PubMed:24126761, PubMed:25550423, PubMed:28534480). Interacts with XPA; the interaction is direct and associates XPA with the RPA complex (PubMed:7700386, PubMed:9699634, PubMed:10563794). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).PTM DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).PTM Sumoylated on lysine residues Lys-449 and Lys-577, with Lys-449 being the major site. Sumoylation promotes recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. Desumoylated by SENP6.SIMILARITY Belongs to the replication factor A protein 1 family. UniProt P27694 2 EQUAL 616 EQUAL Reactome Database ID Release 82 68462 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68462 Reactome R-HSA-68462 11 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68462.11 Reactome DB_ID: 5684128 1 3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 [nucleoplasm] 3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1 Reactome DB_ID: 5685656 1 BRCA1-C complex [nucleoplasm] BRCA1-C complex p-S988,S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1:p-S327,T847,T859-RBBP8 homotetramer p-5S-BRCA1:p-2T-BARD1:p-S327,T847,T859-RBBP8 homotetramer Converted from EntitySet in Reactome Reactome DB_ID: 9707299 1 p-5S-BRCA1:p-2T-BARD1 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 5684137 1 p-S327,T847,T859-RBBP8 homotetramer [nucleoplasm] p-S327,T847,T859-RBBP8 homotetramer Reactome DB_ID: 5684138 4 UniProt:Q99708 RBBP8 RBBP8 CTIP RBBP8 FUNCTION Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double-strand break (DSB) repair through the homologous recombination (HR) pathway (PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:26721387). HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse (PubMed:17965729, PubMed:19202191). Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ) (PubMed:19202191). Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA (PubMed:16581787, PubMed:17965729, PubMed:19759395, PubMed:20064462). Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:15485915, PubMed:16818604). During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations (By similarity).SUBUNIT Homodimer; dimerizes via the coiled coil domain (PubMed:15084581). Interacts (via the PXDLS motif) with CTBP1; the interaction is disrupted via binding of the adenovirus E1A to CTBP1 (PubMed:9535825). Component of the BRCA1-RBBP8 complex. Interacts (the Ser-327 phosphorylated form) with BRCA1 (via the C-terminal BRCA1 domains): the interaction occurs in the G2 phase, ubiquitinates RBBP8 and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:10764811, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:23623683). Interacts with RB1 (PubMed:9721205). Interacts with the MRN complex. Interacts directly with MRE11; the interaction is required for efficient homologous recombination (HR) and regulation of the MRN complex (PubMed:19759395, PubMed:23623683). Interacts directly with RAD50 (PubMed:19759395). Interacts directly with NBN (PubMed:19759395). Interacts with LM04 (via the LIM zinc-binding 1 domain) (PubMed:11751867). Interacts with SIAH1 (PubMed:14654780). Interacts with RNF138 (PubMed:26502057). Interacts with EXD2 (PubMed:26807646). Interacts with CUL3 and KLHL15; this interaction leads to RBBP8 proteasomal degradation (PubMed:27561354). Directly interacts with PIN1; this interaction depends upon RBBP8 phosphorylation, predominantly at Thr-315 (PubMed:23623683). Interacts with FZR1; this interaction leads to APC/C-mediated RBBP8 proteasomal degradation (PubMed:25349192). Interacts with AUNIP; leading to recruit RBBP8 to sites of DNA damage (PubMed:29042561, PubMed:10764811, PubMed:11751867, PubMed:14654780, PubMed:15084581, PubMed:15485915, PubMed:16818604, PubMed:17965729, PubMed:19759395, PubMed:23623683, PubMed:25349192, PubMed:26502057, PubMed:26807646, PubMed:27561354, PubMed:9535825, PubMed:9721205). Interacts with SAMHD1 (PubMed:28834754). Interacts with HDGFL2 (PubMed:26721387).TISSUE SPECIFICITY Expressed in ER-positive breast cancer lines, but tends to be down-regulated ER-negative cells (at protein level).INDUCTION Expression is cell-cycle regulated. Levels increase as dividing cells traverse the G1/S boundary (PubMed:18171986). The protein is degraded by the proteasome pathway during mitotic exit. Also degraded in response to DNA damage in G2 cells; this degradation is mediated by the E3 FZR1/APC/C complex (PubMed:25349192).DOMAIN The PXDLS motif binds to a cleft in CtBP proteins.DOMAIN The damage-recruitment motif is required for DNA binding and translocation to sites of DNA damage.PTM Hyperphosphorylation upon ionizing radiation results in dissociation from BRCA1. Phosphorylation at Thr-847 by CDK1 is essential for the recruitment to DNA and the DNA repair function. Phosphorylated on Ser-327 as cells enter G2 phase. This phosphorylation is required for binding BRCA1 and for the G2/M DNA damage transition checkpoint control. Phosphorylation at Thr-315, probably catalyzed by CDK2, is required for PIN1-binding, while phosphorylation at Ser-276 serves as a PIN1 isomerization site. Phosphorylation at Thr-315 is cell-cycle dependent. It steadily increases during S phase, peaks at late S/G2 phase, and drops at G1 (PubMed:23623683).PTM Ubiquitinated (PubMed:14654780, PubMed:16818604, PubMed:27561354). Ubiquitination at multiple sites by BRCA1 (via its N-terminal RING domain) does not lead to its proteasomal degradation but instead the ubiquitinated RBBP8 binds to chromatin following DNA damage and may play a role in G2/M checkpoint control (PubMed:16818604). Ubiquitinated by RNF138 at its N-terminus (PubMed:26502057). Ubiquitinated through 'Lys-48' by the E3 CUL3-KLHL15 complex; this modification leads to proteasomal degradation (PubMed:27561354). Ubiquitinated by the E3 FZR1/APC/C complex; this modification leads to proteasomal degradation (PubMed:25349192).DISEASE Genetic variability in RBBP8 is noted as a factor in BRCA1-associated breast cancer risk (PubMed:21799032). Associated with sensitivity to tamoxifen in certain breast cancer cell lines (PubMed:18171986).SIMILARITY Belongs to the COM1/SAE2/CtIP family.CAUTION Upon DNA damage, was shown to interact with SIRT6 resulting in its deacetylation. However, this study was later retracted. UniProt Q99708 O-phospho-L-serine at 327 327 EQUAL O-phospho-L-threonine at 847 847 EQUAL O-phospho-L-threonine at 859 859 EQUAL 1 EQUAL 897 EQUAL Reactome Database ID Release 82 5684137 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684137 Reactome R-HSA-5684137 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684137.1 Reactome Database ID Release 82 5685656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5685656 Reactome R-HSA-5685656 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5685656.2 Reactome DB_ID: 5684122 1 3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 [nucleoplasm] 3' overhanging ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 Reactome DB_ID: 5684116 1 3' overhanging ssDNA-DSBs:p-MRN [nucleoplasm] 3' overhanging ssDNA-DSBs:p-MRN Reactome DB_ID: 75156 1 3' overhanging DNA at resected DSB ends [nucleoplasm] 3' overhanging DNA at resected DSB ends Reactome DB_ID: 5682166 1 Reactome Database ID Release 82 5684116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684116 Reactome R-HSA-5684116 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684116.1 Reactome DB_ID: 5693527 1 O-phospho-L-serine at 1981 1981 EQUAL N6-acetyl-L-lysine at 3016 3016 EQUAL 1 EQUAL 3056 EQUAL Reactome DB_ID: 3321979 1 1 EQUAL 513 EQUAL Reactome Database ID Release 82 5684122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684122 Reactome R-HSA-5684122 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684122.1 Reactome DB_ID: 5687710 1 UniProt:Q9BX63 BRIP1 BRIP1 BRIP1 FANCJ BACH1 FUNCTION DNA-dependent ATPase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1.SUBUNIT Binds directly to the BRCT domains of BRCA1 (PubMed:15125843). Interacts with the CIA complex components CIAO1, CIAO2B and MMS19 (PubMed:23585563).TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in testis.DOMAIN 4Fe-4S iron-sulfur-binding is required for helicase activity.PTM Phosphorylated. Phosphorylation is necessary for interaction with BRCA1, and is cell-cycle regulated.PTM Acetylation at Lys-1249 facilitates DNA end processing required for repair and checkpoint signaling.SIMILARITY Belongs to the DEAD box helicase family. DEAH subfamily. UniProt Q9BX63 O-phospho-L-serine at 990 990 EQUAL N6-acetyl-L-lysine at 1249 1249 EQUAL 1 EQUAL 1249 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 5685980 1 EXO1,DNA2:BLM,WRN [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 82 5684128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684128 Reactome R-HSA-5684128 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684128.1 Reactome Database ID Release 82 5693552 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693552 Reactome R-HSA-5693552 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693552.1 Reactome Database ID Release 82 5684874 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5684874 Reactome R-HSA-5684874 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5684874.1 Reactome DB_ID: 5684878 1 UniProt:Q92547 TOPBP1 TOPBP1 KIAA0259 TOPBP1 FUNCTION Required for DNA replication. Plays a role in the rescue of stalled replication forks and checkpoint control. Binds double-stranded DNA breaks and nicks as well as single-stranded DNA. Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage. Induces a large increase in the kinase activity of ATR (PubMed:16530042).SUBUNIT Interacts with POLE (PubMed:11395493). Interacts with RAD9A (PubMed:11395493). Interacts with UBR5 (PubMed:11714696). Interacts with E2F1 (PubMed:12697828, PubMed:15075294). Interacts with PML (PubMed:12773567). Interacts with SMARCA2 (PubMed:15075294). Interacts with SMARCA4 (PubMed:15075294). Interacts with RHNO1 (PubMed:21659603). May interact with TOP2B (PubMed:9461304). Interacts with TICRR (PubMed:20080954). Interacts with HELB (PubMed:25933514).TISSUE SPECIFICITY Highly expressed in heart, brain, placenta, lung and kidney.INDUCTION Up-regulated during the S phase of the cell cycle. Up-regulated by E2F1 and interferon.PTM Phosphorylated on serine and threonine residues in response to X-ray irradiation.PTM Ubiquitinated and degraded by the proteasome. X-ray irradiation reduces ubiquitination. UniProt Q92547 1 EQUAL 1522 EQUAL Reactome DB_ID: 176353 1 RAD17:RFC [nucleoplasm] RAD17:RFC Rad17-RFC complex Reactome DB_ID: 68433 1 UniProt:P35250 RFC2 RFC2 RFC2 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit binds ATP (By similarity).SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. RFC2 also interacts with PRKAR1A; the complex may be involved in cell survival (PubMed:15655353). Interacts with DDX11 (PubMed:18499658).DISEASE RFC2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:11003705).SIMILARITY Belongs to the activator 1 small subunits family. UniProt P35250 1 EQUAL 354 EQUAL Reactome DB_ID: 68431 1 UniProt:P40938 RFC3 RFC3 RFC3 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. Interacts with CNTD1; this interaction facilitates crossover formation (By similarity).SIMILARITY Belongs to the activator 1 small subunits family. UniProt P40938 1 EQUAL 356 EQUAL Reactome DB_ID: 68429 1 UniProt:P35249 RFC4 RFC4 RFC4 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit may be involved in the elongation of the multiprimed DNA template.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. Interacts with CNTD1; this interaction facilitates crossover formation (By similarity).MISCELLANEOUS Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP.SIMILARITY Belongs to the activator 1 small subunits family. UniProt P35249 1 EQUAL 363 EQUAL Reactome DB_ID: 68427 1 UniProt:P40937 RFC5 RFC5 RFC5 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.SIMILARITY Belongs to the activator 1 small subunits family. UniProt P40937 1 EQUAL 340 EQUAL Reactome DB_ID: 3008665 1 UniProt:O75943 RAD17 RAD17 RAD17 R24L FUNCTION Essential for sustained cell growth, maintenance of chromosomal stability, and ATR-dependent checkpoint activation upon DNA damage. Has a weak ATPase activity required for binding to chromatin. Participates in the recruitment of the RAD1-RAD9-HUS1 complex and RHNO1 onto chromatin, and in CHEK1 activation. May also serve as a sensor of DNA replication progression, and may be involved in homologous recombination.SUBUNIT Part of a DNA-binding complex containing RFC2, RFC3, RFC4 and RFC5. Interacts with RAD1 and RAD9 within the RAD1-RAD9-HUS1 complex. Interacts with RAD9B, POLE, SNU13 and MCM7. DNA damage promotes interaction with ATR or ATM and disrupts interaction with the RAD1-RAD9-HUS1 complex.TISSUE SPECIFICITY Overexpressed in various cancer cell lines and in colon carcinoma (at protein level). Isoform 2 and isoform 3 are the most abundant isoforms in non irradiated cells (at protein level). Ubiquitous at low levels. Highly expressed in testis, where it is expressed within the germinal epithelium of the seminiferous tubuli. Weakly expressed in seminomas (testicular tumors).INDUCTION Isoform 1, isoform 3 and isoform 4 are induced by X-ray irradiation.PTM Phosphorylated. Phosphorylation on Ser-646 and Ser-656 is cell cycle-regulated, enhanced by genotoxic stress, and required for activation of checkpoint signaling. Phosphorylation is mediated by ATR upon UV or replication arrest, whereas it may be mediated both by ATR and ATM upon ionizing radiation. Phosphorylation on both sites is required for interaction with RAD1 but dispensable for interaction with RFC3 or RFC4.SIMILARITY Belongs to the rad17/RAD24 family. UniProt O75943 1 EQUAL 681 EQUAL Reactome Database ID Release 82 176353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176353 Reactome R-HSA-176353 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176353.1 Reactome DB_ID: 5684880 1 UniProt:Q9BSD3 RHNO1 RHNO1 RHINO HKMT1188 C12orf32 RHNO1 FUNCTION Plays a role in DNA damage response (DDR) signaling upon genotoxic stresses such as ionizing radiation (IR) during the S phase. Recruited to sites of DNA damage through interaction with the 9-1-1 cell-cycle checkpoint response complex and TOPBP1 in a ATR-dependent manner. Required for the progression of the G1 to S phase transition. Plays a role in the stimulation of CHEK1 phosphorylation.SUBUNIT Interacts with RAD9A, RAD18, TOPBP1 and UBE2N.TISSUE SPECIFICITY Weakly expressed in testis, prostate, ovary, thymus and small intestine. Expressed strongly in breast cancer cells.INDUCTION Up-regulated in breast cancer cells. UniProt Q9BSD3 1 EQUAL 238 EQUAL Reactome DB_ID: 176312 1 RAD9:HUS1:RAD1 [nucleoplasm] RAD9:HUS1:RAD1 9-1-1 complex Rad9-Hus1-Rad1 complex Reactome DB_ID: 176382 1 UniProt:O60671 RAD1 RAD1 REC1 RAD1 FUNCTION Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair (PubMed:10846170, PubMed:10884395). The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex (PubMed:12578958). Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER) (PubMed:15871698). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates (PubMed:15314187, PubMed:15556996, PubMed:15871698). The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase (PubMed:21659603). Isoform 1 possesses 3'-&gt;5' double stranded DNA exonuclease activity (PubMed:9660799).SUBUNIT Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1 (PubMed:10846170, PubMed:10884395). The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2 (PubMed:10846170, PubMed:10884395, PubMed:15314187, PubMed:15556996, PubMed:15871698, PubMed:15897895, PubMed:16216273). The 9-1-1 complex associates with the RAD17-RFC complex (PubMed:12578958). RAD1 interacts with POLB, FEN1, HUS1, HUS1B, RAD9A and RAD9B (PubMed:10359610, PubMed:10777662, PubMed:11944979, PubMed:14500360, PubMed:14611806, PubMed:15314187, PubMed:15556996, PubMed:16216273). Interacts with DNAJC7 (PubMed:11573955).TISSUE SPECIFICITY Expressed in testis, uterus, bladder, spleen, ovaries, lung, brain and muscle (at protein level).SIMILARITY Belongs to the rad1 family. UniProt O60671 1 EQUAL 282 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 176222 1 RAD9 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RAD9B [nucleoplasm] RAD9A [nucleoplasm] UniProt Q6WBX8 UniProt Q99638 Reactome DB_ID: 176374 1 UniProt:O60921 HUS1 HUS1 HUS1 FUNCTION Component of the 9-1-1 cell-cycle checkpoint response complex that plays a major role in DNA repair. The 9-1-1 complex is recruited to DNA lesion upon damage by the RAD17-replication factor C (RFC) clamp loader complex. Acts then as a sliding clamp platform on DNA for several proteins involved in long-patch base excision repair (LP-BER). The 9-1-1 complex stimulates DNA polymerase beta (POLB) activity by increasing its affinity for the 3'-OH end of the primer-template and stabilizes POLB to those sites where LP-BER proceeds; endonuclease FEN1 cleavage activity on substrates with double, nick, or gap flaps of distinct sequences and lengths; and DNA ligase I (LIG1) on long-patch base excision repair substrates. The 9-1-1 complex is necessary for the recruitment of RHNO1 to sites of double-stranded breaks (DSB) occurring during the S phase.SUBUNIT Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1. The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2. The 9-1-1 complex associates with the RAD17-RFC complex. HUS1 interacts with POLB, HDAC1, FEN1, PCNA, RAD1, RAD9A and RAD9B. HUS1 does not interact with RAD17. Interacts with DNAJC7.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the HUS1 family. UniProt O60921 1 EQUAL 280 EQUAL Reactome Database ID Release 82 176312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176312 Reactome R-HSA-176312 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176312.1 Reactome Database ID Release 82 5685039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5685039 Reactome R-HSA-5685039 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5685039.1 Reactome Database ID Release 82 5685163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5685163 Reactome Database ID Release 82 6799332 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799332 Reactome R-HSA-6799332 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6799332.2 9925639 Pubmed 1999 A role for ATR in the DNA damage-induced phosphorylation of p53 Tibbetts, R S Brumbaugh, K M Williams, J M Sarkaria, J N Cliby, W A Shieh, SY Taya, Y Prives, C Abraham, Robert T Genes Dev. 13:152-7 10435622 Pubmed 1999 The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53 Lakin, N D Hann, B C Jackson, SP Oncogene 18:3989-95 2.7.11.1 CHEK1 phosphorylates TP53 CHEK1 phosphorylates TP53 CHEK1, activated by ATR-mediated phosphorylation, can phosphorylate TP53 at serine residue S20, resulting in the increased half-life of TP53 (Shieh et al. 2000). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 Reactome DB_ID: 349474 1 Reactome DB_ID: 29358 4 Reactome DB_ID: 113582 4 Reactome DB_ID: 3222171 1 p-S15,S20-TP53 Tetramer [nucleoplasm] p-S15,S20-TP53 Tetramer Reactome DB_ID: 69683 4 O-phospho-L-serine at 20 20 EQUAL O-phospho-L-serine at 15 15 EQUAL 1 EQUAL 393 EQUAL Reactome Database ID Release 82 3222171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222171 Reactome R-HSA-3222171 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3222171.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 113838 O-phospho-L-serine at 317 317 EQUAL O-phospho-L-serine at 345 345 EQUAL 1 EQUAL 476 EQUAL Reactome Database ID Release 82 182636 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=182636 Reactome Database ID Release 82 6799246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799246 Reactome R-HSA-6799246 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6799246.4 10673501 Pubmed 2000 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Shieh, SY Ahn, J Tamai, K Taya, Y Prives, C Genes Dev 14:289-300 Reactome Database ID Release 82 69473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69473 Reactome R-HSA-69473 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69473.5 G2/M DNA replication checkpoint G2/M DNA replication checkpoint The G2/M DNA replication checkpoint ensures that mitosis is not initiated until DNA replication is complete. If replication is blocked, the DNA replication checkpoint signals to maintain Cyclin B - Cdc2 complexes in their T14Y15 phosphorylated and inactive state. This prevents the phosphorylation of proteins involved in G2/M transition, and prevents mitotic entry.<p>Failure of these checkpoints results in changes of ploidy: in the case of mitosis without completion of DNA replication, aneuploidy of <2C will result, and the opposite is true if DNA replication is completed more than once in a single cell cycle with an overall increase in ploidy. The mechanism by which unreplicated DNA is first detected by the cell is unknown. 2.7.11.1 Myt-1 mediated phosphorylation of Cyclin B:Cdc2 complexes Myt-1 mediated phosphorylation of Cyclin B:Cdc2 complexes Myt1, which localizes preferentially to the endoplasmic reticulum and Golgi complex, phosphorylates Cdc2 on threonine 14 ( Liu et al., 1997). Reactome DB_ID: 113592 1 Reactome DB_ID: 170077 1 CCNB:CDK1 [cytosol] CCNB:CDK1 Cyclin B:Cdc2 complex Converted from EntitySet in Reactome Reactome DB_ID: 157461 1 CCNB [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CCNB1 [cytosol] CCNB2 [cytosol] UniProt O95067 Reactome DB_ID: 170075 1 1 EQUAL 297 EQUAL Reactome Database ID Release 82 170077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170077 Reactome R-HSA-170077 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170077.1 Reactome DB_ID: 29370 1 Reactome DB_ID: 170069 1 CCNB:p-T14-CDK1 [cytosol] CCNB:p-T14-CDK1 Cyclin B:phospho-Cdc2(Thr 14) Converted from EntitySet in Reactome Reactome DB_ID: 157461 1 Reactome DB_ID: 170064 1 O-phospho-L-threonine at 14 14 EQUAL 1 EQUAL 297 EQUAL Reactome Database ID Release 82 170069 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170069 Reactome R-HSA-170069 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170069.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157457 UniProt:Q99640 PKMYT1 PKMYT1 PKMYT1 MYT1 FUNCTION Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.ACTIVITY REGULATION Negatively regulated by hyperphosphorylation during mitosis. The hyperphosphorylated form does not associate with CCNB1-CDC2 complexes. The PLK1 protein kinase may be required for mitotic phosphorylation.SUBUNIT Interacts with CDC2-CCNB1 complex. Can also interact with PIN1 when phosphorylated by CDC2-CCNB1.DOMAIN The membrane-association motif is essential for the localization to membrane of Golgi stack. According to some authors, it is a transmembrane domain; the existence of a transmembrane region is however unproven.PTM Autophosphorylated. Phosphorylated by CDC2-CCNB1 complexes on undefined serine and threonine residues. The phosphorylation by CDC2-CCNB1 complexes may inhibit the catalytic activity.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WEE1 subfamily. UniProt Q99640 1 EQUAL 499 EQUAL Reactome Database ID Release 82 157883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157883 Reactome Database ID Release 82 170055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170055 Reactome R-HSA-170055 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170055.2 9268380 Pubmed 1997 Human Myt1 is a cell cycle-regulated kinase that inhibits Cdc2 but not Cdk2 activity Booher, RN Holman, PS Fattaey, A J Biol Chem 272:22300-6 9001210 Pubmed 1997 The human Myt1 kinase preferentially phosphorylates Cdc2 on threonine 14 and localizes to the endoplasmic reticulum and Golgi complex. Liu, F Stanton, JJ Wu, Z Piwnica-Worms, H Mol Cell Biol 17:571-83 Reactome Database ID Release 82 69478 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69478 Reactome R-HSA-69478 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69478.3 Activation of ATR in response to replication stress Activation of ATR in response to replication stress Genotoxic stress caused by DNA damage or stalled replication forks can lead to genomic instability. To guard against such instability, genotoxically-stressed cells activate checkpoint factors that halt or slow cell cycle progression. Among the pathways affected are DNA replication by reduction of replication origin firing, and mitosis by inhibiting activation of cyclin-dependent kinases (Cdks). A key factor involved in the response to stalled replication forks is the ATM- and rad3-related (ATR) kinase, a member of the phosphoinositide-3-kinase-related kinase (PIKK) family. Rather than responding to particular lesions in DNA, ATR and its binding partner ATRIP (ATR-interacting protein) sense replication fork stalling indirectly by associating with persistent ssDNA bound by RPA. These structures would be formed, for example, by dissociation of the replicative helicase from the leading or lagging strand DNA polymerase when the polymerase encounters a DNA lesion that blocks DNA synthesis. Along with phosphorylating the downstream transducer kinase Chk1 and the tumor suppressor p53, activated ATR modifies numerous factors that regulate cell cycle progression or the repair of DNA damage. The persistent ssDNA also stimulates recruitment of the RFC-like Rad17-Rfc2-5 alternative clamp-loading complex, which subsequently loads the Rad9-Hus1-Rad1 complex onto the DNA. The latter '9-1-1' complex serves to facilitate Chk1 binding to the stalled replication fork, where Chk1 is phosphorylated by ATR and thereby activated. Upon activation, Chk1 can phosphorylate additional substrates including the Cdc25 family of phosphatases (Cdc25A, Cdc25B, and Cdc25C). These enzymes catalyze the removal of inhibitory phosphate residues from cyclin-dependent kinases (Cdks), allowing their activation. In particular, Cdc25A primarily functions at the G1/S transition to dephosphorylate Cdk2 at Thr 14 and Tyr 15, thus positively regulating the Cdk2-cyclin E complex for S-phase entry. Cdc25A also has mitotic functions. Phosphorylation of Cdc25A at Ser125 by Chk1 leads to Cdc25A ubiquitination and degradation, thus inhibiting DNA replication origin firing. In contrast, Cdc25B and Cdc25C regulate the onset of mitosis through dephosphorylation and activation of Cdk1-cyclin B complexes. In response to replication stress, Chk1 phosphorylates Cdc25B and Cdc25C leading to Cdc25B/C complex formation with 14-3-3 proteins. As these complexes are sequestered in the cytoplasm, they are unable to activate the nuclear Cdk1-cyclin B complex for mitotic entry.<p>These events are outlined in the figure. Persistent single-stranded DNA associated with RPA binds claspin (A) and ATR:ATRIP (B), leading to claspin phosphorylation (C). In parallel, the same single-stranded DNA:RPA complex binds RAD17:RFC (D), enabling the loading of RAD9:HUS1:RAD1 (9-1-1) complex onto the DNA (E). The resulting complex of proteins can then repeatedly bind (F) and phosphorylate (G) CHK1, activating multiple copies of CHK1. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Stalling of DNA replication fork and RPA binding Stalling of DNA replication fork and RPA binding When a DNA replication fork encounters DNA lesions (e.g., cyclobutane pyrimidine dimers or alkylated bases) stalling of the replicative DNA polymerase may occur. This can lead to dissociation or 'uncoupling' of the DNA polymerase from the DNA helicase and generation of long regions of persistent ssDNA. Uncoupling can also occur in response to other genotoxic stresses such as reduced dNTP pools caused by hydroxyurea treatment which inhibits cellular ribonucleotide diphosphate reductase. The exposed ssDNA is bound by the single-stranded DNA binding protein RPA. The persistent nature of this RPA-ssDNA complex (as opposed to a more-transient complex found at an active replication fork) allows it to serve as a signal for replication stress that can be recognized by the ATR-ATRIP and Rad17-Rfc2-5 complexes.<p>RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 176104 1 Persistent single-stranded DNA [nucleoplasm] Persistent single-stranded DNA Reactome DB_ID: 68462 1 Reactome DB_ID: 176293 1 RPA complexed to ssDNA [nucleoplasm] RPA complexed to ssDNA RPA-ssDNA complex Reactome DB_ID: 176104 1 Reactome DB_ID: 68462 1 Reactome Database ID Release 82 176293 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176293 Reactome R-HSA-176293 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176293.1 Reactome Database ID Release 82 176175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176175 Reactome R-HSA-176175 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176175.2 10373362 Pubmed 1999 Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand Cordeiro-Stone, M Makhov, AM Zaritskaya, LS Griffith, JD J Mol Biol 289:1207-18 15833913 Pubmed 2005 Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint Byun, TS Pacek, M Yee, MC Walter, JC Cimprich, KA Genes Dev 19:1040-52 10051570 Pubmed 1999 Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage Raderschall, E Golub, EI Haaf, T Proc Natl Acad Sci U S A 96:1921-6 12791985 Pubmed 2003 Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes Zou, L Elledge, SJ Science 300:1542-8 8196638 Pubmed 1994 Human replication protein A binds single-stranded DNA in two distinct complexes Blackwell, LJ Borowiec, James A Mol Cell Biol 14:3993-4001 9242902 Pubmed 1997 Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Wold, MS Annu Rev Biochem 66:61-92 10473346 Pubmed 1999 Replication protein A (RPA): the eukaryotic SSB. Iftode, C Daniely, Y Borowiec, James A Crit Rev Biochem Mol Biol 34:141-80 16387650 Pubmed 2006 Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions Lopes, M Foiani, M Sogo, JM Mol Cell 21:15-27 12142537 Pubmed 2002 Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects Sogo, JM Lopes, M Foiani, M Science 297:599-602 Binding of ATR-ATRIP to the RPA-ssDNA complex Binding of ATR-ATRIP to the RPA-ssDNA complex ATR kinase activity is stimulated upon binding of the ATR-ATRIP complex to an RPA-ssDNA complex. ATR can subsequently phosphorylate and activate the checkpoint kinase Chk1, allowing further amplification of the checkpoint signal. The ATR and Chk1 kinases then modify a variety of factors that can lead to stabilization of stalled DNA replication forks, inhibition of origin firing, inhibition of cell cycle progression, mobilization of DNA repair factors, and induction of apoptosis. This checkpoint signaling mechanism is highly conserved in eukaryotes, and homologues of ATR and ATRIP are found in such organisms as S. cerevisiae (Mec1 and Ddc2, respectively), S. pombe (rad3 and rad26, respectively), and X. laevis (Xatr and Xatrip, respectively).<p>The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR protein without affecting ATR mRNA levels indicating that complex formation stabilizes the ATR protein. ATRIP is also a substrate for the ATR kinase, but modification of ATRIP does not significantly regulate the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.<p>While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest affinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 176269 1 Reactome DB_ID: 176293 1 Reactome DB_ID: 176281 1 ATR:ATRIP:RPA:ssDNA signaling complex [nucleoplasm] ATR:ATRIP:RPA:ssDNA signaling complex ATR-ATRIP-RPA-ssDNA signaling complex Reactome DB_ID: 176269 1 Reactome DB_ID: 176293 1 Reactome Database ID Release 82 176281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176281 Reactome R-HSA-176281 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176281.1 Reactome Database ID Release 82 176250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176250 Reactome R-HSA-176250 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176250.2 16327781 Pubmed 2006 ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks Jazayeri, A Falck, J Lukas, C Bartek, J Smith, GC Lukas, J Jackson, SP Nat Cell Biol 8:37-45 8019001 Pubmed 1994 Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeast al-Khodairy, F Fotou, E Sheldrick, KS Griffiths, DJ Lehmann, AR Carr, AM Mol Biol Cell 5:147-60 15743907 Pubmed 2005 ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation Ball, HL Myers, JS Cortez, D Mol Biol Cell 16:2372-81 16407120 Pubmed 2006 ATRIP associates with replication protein A-coated ssDNA through multiple interactions Namiki, Y Zou, L Proc Natl Acad Sci U S A 103:580-5 10559981 Pubmed 1999 A Rad3-Rad26 complex responds to DNA damage independently of other checkpoint proteins Edwards, RJ Bentley, NJ Carr, AM Nat Cell Biol 1:393-8 10950868 Pubmed 2000 The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Paciotti, V Clerici, M Lucchini, G Longhese, MP Genes Dev 14:2046-59 15451423 Pubmed 2004 ATR-dependent phosphorylation of ATRIP in response to genotoxic stress Itakura, E Umeda, K Sekoguchi, E Takata, H Ohsumi, M Matsuura, A Biochem Biophys Res Commun 323:1197-202 12015327 Pubmed 2002 The role of single-stranded DNA and polymerase alpha in establishing the ATR, Hus1 DNA replication checkpoint You, Z Kong, L Newport, J J Biol Chem 277:27088-93 15371427 Pubmed 2004 Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1 Kumagai, A Kim, SM Dunphy, WG J Biol Chem 279:49599-608 Recruitment of Rad17-RFC complex to DNA Recruitment of Rad17-RFC complex to DNA The Rad17-RFC complex is involved in an early stage of the genotoxic stress response. The major function of the protein complex is to load the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA at sites of damage and/or stalled replication forks. This reaction is conceptually similar to the loading of the PCNA sliding clamp onto DNA by RFC. The association of the Rad17-RFC complex with ssDNA or gapped or primed DNA is significantly stimulated by RPA, but not by the heterologous E. coli SSB. Loading of the human 9-1-1 complex onto such DNA templates is also strongly stimulated by cognate RPA, but not yeast RPA. Although Rad17 and Rad9 are substrates of the ATR kinase activity, loading of the Rad17 and 9-1-1 complexes onto DNA occurs independent of ATR.<p>The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is slightly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.<p>The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.<p>Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 176353 1 Reactome DB_ID: 176293 1 Reactome DB_ID: 176204 1 Rad17-RFC complex bound to DNA [nucleoplasm] Rad17-RFC complex bound to DNA Reactome DB_ID: 176353 1 Reactome DB_ID: 176293 1 Reactome Database ID Release 82 176204 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176204 Reactome R-HSA-176204 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176204.1 Reactome Database ID Release 82 176101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176101 Reactome R-HSA-176101 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176101.2 14624239 Pubmed 2003 Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNA Ellison, V Stillman, B PLoS Biol 1:E33 14605214 Pubmed 2003 Replication protein A-mediated recruitment and activation of Rad17 complexes Zou, L Liu, D Elledge, SJ Proc Natl Acad Sci U S A 100:13827-32 15279787 Pubmed 2004 Dial 9-1-1 for DNA damage: the Rad9-Hus1-Rad1 (9-1-1) clamp complex Parrilla-Castellar, ER Arlander, SJ Karnitz, L DNA Repair (Amst) 3:1009-14 12578958 Pubmed 2003 Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro Bermudez, VP Lindsey-Boltz, LA Cesare, AJ Maniwa, Y Griffith, JD Hurwitz, J Sancar, A Proc Natl Acad Sci U S A 100:1633-8 Recruitment of the Rad9-Hus1-Rad1 complex to DNA Recruitment of the Rad9-Hus1-Rad1 complex to DNA Recruitment of the 9-1-1 complex to DNA The 9-1-1 complex is a heterotrimeric ring-shaped structure that is loaded onto DNA by the Rad17-RFC complex. In vitro studies indicate that loading is preferred onto DNA substrates containing ssDNA gaps that presumably resemble structures found upon replication fork stalling and DNA polymerase/helicase uncoupling. The Rad17-RFC and 9-1-1 complexes are structurally similar to the RFC (replication factor C) clamp loader and PCNA sliding clamp, respectively, and similar mechanisms are thought to be used during loading of the 9-1-1 complex and PCNA. Upon loading, the 9-1-1 complex can recruit Chk1 onto sites of replication fork uncoupling or DNA damage.<p>The purified Rad17 and Rad9-Hus1-Rad1 (9-1-1) complexes can form a stable co-complex in the presence of ATP, using Rad17-Rad9 interactions. From computer modeling studies, the Rad17 subunit of the complex is also proposed to interact with the C-terminus of Rad1, p36 with the C-terminus of Hus1, and p38 with the C-terminus of Rad9. A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phosphorylated, perhaps suggesting that 9-1-1 may regulate the recruiment of additional ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 176204 1 Reactome DB_ID: 176312 1 Reactome DB_ID: 176256 1 Rad9-Hus1-Rad1 bound to DNA [nucleoplasm] Rad9-Hus1-Rad1 bound to DNA Reactome DB_ID: 176204 1 Reactome DB_ID: 176312 1 Reactome Database ID Release 82 176256 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176256 Reactome R-HSA-176256 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176256.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 176204 GO 0003689 GO molecular function Reactome Database ID Release 82 176122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176122 Reactome Database ID Release 82 176264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176264 Reactome R-HSA-176264 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176264.2 12237462 Pubmed 2002 Molecular modeling-based analysis of interactions in the RFC-dependent clamp-loading process Venclovas, C Colvin, ME Thelen, MP Protein Sci 11:2403-16 14500360 Pubmed 2003 Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissue Hopkins, KM Wang, X Berlin, A Hang, H Thaker, HM Lieberman, HB Cancer Res 63:5291-8 15210332 Pubmed 2004 The PCNA-RFC families of DNA clamps and clamp loaders Majka, J Burgers, PM Prog Nucleic Acid Res Mol Biol 78:227-60 8943031 Pubmed 1996 A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene Lieberman, HB Hopkins, KM Nass, M Demetrick, D Davey, S Proc Natl Acad Sci U S A 93:13890-5 10777662 Pubmed 2000 Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progression Hang, H Lieberman, HB Genomics 65:24-33 Loading of claspin onto DNA during replication origin firing Loading of claspin onto DNA during replication origin firing Claspin is loaded onto DNA replication origins during replication initiation. Studies in Xenopus egg extracts indicate claspin loading requires the presence of Cdc45, a factor that promotes the initial unwinding of the origin DNA in the presence of Cdk2. This step is followed by RPA binding which is a prerequisite for recruitment of PCNA and DNA polymerases alpha and delta. As RPA is not required for claspin binding, it is postulated that claspin binds at the time of initial origin unwinding but prior to the initiation of DNA synthesis. Claspin would then continue to associate with replication fork machinery where it can serve as a checkpoint sensor protein. Even though associated with the replication fork, claspin is not an essential DNA replication factor.<p>Studies of Xenopus claspin indicate that it can physically associate with cognate Cdc45, DNA polymerase epsilon, RPA, RFC, and Rad17-RFC on chromatin. Studies of purified human claspin indicate that it binds with high affinity to branched (or forked) DNA structures that resemble stalled replication forks. Electron microscopy of these complexes indicates that claspin binds as a ring-like structure near the branch. The protein is hypothesized to encircle the DNA at these sites. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 68564 1 CDK:DDK:MCM10:active pre-replicative complex:CDC45 [nucleoplasm] CDK:DDK:MCM10:active pre-replicative complex:CDC45 Reactome DB_ID: 68563 1 UniProt:O75419 CDC45 CDC45 UNQ374/PRO710 CDC45 CDC45L2 CDC45L FUNCTION Required for initiation of chromosomal DNA replication.SUBUNIT Associated with ORC2. Interacts with HELB (PubMed:25933514). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity).TISSUE SPECIFICITY Widely expressed, highest levels are found in adult testis and thymus and in fetal liver.DEVELOPMENTAL STAGE Transcript peaks at G1-S transition, but total protein remains constant throughout the cell cycle. Expressed in multiple tissues during embryogenesis, including neural crest-derived structures.SIMILARITY Belongs to the CDC45 family. UniProt O75419 1 EQUAL 566 EQUAL Reactome DB_ID: 68561 1 CDK:DDK:MCM10:active pre-replicative complex [nucleoplasm] CDK:DDK:MCM10:active pre-replicative complex Reactome DB_ID: 68388 1 DDK [nucleoplasm] DDK Reactome DB_ID: 68387 1 UniProt:Q9UBU7 DBF4 DBF4 DBF4 ZDBF1 DBF4A ASK FUNCTION Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.SUBUNIT Forms a complex with CDC7. Note that CDC7 forms distinct complex either with DBF4A or DBF4B. Such complexes are stable upon replication stress. Interacts with MEN1, MCM2, ORC2, ORC4 and ORC6. Interacts (via IBM motifs) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).TISSUE SPECIFICITY Highly expressed in testis and thymus. Expressed also in most cancer cells lines.INDUCTION Induced in G1 phase at low level, increased during G1-S phase and remain high during S and G2-M phase.PTM Phosphorylation increases its interaction with PSIP1. UniProt Q9UBU7 1 EQUAL 674 EQUAL Reactome DB_ID: 51781 1 UniProt:O00311 CDC7 CDC7 CDC7L1 CDC7 FUNCTION Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylate MCM2 and MCM3.SUBUNIT Forms a complex with either DBF4/DBF4A or DBF4B, leading to the activation of the kinase activity.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC7 subfamily. UniProt O00311 1 EQUAL 574 EQUAL Reactome Database ID Release 82 68388 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68388 Reactome R-HSA-68388 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68388.1 Reactome DB_ID: 68380 1 CDK [nucleoplasm] CDK Reactome DB_ID: 68379 1 cyclin [nucleoplasm] cyclin Reactome DB_ID: 68365 1 UniProt:P24941 CDK2 CDK2 CDK2 CDKN2 FUNCTION Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21).SUBUNIT Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148).INDUCTION Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis.PTM Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.PTM Nitrosylated after treatment with nitric oxide (DETA-NO).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P24941 1 EQUAL 298 EQUAL Reactome Database ID Release 82 68380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68380 Reactome R-HSA-68380 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68380.1 Reactome DB_ID: 156564 1 MCM10:active pre-replicative complex [nucleoplasm] MCM10:active pre-replicative complex Reactome DB_ID: 156562 1 active pre-replicative complex [nucleoplasm] active pre-replicative complex Reactome DB_ID: 68558 1 MCM2-7 [nucleoplasm] MCM2-7 Reactome DB_ID: 9757255 1 MCM2:MCM4:MCM6:MCM7 [nucleoplasm] MCM2:MCM4:MCM6:MCM7 Reactome DB_ID: 69018 1 MCM4:MCM6:MCM7 [nucleoplasm] MCM4:MCM6:MCM7 replicative helicase Mcm4:Mcm6:Mcm7 Mcm4,6,7 complex Reactome DB_ID: 68549 1 UniProt:P33991 MCM4 MCM4 CDC21 MCM4 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.SUBUNIT Component of the MCM2-7 complex (PubMed:16899510, PubMed:9305914). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:9305914). Interacts with MCMBP (PubMed:17296731). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity).PTM Sumoylated; SUMO2 modified in response to stress caused by inhibition of proteasome activity (in vitro).MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt P33991 2 EQUAL 863 EQUAL Reactome DB_ID: 68555 1 UniProt:P33993 MCM7 MCM7 MCM7 CDC47 MCM2 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for S-phase checkpoint activation upon UV-induced damage.SUBUNIT Component of the MCM2-7 complex (PubMed:9305914, PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:9305914, PubMed:16899510, PubMed:17296731). Interacts with the ATR-ATRIP complex and with RAD17 (PubMed:15210935, PubMed:15538388). Interacts with TIPIN (PubMed:17116885). Interacts with MCMBP (PubMed:17296731). Interacts with ANKRD17 (PubMed:23711367). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity).PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.PTM Ubiquitinated by traip when forks converge following formation of DNA interstrand cross-links. Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3. If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt P33993 2 EQUAL 719 EQUAL Reactome DB_ID: 68553 1 UniProt:Q14566 MCM6 MCM6 MCM6 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.SUBUNIT Component of the MCM2-7 complex (PubMed:16899510, PubMed:17296731, PubMed:9305914). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:17296731, PubMed:9305914). May interact with MCM10 (PubMed:11095689). Interacts with TIPIN (PubMed:17116885). Interacts with CDT1 (PubMed:20202939). Interacts with MCMBP (PubMed:17296731). Interacts with DDI2 (PubMed:29290612). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity).PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.POLYMORPHISM Intronic variations in MCM6 upstream from the LCT gene are associated with adult-type hypolactasia [MIM:223100] leading to lactose intolerance, or with lactase persistance. Lactose intolerance is a normal physiological phenomenon caused by developmental down-regulation of lactase activity during childhood or early adulthood. A non-coding variation in MCM6 affects the transcriptional regulation of the LCT gene resulting in down-regulation of lactase activity. However, the majority of Northern Europeans and some African populations have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence).MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt Q14566 1 EQUAL 821 EQUAL Reactome Database ID Release 82 69018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69018 Reactome R-HSA-69018 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69018.2 Reactome DB_ID: 68557 1 UniProt:P49736 MCM2 MCM2 CDCL1 CCNL1 BM28 MCM2 KIAA0030 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for the entry in S phase and for cell division. Plays a role in terminally differentiated hair cells development of the cochlea and induces cells apoptosis.SUBUNIT Component of the MCM2-7 complex (PubMed:9305914, PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:9305914, PubMed:16899510, PubMed:17296731). Interacts with DBF4 (By similarity). Interacts with KAT7 (PubMed:16387653). May interact with MCM10 (PubMed:11095689). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity). Forms a co-chaperone complex with DNAJC9 and histone H3.3-H4 heterodimers (PubMed:33857403). Within the complex, interacts (via N-terminus) with DNAJC9 (via C-terminus); the interaction is histone-dependent (PubMed:33857403). Interacts with histones H3.1 and H3.3 (PubMed:33857403).PTM Phosphorylated on Ser-108 by ATR in proliferating cells. Ser-108 proliferation is increased by genotoxic agents. Ser-40 is mediated by the CDC7-DBF4 and CDC7-DBF4B complexes, while Ser-53 phosphorylation is only mediated by the CDC7-DBF4 complex. Phosphorylation by the CDC7-DBF4 complex during G1/S phase is required for the initiation of DNA replication.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt P49736 2 EQUAL 904 EQUAL Reactome Database ID Release 82 9757255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9757255 Reactome R-HSA-9757255 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9757255.1 Reactome DB_ID: 9757259 1 MCM3:MCM5 [nucleoplasm] MCM3:MCM5 Reactome DB_ID: 68551 1 UniProt:P33992 MCM5 MCM5 CDC46 MCM5 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.SUBUNIT Component of the MCM2-7 complex (PubMed:17296731, PubMed:16899510). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:17296731, PubMed:16899510). Interacts with ANKRD17 (PubMed:23711367). Interacts with MCMBP (PubMed:17296731). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity). Interacts with TONSL; the interaction is direct (PubMed:26527279).MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt P33992 1 EQUAL 734 EQUAL Reactome DB_ID: 68546 1 UniProt:P25205 MCM3 MCM3 MCM3 FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for DNA replication and cell proliferation.SUBUNIT Component of the MCM2-7 complex (PubMed:16899510, PubMed:17296731). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (PubMed:16899510, PubMed:17296731). Associated with the replication-specific DNA polymerase alpha (By similarity). Interacts with MCMBP (PubMed:17296731). Interacts with ANKRD17 (PubMed:23711367). Interacts with MCM3AP isoform MCM3AP; this interaction leads to MCM3 acetylation (PubMed:9712829, PubMed:11258703, PubMed:12226073). Component of the CMG helicase complex, composed of the MCM2-7 complex, the GINS complex and CDC45 (By similarity).PTM Acetylated by MCM3AP.PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family. UniProt P25205 2 EQUAL 808 EQUAL Reactome Database ID Release 82 9757259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9757259 Reactome R-HSA-9757259 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9757259.1 Reactome Database ID Release 82 68558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68558 Reactome R-HSA-68558 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68558.4 Reactome DB_ID: 68543 1 CDC6:ORC:origin complex [nucleoplasm] CDC6:ORC:origin complex Reactome DB_ID: 68540 1 ORC:origin of replication [nucleoplasm] ORC:origin of replication Reactome DB_ID: 9734715 1 UniProt:Q9Y5N6 ORC6 ORC6 ORC6 ORC6L FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Does not bind histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with DBF4 (By similarity).SIMILARITY Belongs to the ORC6 family. UniProt Q9Y5N6 O-phospho-L-threonine at 195 195 EQUAL 1 EQUAL 252 EQUAL Reactome DB_ID: 176970 1 Orc2 associated with MCM8 [nucleoplasm] Orc2 associated with MCM8 Reactome DB_ID: 3006646 1 UniProt:Q9UJA3 MCM8 MCM8 C20orf154 MCM8 FUNCTION Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093).SUBUNIT Component of the MCM8-MCM9 complex, which forms a hexamer composed of MCM8 and MCM9 (PubMed:23401855, PubMed:26300262). Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855). Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1 (PubMed:26215093). Interacts with CDC6 and ORC2 (PubMed:15684404). Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites (PubMed:31467087).TISSUE SPECIFICITY Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers.INDUCTION By E2F1.SIMILARITY Belongs to the MCM family.CAUTION Was initially thought to play a role in DNA replication (PubMed:15684404). However, it was later shown that it is mainly involved in homologous recombination repair (PubMed:23401855). UniProt Q9UJA3 1 EQUAL 840 EQUAL Reactome DB_ID: 68405 1 UniProt:Q13416 ORC2 ORC2 ORC2L ORC2 FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K20me3 and H4K27me3. Stabilizes LRWD1, by protecting it from ubiquitin-mediated proteasomal degradation. Also stabilizes ORC3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase (PubMed:12909626, PubMed:17716973). Interacts with DBF4 (By similarity). Interacts with MCM10 (PubMed:11095689). Interacts with LRWD1 throughout the cell cycle; this interaction, wich occurs only with non-ubiquitinated form of LRWD1, prevents LRWD1 ubiquitination and hence stabilizes the protein (PubMed:22645314). Interacts with POLQ (PubMed:24989122).SIMILARITY Belongs to the ORC2 family. UniProt Q13416 1 EQUAL 577 EQUAL Reactome Database ID Release 82 176970 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176970 Reactome R-HSA-176970 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176970.1 Reactome DB_ID: 68516 1 UniProt:O43913 ORC5 ORC5 ORC5 ORC5L FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.TISSUE SPECIFICITY Abundant in spleen, ovary, prostate, testis, and colon mucosa.PTM Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.SIMILARITY Belongs to the ORC5 family. UniProt O43913 1 EQUAL 435 EQUAL Reactome DB_ID: 68513 1 UniProt:Q9UBD5 ORC3 ORC3 ORC3 ORC3L LATHEO FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.PTM Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.SIMILARITY Belongs to the ORC3 family. UniProt Q9UBD5 1 EQUAL 711 EQUAL Reactome DB_ID: 68522 1 UniProt:Q13415 ORC1 ORC1 ORC1 ORC1L PARC1 FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with CDC6 and KAT7/HBO1. Interacts with LRWD1 predominantly during the G1 phase and with less affinity during mitosis, when phosphorylated.DEVELOPMENTAL STAGE Expression is cell-cycle regulated, it starts to accumulate in mid-G1 phase, reaches a peak at the G1/S boundary, and decreases to a basal level in S phase (at protein level).DOMAIN The BAH domain mediates binding to dimethylated histone H4 'Lys-20' (H4K20me2), which is enriched at replication origins.PTM Phosphorylated during mitosis.SIMILARITY Belongs to the ORC1 family. UniProt Q13415 1 EQUAL 861 EQUAL Reactome DB_ID: 68519 1 UniProt:O43929 ORC4 ORC4 ORC4 ORC4L FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase (PubMed:12909626, PubMed:17716973). Interacts with DBF4 (By similarity). Interacts with POLQ (PubMed:24989122).SIMILARITY Belongs to the ORC4 family. UniProt O43929 1 EQUAL 436 EQUAL Reactome DB_ID: 9749102 1 origin of replication [nucleoplasm] origin of replication ARS autonomously replicating sequence origin Reactome Database ID Release 82 68540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68540 Reactome R-HSA-68540 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68540.3 Reactome DB_ID: 68542 1 UniProt:Q99741 CDC6 CDC6 CDC18L CDC6 FUNCTION Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.SUBUNIT Interacts with PCNA, ORC1, cyclin-CDK (PubMed:9566895). Interacts with HUWE1 (PubMed:17567951). Interacts with ANKRD17 (PubMed:23711367). Interacts with GRWD1; origin binding of GRWD1 is dependent on CDC6 (PubMed:25990725). Interacts with CDT1; are mutually dependent on one another for loading MCM complexes onto chromatin (PubMed:14672932). Interacts with TTC4 (PubMed:18320024). Interacts (via Cy motif) with CCNF; the interaction takes place during G2 and M phase (PubMed:26818844). Interacts with CDH1 (PubMed:26818844).PTM Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex.SIMILARITY Belongs to the CDC6/cdc18 family. UniProt Q99741 1 EQUAL 560 EQUAL Reactome Database ID Release 82 68543 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68543 Reactome R-HSA-68543 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68543.1 Reactome Database ID Release 82 156562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156562 Reactome R-HSA-156562 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156562.1 Reactome DB_ID: 68403 1 UniProt:Q7L590 MCM10 MCM10 PRO2249 MCM10 FUNCTION Acts as a replication initiation factor that brings together the MCM2-7 helicase and the DNA polymerase alpha/primase complex in order to initiate DNA replication. Additionally, plays a role in preventing DNA damage during replication. Key effector of the RBBP6 and ZBTB38-mediated regulation of DNA-replication and common fragile sites stability; acts as a direct target of transcriptional repression by ZBTB38 (PubMed:24726359).SUBUNIT Self-associates (By similarity). Interacts with ORC2. May interact with MCM2 and MCM6. Interacts with the DNA polymerase alpha subunit POLA1. Interacts with RECQL4; this interaction regulates RECQL4 unwinding activity. Interacts with WDHD1.DEVELOPMENTAL STAGE Expression is cell cycle regulated. Expression increases at the G1/S-boundary. Expression decreases in late M phase, remains low during G(1) phase, and starts to accumulate at the onset of S phase.DOMAIN Each zinc finger-like domain binds a zinc ion and is involved in both ssDNA and dsDNA binding, as is the OB-fold domain.DOMAIN The N-terminal domain mediates homodimerization.SIMILARITY Belongs to the MCM10 family. UniProt Q7L590 1 EQUAL 875 EQUAL Reactome Database ID Release 82 156564 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156564 Reactome R-HSA-156564 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156564.2 Reactome Database ID Release 82 68561 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68561 Reactome R-HSA-68561 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68561.2 Reactome Database ID Release 82 68564 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68564 Reactome R-HSA-68564 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68564.2 Reactome DB_ID: 176282 1 UniProt:Q9HAW4 CLSPN CLSPN CLSPN FUNCTION Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation. Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins. Can also bind specifically to branched DNA structures and may associate with S-phase chromatin following formation of the pre-replication complex (pre-RC). This may indicate a role for this protein as a sensor which monitors the integrity of DNA replication forks.SUBUNIT Interacts (phosphorylation-dependent) with CHEK1; regulates CLSPN function in checkpoint for DNA damage and replication. Interacts with ATR and RAD9A and these interactions are slightly reduced during checkpoint activation. Interacts with BRCA1 and this interaction increases during checkpoint activation. Interacts with TIMELESS.INDUCTION Expression peaks at S/G2 phases of the cell cycle.DOMAIN The C-terminus of the protein contains 3 potential CHEK1-binding motifs (CKB motifs). Potential phosphorylation sites within CKB motif 1 and CKB motif 2 are required for interaction with CHEK1.PTM Phosphorylated. Undergoes ATR-dependent phosphorylation by CHEK1 during activation of DNA replication or damage checkpoints. Phosphorylation by CSNK1G1/CK1 promotes CHEK1 binding.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) during G1 phase, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Following DNA damage, it is deubiquitinated by USP28 in G2 phase, preventing its degradation.SIMILARITY Belongs to the claspin family. UniProt Q9HAW4 1 EQUAL 1339 EQUAL Reactome DB_ID: 176229 1 Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complex [nucleoplasm] Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complex claspin bound to DNA replication fork Reactome DB_ID: 68564 1 Reactome DB_ID: 176282 1 1 EQUAL 1339 EQUAL Reactome Database ID Release 82 176229 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176229 Reactome R-HSA-176229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176229.1 Reactome Database ID Release 82 176318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176318 Reactome R-HSA-176318 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176318.2 12620222 Pubmed 2003 Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17 Lee, J Kumagai, A Dunphy, WG Mol Cell 11:329-40 12545175 Pubmed 2003 Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1 Kumagai, A Dunphy, WG Nat Cell Biol 5:161-5 16148040 Pubmed 2005 Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response Lee, J Gold, DA Shevchenko, Anna Shevchenko, Andrej Dunphy, WG Mol Biol Cell 16:5269-82 15279790 Pubmed 2004 Claspin, a regulator of Chk1 in DNA replication stress pathway Chini, CC Chen, J DNA Repair (Amst) 3:1033-7 15226314 Pubmed 2004 Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures Sar, F Lindsey-Boltz, LA Subramanian, D Croteau, DL Hutsell, SQ Griffith, JD Sancar, A J Biol Chem 279:39289-95 2.7.11.1 Activation of claspin Activation of claspin Claspin is a replication fork-associated protein important for Chk1 activation. Claspin loads onto the fork during replication origin firing and travels with the fork during DNA synthesis. Upon fork uncoupling and ATR-ATRIP binding to persistent ssDNA, the activated ATR kinase phosphorylates claspin at two primary sites. Modification increases the affinity of claspin for Chk1. Studies of human or Xenopus claspin indicate that phosphorylation of both sites is essential for significant claspin-Chk1 association. Following claspin modification by ATR, Chk1 can be transiently recruited to the stalled replication fork for subsequent phosphorylation and activation by ATR. Activation of Chk1 allows modification of additional downstream targets, thus amplifying the checkpoint signal. While much of the mechanistic information concerning claspin action has been obtained using Xenopus laevis egg extracts and Xenopus claspin, factors with similar activity have been found in various eukaryotic species including S. cerevisiae (MRC1), S. pombe (mrc1), and humans.<p>Activated ATR phosphorylates human claspin on two sites, threonine 916 and serine 945. Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Reactome DB_ID: 176229 1 Reactome DB_ID: 29358 2 Reactome DB_ID: 113582 2 Reactome DB_ID: 176182 1 Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complex [nucleoplasm] Cdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complex Activated claspin bound to DNA replication fork Reactome DB_ID: 68564 1 Reactome DB_ID: 176296 1 O-phospho-L-serine at 945 945 EQUAL O-phospho-L-threonine at 916 916 EQUAL 1 EQUAL 1339 EQUAL Reactome Database ID Release 82 176182 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176182 Reactome R-HSA-176182 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176182.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 176269 Reactome Database ID Release 82 176298 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176298 Reactome R-HSA-176298 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176298.2 15707391 Pubmed 2005 DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system Clarke, CA Clarke, PR Biochem J 388:705-12 2.7.11.1 Phosphorylation of Cdc25A at Ser-123 by Chk1 Phosphorylation of Cdc25A at Ser-123 by Chk1 Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk1, inhibiting Cdc25A. Reactome DB_ID: 143487 1 UniProt:P30304 CDC25A CDC25A CDC25A FUNCTION Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro.ACTIVITY REGULATION Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation.SUBUNIT Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage. Interacts with PIM1. Interacts with CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495).DOMAIN The phosphodegron motif mediates interaction with specific F-box proteins when phosphorylated. Putative phosphorylation sites at Ser-79 and Ser-82 appear to be essential for this interaction.PTM Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-293 and Thr-507 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 may also promote ubiquitin-dependent proteolysis of CDC25A by the SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11. Phosphorylation by NEK11 is required for BTRC-mediated polyubiquitination and degradation. Phosphorylation by PIM1 leads to an increase in phosphatase activity. Phosphorylated by PLK3 following DNA damage, leading to promote its ubiquitination and degradation.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase leading to its degradation by the proteasome. Ubiquitinated by a SCF complex containing BTRC and FBXW11 during S phase leading to its degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads to its stabilization.SIMILARITY Belongs to the MPI phosphatase family. UniProt P30304 1 EQUAL 524 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 143488 1 O-phospho-L-serine at 123 123 EQUAL 1 EQUAL 524 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 113838 O-phospho-L-serine at 317 317 EQUAL O-phospho-L-serine at 345 345 EQUAL 1 EQUAL 476 EQUAL Reactome Database ID Release 82 69604 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69604 Reactome R-HSA-69604 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69604.3 12399544 Pubmed 2002 Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Zhao, H Watkins, JL Piwnica-Worms, H Proc Natl Acad Sci U S A 99:14795-800 2.7.11.1 Phosphorylation of Cdc25C at Ser 216 by Chk1 Phosphorylation of Cdc25C at Ser 216 by Chk1 Phosphorylation of Cdc25C at Ser 216 results in both the inhibition of Cdc25C phosphatase activity and the creation of a 14-3-3 docking site (Peng et al. 1997). Authored: Matthews, L, 2003-08-05 01:10:00 Edited: Matthews, L, 2006-07-10 19:19:59 Reactome DB_ID: 69741 1 1 EQUAL 473 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 113582 1 Reactome DB_ID: 156496 1 O-phospho-L-serine at 216 216 EQUAL 1 EQUAL 473 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 113838 O-phospho-L-serine at 317 317 EQUAL O-phospho-L-serine at 345 345 EQUAL 1 EQUAL 476 EQUAL Reactome Database ID Release 82 75010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75010 Reactome R-HSA-75010 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75010.4 Reactome Database ID Release 82 176187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176187 Reactome R-HSA-176187 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176187.2 16314342 Pubmed 2005 DNA damage checkpoints in mammals Niida, H Nakanishi, M Mutagenesis 15530773 Pubmed 2004 The DNA damage response: sensing and signaling McGowan, CH Russell, P Curr Opin Cell Biol 16:629-33 GTSE1 binds TP53 GTSE1 binds TP53 Since MDM2-mediated ubiquitination of TP53 promotes translocation of TP53 to the cytosol, and since GTSE1-facilitated translocation of TP53 to the cytosol depends on the functional MDM2 (with no reported interaction between GTSE1 and MDM2) (Monte et al. 2004), it is plausible that GTSE1 binds to TP53 polyubiquitinated by MDM2. The interaction between TP53 and GTSE1 involves the C-terminal regulatory domain of TP53 and the C-terminus of GTSE1 (Monte et al. 2003). Authored: Orlic-Milacic, Marija, 2016-01-15 Reviewed: Bird, Alexander W, 2016-01-22 Edited: Orlic-Milacic, Marija, 2016-01-15 Reactome DB_ID: 8852332 1 UniProt:Q9NYZ3 GTSE1 GTSE1 GTSE1 FUNCTION May be involved in p53-induced cell cycle arrest in G2/M phase by interfering with microtubule rearrangements that are required to enter mitosis. Overexpression delays G2/M phase progression.DEVELOPMENTAL STAGE Expressed in G2/M phase. Not detected in quiescent cells.PTM Phosphorylated in mitosis. UniProt Q9NYZ3 O-phospho-L-serine at 435 435 EQUAL 1 EQUAL 720 EQUAL Reactome DB_ID: 3209186 1 PolyUb-TP53 Tetramer [nucleoplasm] PolyUb-TP53 Tetramer Reactome DB_ID: 6793679 4 ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position 1 EQUAL 393 EQUAL Reactome Database ID Release 82 3209186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3209186 Reactome R-HSA-3209186 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3209186.2 Reactome DB_ID: 8852344 1 p-S435-GTSE1:PolyUb-TP53 Tetramer [nucleoplasm] p-S435-GTSE1:PolyUb-TP53 Tetramer Reactome DB_ID: 8852332 1 O-phospho-L-serine at 435 435 EQUAL 1 EQUAL 720 EQUAL Reactome DB_ID: 3209186 1 Reactome Database ID Release 82 8852344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852344 Reactome R-HSA-8852344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852344.1 Reactome Database ID Release 82 8852337 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852337 Reactome R-HSA-8852337 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852337.1 12750368 Pubmed 2003 The cell cycle-regulated protein human GTSE-1 controls DNA damage-induced apoptosis by affecting p53 function Monte, Martin Benetti, Roberta Buscemi, Giacomo Sandy, Peter Del Sal, Giannino Schneider, C J. Biol. Chem. 278:30356-64 14707141 Pubmed 2004 hGTSE-1 expression stimulates cytoplasmic localization of p53 Monte, Martin Benetti, Roberta Collavin, Licio Marchionni, Luigi Del Sal, Giannino Schneider, C J. Biol. Chem. 279:11744-52 GTSE1 promotes translocation of TP53 to the cytosol GTSE1 promotes translocation of TP53 to the cytosol Binding of GTSE1 to TP53 (p53) in the nucleus promotes translocation of TP53 to the cytosol. This process is dependent on the nuclear export signal (NES) of GTSE1 (Monte et al. 2004). Authored: Orlic-Milacic, Marija, 2016-01-15 Reviewed: Bird, Alexander W, 2016-01-22 Edited: Orlic-Milacic, Marija, 2016-01-15 Reactome DB_ID: 8852344 1 Reactome DB_ID: 8852349 1 p-S435-GTSE1:PolyUb-TP53 Tetramer [cytosol] p-S435-GTSE1:PolyUb-TP53 Tetramer Reactome DB_ID: 8852348 1 PolyUb-TP53 Tetramer [cytosol] PolyUb-TP53 Tetramer Reactome DB_ID: 6793681 4 ubiquitinylated lysine (PolyUb [nucleoplasm]) at unknown position 1 EQUAL 393 EQUAL Reactome Database ID Release 82 8852348 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852348 Reactome R-HSA-8852348 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852348.1 Reactome DB_ID: 8852316 1 O-phospho-L-serine at 435 435 EQUAL 1 EQUAL 720 EQUAL Reactome Database ID Release 82 8852349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852349 Reactome R-HSA-8852349 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852349.1 Reactome Database ID Release 82 8852351 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852351 Reactome R-HSA-8852351 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852351.1 GO 0046827 GO biological process GTSE1 facilitates proteasome-mediated degradation of TP53 GTSE1 facilitates proteasome-mediated degradation of TP53 GTSE1 promotes down-regulation of TP53 in a proteasome-dependent way. Nuclear export of TP53 facilitated by GTSE1 and MDM2likely makes ubiquitinated TP53 available to the proteasome machinery. GTSE1-mediated decrease of TP53 levels is needed for the G2 checkpoint recovery (cell cycle re-entry after DNA damage induced G2 arrest) and rescues cells from DNA damage induced apoptosis during S/G2 phase (Monte et al. 2003, Monte et al. 2004). Authored: Orlic-Milacic, Marija, 2016-01-15 Reviewed: Bird, Alexander W, 2016-01-22 Edited: Orlic-Milacic, Marija, 2016-01-15 Reactome DB_ID: 8852349 1 Reactome DB_ID: 8852316 1 O-phospho-L-serine at 435 435 EQUAL 1 EQUAL 720 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBB(1-76) [cytosol] UBC(457-532) [cytosol] UBC(153-228) [cytosol] UBA52(1-76) [cytosol] UBC(609-684) [cytosol] UBC(381-456) [cytosol] UBC(305-380) [cytosol] UBB(77-152) [cytosol] UBC(77-152) [cytosol] UBC(229-304) [cytosol] UBC(533-608) [cytosol] UBB(153-228) [cytosol] RPS27A(1-76) [cytosol] UBC(1-76) [cytosol] UniProt P0CG47 UniProt P0CG48 UniProt P62987 UniProt P62979 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 68819 26S proteasome [cytosol] 26S proteasome Reactome DB_ID: 68792 1 UniProt:O00232 PSMD12 PSMD12 PSMD12 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family. UniProt O00232 2 EQUAL 456 EQUAL Reactome DB_ID: 68818 1 UniProt:Q92530 PSMF1 PSMF1 PSMF1 FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family. UniProt Q92530 1 EQUAL 271 EQUAL Reactome DB_ID: 68812 1 UniProt:Q06323 PSME1 PSME1 PSME1 IFI5111 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q06323 1 EQUAL 249 EQUAL Reactome DB_ID: 68756 1 UniProt:P28072 PSMB6 PSMB6 PSMB6 LMPY Y FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P28072 35 EQUAL 239 EQUAL Reactome DB_ID: 68750 1 UniProt:P28070 PSMB4 PSMB4 PSMB4 PROS26 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:9344905, PubMed:34711951). Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome (PubMed:11571290, PubMed:12097147). Interacts with PRPF19 (PubMed:15660529).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result. UniProt P28070 46 EQUAL 264 EQUAL Reactome DB_ID: 947607 1 UniProt:A5LHX3 PSMB11 PSMB11 PSMB11 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family. UniProt A5LHX3 50 EQUAL 300 EQUAL Reactome DB_ID: 68732 1 UniProt:P28066 PSMA5 PSMA5 PSMA5 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family. UniProt P28066 1 EQUAL 241 EQUAL Reactome DB_ID: 68759 1 UniProt:Q99436 PSMB7 PSMB7 PSMB7 Z FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family. UniProt Q99436 44 EQUAL 277 EQUAL Reactome DB_ID: 68790 1 UniProt:O00231 PSMD11 PSMD11 PSMD11 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family. UniProt O00231 2 EQUAL 422 EQUAL Reactome DB_ID: 68753 1 UniProt:P28074 PSMB5 PSMB5 PSMB5 X LMPX MB1 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:8163024, PubMed:34711951). Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family. UniProt P28074 60 EQUAL 263 EQUAL Reactome DB_ID: 68788 1 UniProt:O75832 PSMD10 PSMD10 PSMD10 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt O75832 1 EQUAL 226 EQUAL Reactome DB_ID: 68780 1 UniProt:P62195 PSMC5 PSMC5 PSMC5 SUG1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family. UniProt P62195 2 EQUAL 406 EQUAL Reactome DB_ID: 68768 1 UniProt:P62191 PSMC1 PSMC1 PSMC1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family. UniProt P62191 2 EQUAL 440 EQUAL Reactome DB_ID: 68777 1 UniProt:P43686 PSMC4 PSMC4 TBP7 PSMC4 MIP224 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family. UniProt P43686 1 EQUAL 418 EQUAL Reactome DB_ID: 68804 1 UniProt:Q15008 PSMD6 PSMD6 PSMD6 KIAA0107 PFAAP4 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family. UniProt Q15008 1 EQUAL 389 EQUAL Reactome DB_ID: 68765 1 UniProt:P28065 PSMB9 PSMB9 LMP2 PSMB6i RING12 PSMB9 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family. UniProt P28065 21 EQUAL 219 EQUAL Reactome DB_ID: 68774 1 UniProt:P17980 PSMC3 PSMC3 PSMC3 TBP1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family. UniProt P17980 1 EQUAL 439 EQUAL Reactome DB_ID: 68796 1 UniProt:Q13200 PSMD2 PSMD2 TRAP2 PSMD2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family. UniProt Q13200 1 EQUAL 908 EQUAL Reactome DB_ID: 68728 1 UniProt:P25788 PSMA3 PSMA3 PSMA3 HC8 PSC8 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:26657688, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with AURKB (PubMed:14674694). Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family. UniProt P25788 2 EQUAL 255 EQUAL Reactome DB_ID: 68810 1 UniProt:O00233 PSMD9 PSMD9 PSMD9 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome. UniProt O00233 1 EQUAL 223 EQUAL Reactome DB_ID: 68794 1 UniProt:Q9UNM6 PSMD13 PSMD13 PSMD13 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family. UniProt Q9UNM6 1 EQUAL 376 EQUAL Reactome DB_ID: 68816 1 UniProt:P61289 PSME3 PSME3 PSME3 FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family. UniProt P61289 2 EQUAL 254 EQUAL Reactome DB_ID: 68802 1 UniProt:Q16401 PSMD5 PSMD5 PSMD5 KIAA0072 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt Q16401 2 EQUAL 504 EQUAL Reactome DB_ID: 68814 1 UniProt:Q9UL46 PSME2 PSME2 PSME2 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q9UL46 2 EQUAL 239 EQUAL Reactome DB_ID: 947606 1 UniProt:Q14997 PSME4 PSME4 PSME4 KIAA0077 FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family. UniProt Q14997 1 EQUAL 1843 EQUAL Reactome DB_ID: 68738 1 UniProt:P20618 PSMB1 PSMB1 PSC5 PSMB1 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with SERPINB2 (PubMed:14732874). Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family. UniProt P20618 29 EQUAL 241 EQUAL Reactome DB_ID: 68771 1 UniProt:P35998 PSMC2 PSMC2 MSS1 PSMC2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775, PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase (PubMed:9295362, PubMed:10409732). Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.PTM Monoubiquitinated by RNF181.SIMILARITY Belongs to the AAA ATPase family. UniProt P35998 2 EQUAL 433 EQUAL Reactome DB_ID: 68736 1 UniProt:O14818 PSMA7 PSMA7 PSMA7 HSPC FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A (PubMed:11389899). Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family. UniProt O14818 1 EQUAL 248 EQUAL Reactome DB_ID: 68724 1 UniProt:P25786 PSMA1 PSMA1 PSMA1 HC2 NU PSC2 PROS30 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187). Interacts with NOTCH3 (PubMed:17292860). Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family. UniProt P25786 1 EQUAL 263 EQUAL Reactome DB_ID: 68741 1 UniProt:P40306 PSMB10 PSMB10 LMP10 MECL1 PSMB10 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P40306 40 EQUAL 273 EQUAL Reactome DB_ID: 68747 1 UniProt:P49720 PSMB3 PSMB3 PSMB3 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family. UniProt P49720 2 EQUAL 205 EQUAL Reactome DB_ID: 947610 1 UniProt:Q8TAA3 PSMA8 PSMA8 PSMA7L PSMA8 FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complex that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.SIMILARITY Belongs to the peptidase T1A family. UniProt Q8TAA3 1 EQUAL 256 EQUAL Reactome DB_ID: 68800 1 UniProt:P55036 PSMD4 PSMD4 MCB1 PSMD4 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family. UniProt P55036 1 EQUAL 377 EQUAL Reactome DB_ID: 68806 1 UniProt:P51665 PSMD7 PSMD7 MOV34L PSMD7 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family. UniProt P51665 1 EQUAL 324 EQUAL Reactome DB_ID: 68808 1 UniProt:P48556 PSMD8 PSMD8 PSMD8 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator. UniProt P48556 1 EQUAL 350 EQUAL Reactome DB_ID: 68783 1 UniProt:P62333 PSMC6 PSMC6 PSMC6 SUG2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924. UniProt P62333 1 EQUAL 389 EQUAL Reactome DB_ID: 68722 1 UniProt:O00487 PSMD14 PSMD14 PSMD14 POH1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily. UniProt O00487 1 EQUAL 310 EQUAL Reactome DB_ID: 68786 1 UniProt:Q99460 PSMD1 PSMD1 PSMD1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family. UniProt Q99460 1 EQUAL 953 EQUAL Reactome DB_ID: 68730 1 UniProt:P25789 PSMA4 PSMA4 PSMA4 PSC9 HC9 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family. UniProt P25789 1 EQUAL 261 EQUAL Reactome DB_ID: 68726 1 UniProt:P25787 PSMA2 PSMA2 PSMA2 PSC3 HC3 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P25787 2 EQUAL 234 EQUAL Reactome DB_ID: 68734 1 UniProt:P60900 PSMA6 PSMA6 PSMA6 PROS27 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7 (PubMed:25599644, PubMed:26133119, PubMed:27342858, PubMed:27428775, PubMed:27493187, PubMed:34711951). Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family. UniProt P60900 1 EQUAL 246 EQUAL Reactome DB_ID: 68744 1 UniProt:P49721 PSMB2 PSMB2 PSMB2 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P49721 1 EQUAL 201 EQUAL Reactome DB_ID: 68762 1 UniProt:P28062 PSMB8 PSMB8 PSMB5i RING10 Y2 LMP7 PSMB8 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P28062 73 EQUAL 276 EQUAL Reactome DB_ID: 68798 1 UniProt:O43242 PSMD3 PSMD3 PSMD3 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family. UniProt O43242 1 EQUAL 534 EQUAL Reactome DB_ID: 8866674 1 UniProt:P60896 SEM1 SEM1 SEM1 C7orf76 SHFDG1 SHFM1 DSS1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family. UniProt P60896 1 EQUAL 70 EQUAL Reactome Database ID Release 82 68819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68819 Reactome R-HSA-68819 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68819.2 GO 0004175 GO molecular function Reactome Database ID Release 82 68824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68824 Reactome Database ID Release 82 8852354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852354 Reactome R-HSA-8852354 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852354.2 GO 0043161 GO biological process Reactome Database ID Release 82 69481 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69481 Reactome R-HSA-69481 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69481.3