BioPAX pathway converted from "ERCC1:XPF cleaves flaps generated by SSA" in the Reactome database.LEFT-TO-RIGHTERCC1:XPF cleaves flaps generated by SSAThe endonuclease complex ERCC1:XPF (ERCC1:ERCC4) is recruited to single strand annealing (SSA) sites of DNA double strand break (DSB) repair through direct interaction between XPF (ERCC4) and RAD52 (Motycka et al. 2004). ERCC1:XPF cleaves the ssDNA flaps generated by displacement of non-complementary 3' parts of 3' ssDNA overhangs during RAD52-mediated annealing. The enzymatic activity of ERCC1:XPF is necessary for the completion of SSA (Motycka et al. 2004, Al-Minawi et al. 2008, Ahmad et al. 2008).Authored: Orlic-Milacic, Marija, 2015-05-12Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12RAD51:p-Y104-RAD52:p-RPA:ATR:ATRIP:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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:TOPBP1Reactome DB_ID: 5686613nucleoplasmGENE ONTOLOGYGO:0005654RAD51DNA repair protein RAD51 homolog 1 (hRAD51) (HsRAD51)DNA repair protein RAD51 homolog 1hRAD51HsRAD51Reactome DB_ID: 62637UniProt:Q06609 RAD51RAD51RAD51ARECAFUNCTION Plays an important role in homologous strand exchange, a key step in DNA repair through homologous recombination (HR) (PubMed:28575658). Binds to single and double-stranded DNA and exhibits DNA-dependent ATPase activity. Catalyzes the recognition of homology and strand exchange between homologous DNA partners to form a joint molecule between a processed DNA break and the repair template. Binds to single-stranded DNA in an ATP-dependent manner to form nucleoprotein filaments which are essential for the homology search and strand exchange (PubMed:26681308). Part of a PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is thought to play a role in DNA repair by HR. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51C and XRCC3. Also involved in interstrand cross-link repair (PubMed:26253028).SUBUNIT Forms linear homooligomers, giving rise to a RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. Interacts with BRCA1 and either directly or indirectly with p53. Interacts with XRCC3, RAD54L and RAD54B. Interacts with the BCDX2 subcomplex RAD51C:RAD51B. Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3. Interacts with RAD51AP1 and RAD51AP2. Interacts with CHEK1, and this may require prior phosphorylation of CHEK1. Interacts with the MND1-PSMC3IP heterodimer. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with SPIDR; the interaction is direct and recruits RAD51 to DNA damage sites. Interacts with FIGNL1 (via N-terminal one-half region); the interaction is direct. Interacts with RAD51AP1 (via C-terminal region); the interaction is direct. Interacts with NABP2, RPA1, PALB2 and RAD51. Interacts with SWI5/C9orf119, and at lower level with SFR1/MEIR5. Interacts with hyperphosphorylated RPA2; this interaction is necessary for efficient recruitment to chromatin in response to DNA damage. Interacts with SWSAP1; involved in homologous recombination repair. Interacts with PARPBP, BRCA2 and RECQL5; these interactions interfere with the formation of the RAD51-DNA homologous recombination structure. Interacts with POLQ; POLQ acts as an inhibitor of homology-recombination repair (HR) pathway by limiting RAD51 accumulation at resected ends (PubMed:25642963). Interacts with FBH1 (PubMed:23393192). Interacts with POLN (PubMed:19995904). Interacts with RFWD3 (PubMed:28575658). Interacts with the MCM8-MCM9 complex; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855).TISSUE SPECIFICITY Highly expressed in testis and thymus, followed by small intestine, placenta, colon, pancreas and ovary. Weakly expressed in breast.INDUCTION Stress-induced increase in the mitochondrial levels is seen.DOMAIN The nuclear localization may reside in the C-terminus (between 259 and 339 AA).PTM Ubiquitinated by the SCF(FBH1) E3 ubiquitin ligase complex, regulating RAD51 subcellular location and preventing its association with DNA. Ubiquitinated by RFWD3 in response to DNA damage: ubiquitination leads to degradation by the proteasome, promoting homologous recombination (PubMed:28575658).PTM Phosphorylated. Phosphorylation of Thr-309 by CHEK1 may enhance association with chromatin at sites of DNA damage and promote DNA repair by homologous recombination. Phosphorylation by ABL1 inhibits function.SIMILARITY Belongs to the RecA family. RAD51 subfamily.Homo sapiensNCBI Taxonomy9606UniProtQ066091EQUAL339EQUALReactome Database ID Release 7062637Database 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=62637ReactomeR-HSA-626371Reactome 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-62637.1Reactomehttp://www.reactome.org1p-Y104-RAD52:p-RPA:ATR:ATRIP:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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:TOPBP1Reactome DB_ID: 5686617p-Y104-RAD52 heptamerReactome DB_ID: 5686589p-Y104-RAD52Reactome DB_ID: 5686588UniProt:P43351 RAD52RAD52FUNCTION Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase.SUBUNIT The full-length protein forms heptameric rings. Interacts with ABL1. Interacts with RPA2; the interaction is direct and associates RAD52 with the RPA complex.PTM Phosphorylated upon DNA damage by ABL1, and probably by ATM or ATR.SIMILARITY Belongs to the RAD52 family.UniProtP43351104EQUALO4'-phospho-L-tyrosineMODMOD:000481EQUAL418EQUALReactome Database ID Release 705686588Database 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=5686588ReactomeR-HSA-56865881Reactome 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-5686588.17Reactome Database ID Release 705686589Database 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=5686589ReactomeR-HSA-56865891Reactome 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-5686589.11ATR:ATRIP:p-RPA:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps: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:TOPBP1Reactome DB_ID: 5686616Converted from EntitySet in ReactomeEXO1,DNA2:BLM,WRNReactome DB_ID: 5685980DNA2:BLM:TOP3A:RMI1:RMI2Reactome DB_ID: 5685974BTRR complexBLM:TOP3A:RMI1:RMI2Reactome DB_ID: 5685972RMI2RecQ-mediated genome instability protein 2BLAP18BLM-associated protein of 18 kDaReactome DB_ID: 5685951UniProt:Q96E14 RMI2RMI2C16orf75FUNCTION Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates. It is required to regulate sister chromatid segregation and to limit DNA crossover. Essential for the stability, localization, and function of BLM, TOP3A, and complexes containing BLM. In the RMI complex, it is required to target BLM to chromatin and stress-induced nuclear foci and mitotic phosphorylation of BLM.SUBUNIT Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM.PTM Phosphorylated during mitosis.DISEASE A homozygous deletion of RMI2 has been found in a family with a Bloom-like syndrome and is probable responsible for the phenotype. Patients manifest depigmented skin lesions, multiple cafe-au-lait macules, and growth deficiency. Cells from affected individuals show a high rate of sister chromatid exchange and increased chromosomal breaks.SIMILARITY Belongs to the RMI2 family.UniProtQ96E142EQUAL147EQUALReactome Database ID Release 705685951Database 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=5685951ReactomeR-HSA-56859511Reactome 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-5685951.11TOP3ADNA topoisomerase 3-alphaTOP3A_HUMANReactome DB_ID: 912452UniProt:Q13472 TOP3ATOP3ATOP3FUNCTION Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone. As an essential component of the RMI complex it is involved in chromosome separation and the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Has DNA decatenation activity (PubMed:30057030). It is required for mtDNA decatenation and segregation after completion of replication, in a process that does not require BLM, RMI1 and RMI2 (PubMed:29290614).SUBUNIT Binds ssDNA (PubMed:29290614). Interacts (via N-terminal region) with BLM; the interaction is direct. Directly interacts with RMI1. Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM.TISSUE SPECIFICITY High expression is found in testis, heart, skeletal muscle and pancreas.SIMILARITY Belongs to the type IA topoisomerase family.UniProtQ134721EQUAL1001EQUALReactome Database ID Release 70912452Database 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=912452ReactomeR-HSA-9124521Reactome 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-912452.11RMI1BLAP75RecQ-mediated genome instability protein 1BLM-associated protein of 75 kDaFAAP75Reactome DB_ID: 5685949UniProt:Q9H9A7 RMI1RMI1C9orf76FUNCTION Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates to limit DNA crossover formation in cells. Promotes TOP3A binding to double Holliday junctions (DHJ) and hence stimulates TOP3A-mediated dissolution. Required for BLM phosphorylation during mitosis. Within the BLM complex, required for BLM and TOP3A stability.SUBUNIT Component of the RMI complex, containing at least TOP3A, RMI1 and RMI2. The RMI complex interacts with BLM. Directly interacts with RMI2 and TOP3A. May bind DHJ. Interacts (via N-terminal region) with BLM; the interaction is direct.SIMILARITY Belongs to the RMI1 family.UniProtQ9H9A71EQUAL625EQUALReactome Database ID Release 705685949Database 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=5685949ReactomeR-HSA-56859491Reactome 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-5685949.11BLMReactome DB_ID: 174881UniProt:P54132 BLMBLMRECQ2RECQL3FUNCTION ATP-dependent DNA helicase that unwinds single- and double-stranded DNA in a 3'-5' direction (PubMed:9388193, PubMed:24816114, PubMed:25901030). Participates in DNA replication and repair (PubMed:12019152, PubMed:21325134, PubMed:23509288). Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA (PubMed:21325134). Negatively regulates sister chromatid exchange (SCE) (PubMed:25901030). Stimulates DNA 4-way junction branch migration and DNA Holliday junction dissolution (PubMed:25901030). Binds single-stranded DNA (ssDNA), forked duplex DNA and DNA Holliday junction (PubMed:20639533, PubMed:24257077, PubMed:25901030).SUBUNIT Monomer (PubMed:28228481). Homodimer (via N-terminus) (PubMed:28228481). Homotetramer (via N-terminus); dimer of dimers (PubMed:28228481). Homohexamer (via N-terminus) (PubMed:28228481). Self-association negatively regulates DNA unwinding amplitude and rate. Oligomeric complexes dissociate into monomer in presence of ATP (PubMed:28228481). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with ubiquitinated FANCD2. Interacts with RMI complex. Interacts directly with RMI1 (via N-terminal region) component of RMI complex. Interacts with SUPV3L1. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with TOP3A (via N-terminal region). Interacts with SPIDR (via C-terminal region); the interaction is direct and required to target BLM to sites of DNA damage.DOMAIN The N-terminal region mediates dimerization and homooligomerization (PubMed:28228481). Both the helicase ATP-binding domain and the helicase C-terminal domain form intramolecular interactions with the HRDC domain in a ATP-dependent manner (PubMed:25901030). The HRDC domain is required for single-stranded DNA (ssDNA) and DNA Holliday junction binding (PubMed:20639533).PTM Phosphorylated in response to DNA damage. Phosphorylation requires the FANCA-FANCC-FANCE-FANCF-FANCG protein complex, as well as the presence of RMI1.SIMILARITY Belongs to the helicase family. RecQ subfamily.UniProtP541321EQUAL1417EQUALReactome Database ID Release 70174881Database 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=174881ReactomeR-HSA-1748811Reactome 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-174881.11Reactome Database ID Release 705685972Database 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=5685972ReactomeR-HSA-56859721Reactome 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-5685972.11DNA2dna2 endonucleaseDNA2-like homologDNA replication helicase-like homolog Reactome DB_ID: 68465UniProt:P51530 DNA2DNA2DNA2LKIAA0083FUNCTION Key enzyme involved in DNA replication and DNA repair in nucleus and mitochondrion. Involved in Okazaki fragments processing by cleaving long flaps that escape FEN1: flaps that are longer than 27 nucleotides are coated by replication protein A complex (RPA), leading to recruit DNA2 which cleaves the flap until it is too short to bind RPA and becomes a substrate for FEN1. Also involved in 5'-end resection of DNA during double-strand break (DSB) repair: recruited by BLM and mediates the cleavage of 5'-ssDNA, while the 3'-ssDNA cleavage is prevented by the presence of RPA. Also involved in DNA replication checkpoint independently of Okazaki fragments processing. Possesses different enzymatic activities, such as single-stranded DNA (ssDNA)-dependent ATPase, 5'-3' helicase and endonuclease activities. While the ATPase and endonuclease activities are well-defined and play a key role in Okazaki fragments processing and DSB repair, the 5'-3' DNA helicase activity is subject to debate. According to various reports, the helicase activity is weak and its function remains largely unclear. Helicase activity may promote the motion of DNA2 on the flap, helping the nuclease function.SUBUNIT Interacts with BLM and WDHD1.PTM Acetylated by EP300, leading to stimulate the 5'-3' endonuclease, the 5'-3' helicase and DNA-dependent ATPase activities, possibly by increasing DNA substrate affinity.SIMILARITY Belongs to the DNA2/NAM7 helicase family.UniProtP515301EQUAL1060EQUALReactome Database ID Release 7068465Database 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=68465ReactomeR-HSA-684652Reactome 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-68465.21Reactome Database ID Release 705685974Database 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=5685974ReactomeR-HSA-56859741Reactome 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-5685974.1EXO1:BLM,WRNReactome DB_ID: 5685976EXO1Exonuclease 1EXO1_HUMANReactome DB_ID: 5357514UniProt:Q9UQ84 EXO1EXO1EXOIHEX1FUNCTION 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.SUBUNIT Interacts with the MLH1-PMS2 heterodimer via MLH1. Interacts with MSH3. Interacts with the MSH2-MSH6 heterodimer via MSH2, and this interaction may increase the processivity of the 5'->3' exonuclease activity. Interacts with PCNA, and this interaction may both stimulate the cryptic 3'->5' exonuclease activity and suppress the 5'->3' exonuclease activity. Interacts with WRN, and this interaction stimulates both the 5'->3' exonuclease activity and cleavage of 5'-overhanging flap structures. Interacts with RECQL/RECQ1, and this interaction stimulates cleavage of 5'-overhanging flap structures.TISSUE SPECIFICITY Highly expressed in bone marrow, testis and thymus. Expressed at lower levels in colon, lymph nodes, ovary, placenta, prostate, small intestine, spleen and stomach.DEVELOPMENTAL STAGE Highly expressed in fetal liver and at lower levels in fetal brain, heart, kidney, spleen and thymus.PTM Phosphorylated upon DNA damage and in response to agents stalling DNA replication, probably by ATM or ATR. Phosphorylation at Ser-454, Thr-621 and Ser-714 is induced upon DNA-damage caused by treatment with hydroxyurea (HU) but not upon IR treatment. The HU-induced EXO1 triple phosphorylation facilitates destabilisation/degradation of the protein.POLYMORPHISM Most naturally occurring variants in this protein are not associated with familial disposition to hereditary non-polyposis colorectal cancer (HNPCC) (PubMed:12517792). Furthermore, germline deletions involving this locus are not associated with clinically manifested colorectal tumors (PubMed:14623461).SIMILARITY Belongs to the XPG/RAD2 endonuclease family. EXO1 subfamily.UniProtQ9UQ841EQUAL846EQUALReactome Database ID Release 705357514Database 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=5357514ReactomeR-HSA-53575141Reactome 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-5357514.11Converted from EntitySet in ReactomeBLM,WRNReactome DB_ID: 5685968WRNWerner syndrome helicaseReactome DB_ID: 67387UniProt:Q14191 WRNWRNRECQ3RECQL2FUNCTION Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation.SUBUNIT Monomer, and homooligomer. May exist as homodimer, homotrimer, homotetramer and/or homohexamer. Homotetramer, or homohexamer, when bound to DNA. Interacts via its N-terminal domain with WRNIP1 (By similarity). Interacts with EXO1, PCNA and SUPV3L1. Interacts with PML (isoform PML-4).PTM Phosphorylated by PRKDC.SIMILARITY Belongs to the helicase family. RecQ subfamily.UniProtQ141911EQUAL1432EQUALReactome Database ID Release 7067387Database 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=67387ReactomeR-HSA-673871Reactome 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-67387.1Reactome Database ID Release 705685968Database 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=5685968ReactomeR-HSA-56859681Reactome 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-5685968.11Reactome Database ID Release 705685976Database 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=5685976ReactomeR-HSA-56859761Reactome 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-5685976.1DNA2:WRNReactome DB_ID: 568596911Reactome Database ID Release 705685969Database 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=5685969ReactomeR-HSA-56859691Reactome 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-5685969.1Reactome Database ID Release 705685980Database 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=5685980ReactomeR-HSA-56859801Reactome 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-5685980.11p-S990,Ac-K1249-BRIP1p-S990,Ac-K1249-FANCJp-S990,Ac-K1249-BACH1Reactome DB_ID: 5687710UniProt:Q9BX63 BRIP1BRIP1BACH1FANCJFUNCTION 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.UniProtQ9BX63990EQUALO-phospho-L-serineMODMOD:000461249EQUALN6-acetyl-L-lysineMODMOD:000641EQUAL1249EQUALReactome Database ID Release 705687710Database 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=5687710ReactomeR-HSA-56877101Reactome 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-5687710.11RAD17:RFCRad17-RFC complexReactome DB_ID: 176353RFC4RFC37Activator 1 37 kDa subunitReplication factor C 37 kDa subunitA1 37 kDa subunitRF-C 37 kDa subunitReactome DB_ID: 68429UniProt:P35249 RFC4RFC4FUNCTION 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.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.UniProtP352491EQUAL363EQUALReactome Database ID Release 7068429Database 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=68429ReactomeR-HSA-684292Reactome 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-68429.21RAD17Cell cycle checkpoint protein RAD17RAD17_HUMANReactome DB_ID: 3008665UniProt:O75943 RAD17RAD17R24LFUNCTION 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.UniProtO759431EQUAL681EQUALReactome Database ID Release 703008665Database 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=3008665ReactomeR-HSA-30086651Reactome 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-3008665.11RFC3RFC38Activator 1 38 kDa subunitReplication factor C 38 kDa subunitA1 38 kDa subunitRF-C 38 kDa subunitReplication factor C subunit 3Reactome DB_ID: 68431UniProt:P40938 RFC3RFC3FUNCTION 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.UniProtP409381EQUAL356EQUALReactome Database ID Release 7068431Database 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=68431ReactomeR-HSA-684312Reactome 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-68431.21RFC5RFC36Activator 1 36 kDa subunit (Replication factor C 36 kDa subunit) (A1 36 kDa subunit) (RF-C 36 kDa subunit) (RFC36)Activator 1 36 kDa subunitReplication factor C 36 kDa subunitA1 36 kDa subunitRF-C 36 kDa subunitReplication factor C subunit 5Reactome DB_ID: 68427UniProt:P40937 RFC5RFC5FUNCTION 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.UniProtP409371EQUAL340EQUALReactome Database ID Release 7068427Database 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=68427ReactomeR-HSA-684272Reactome 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-68427.21RFC2RFC40Activator 1 40 kDa subunitReplication factor C 40 kDa subunitA1 40 kDa subunitRF-C 40 kDa subunitReactome DB_ID: 68433UniProt:P35250 RFC2RFC2FUNCTION 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.UniProtP352501EQUAL354EQUALReactome Database ID Release 7068433Database 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=68433ReactomeR-HSA-684332Reactome 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-68433.21Reactome Database ID Release 70176353Database 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=176353ReactomeR-HSA-1763531Reactome 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-176353.119-1-1 complexRAD9:HUS1:RAD1Rad9-Hus1-Rad1 complexReactome DB_ID: 176312RAD1Reactome DB_ID: 176382UniProt:O60671 RAD1RAD1REC1FUNCTION 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'->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.UniProtO606711EQUAL282EQUALReactome Database ID Release 70176382Database 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=176382ReactomeR-HSA-1763821Reactome 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-176382.11Converted from EntitySet in ReactomeRAD9Reactome DB_ID: 176222RAD9AReactome DB_ID: 176372UniProt:Q99638 RAD9ARAD9AFUNCTION 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. RAD9A possesses 3'->5' double stranded DNA exonuclease activity. Its phosphorylation by PRKCD may be required for the formation of the 9-1-1 complex.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. RAD9A interacts with BCL2L1, FEN1, PRKCD, RAD9B, HUS1, RAD1, ABL1, RPA1, ATAD5 and RPA2. Interacts with DNAJC7 and RHNO1.PTM Constitutively phosphorylated on serine and threonine amino acids in absence of DNA damage. Hyperphosphorylated by PRKCD and ABL1 upon DNA damage. Its phosphorylation by PRKCD may be required for the formation of the 9-1-1 complex.SIMILARITY Belongs to the rad9 family.UniProtQ996381EQUAL391EQUALReactome Database ID Release 70176372Database 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=176372ReactomeR-HSA-1763721Reactome 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-176372.1RAD9BReactome DB_ID: 176325UniProt:Q6WBX8 RAD9BRAD9BSUBUNIT Interacts with HUS1, HUS1B, RAD1, RAD9A and RAD17.TISSUE SPECIFICITY Expressed in testis and skeletal muscle.SIMILARITY Belongs to the rad9 family.UniProtQ6WBX81EQUAL426EQUALReactome Database ID Release 70176325Database 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=176325ReactomeR-HSA-1763251Reactome 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-176325.1Reactome Database ID Release 70176222Database 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=176222ReactomeR-HSA-1762221Reactome 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-176222.11HUS1Reactome DB_ID: 176374UniProt:O60921 HUS1HUS1FUNCTION 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.UniProtO609211EQUAL280EQUALReactome Database ID Release 70176374Database 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=176374ReactomeR-HSA-1763741Reactome 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-176374.11Reactome Database ID Release 70176312Database 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=176312ReactomeR-HSA-1763121Reactome 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-176312.11RHNO1RHINORAD9, HUS1, RAD1-interacting nuclear orphan protein 1Reactome DB_ID: 5684880UniProt:Q9BSD3 RHNO1RHNO1C12orf32RHINOHKMT1188FUNCTION 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.UniProtQ9BSD31EQUAL238EQUALReactome Database ID Release 705684880Database 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=5684880ReactomeR-HSA-56848801Reactome 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-5684880.11ATR:ATRIP:p-RPA:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complexReactome DB_ID: 5686619ATR:ATRIPATR-ATRIPATM- and rad3-related (ATR)ATR-interacting protein (ATRIP)Reactome DB_ID: 176269ATRSerine/threonine-protein kinase ATRATR_HUMANReactome DB_ID: 912443UniProt:Q13535 ATRATRFRP1FUNCTION 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/H2AFX 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.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 Interacts with ATRIP; forming 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 BCR-ABL after genotoxic stress. Interacts with EEF1E1. This interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1.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.UniProtQ135351EQUAL2644EQUALReactome Database ID Release 70912443Database 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=912443ReactomeR-HSA-9124431Reactome 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-912443.11ATRIPATRIP monomerATR interacting proteinReactome DB_ID: 176231UniProt:Q8WXE1 ATRIPATRIPAGS1FUNCTION 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.UniProtQ8WXE11EQUAL791EQUALReactome Database ID Release 70176231Database 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=176231ReactomeR-HSA-1762311Reactome 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-176231.11Reactome Database ID Release 70176269Database 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=176269ReactomeR-HSA-1762691Reactome 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-176269.11p-RPA:DNA DSBs with annealed 3' ssDNA overhangs and displaced flaps:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complexReactome DB_ID: 5686615BRCA1-C complexp-S988,S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1:p-S327,T847,T859-RBBP8 homotetramerp-5S-BRCA1:p-2T-BARD1:p-S327,T847,T859-RBBP8 homotetramerReactome DB_ID: 5685656p-5S-BRCA1:p-2T-BARD1p-S988,S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1Reactome DB_ID: 5683809p-5S-BRCA1p-S988,S1387,S1423,S1524,S1547-BRCA1Reactome DB_ID: 5683800UniProt:P38398 BRCA1BRCA1RNF53FUNCTION E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator (PubMed:20160719).ACTIVITY REGULATION The E3 ubiquitin-protein ligase activity is inhibited by phosphorylation by AURKA. Activity is increased by phosphatase treatment.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with BARD1 (PubMed:11573085, PubMed:12890688, PubMed:14976165). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261748, PubMed:19261749, PubMed:20351172). Interacts (via the BRCT domains) with ABRAXAS1 (phosphorylated form); this is important for recruitment to sites of DNA damage (PubMed:17525340, PubMed:17643121, PubMed:17643122, PubMed:24316840, PubMed:26778126, PubMed:23269703). Can form a heterotetramer with two molecules of ABRAXAS1 (phosphorylated form) (PubMed:26778126). Component of the BRCA1-RBBP8 complex (PubMed:16101277). Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:16818604, PubMed:9811458). Associates with RNA polymerase II holoenzyme (PubMed:9662397). Interacts with SMC1A, NELFB, DCLRE1C, CLSPN (PubMed:11877377, PubMed:15096610, PubMed:15456891, PubMed:11739404). Interacts with CHEK1, CHEK2, BAP1, BRCC3, AURKA, UBXN1 and PCLAF (PubMed:10724175, PubMed:11836499, PubMed:14636569, PubMed:14990569, PubMed:20351172, PubMed:21673012). Interacts (via BRCT domains) with BRIP1 (phosphorylated form) (PubMed:11301010, PubMed:15133502, PubMed:21473589). Interacts with FANCD2 (ubiquitinated form) (PubMed:11239454). Interacts with H2AFX (phosphorylated on 'Ser-140') (PubMed:12419185). Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA (PubMed:12360400, PubMed:16326698, PubMed:16698035, PubMed:18452305). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Interacts directly with PALB2; the interaction is essential for its function in HRR (PubMed:19369211, PubMed:28319063). Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein (PubMed:19369211). Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1 (PubMed:11751867). Interacts (via the BRCT domains) with CCAR2 (via N-terminus); the interaction represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Interacts with EXD2 (PubMed:26807646). Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme (PubMed:9662397).TISSUE SPECIFICITY Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines.DOMAIN The BRCT domains recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of ABRAXAS1, recruits BRCA1 at DNA damage sites.DOMAIN The RING-type zinc finger domain interacts with BAP1.PTM Phosphorylation at Ser-308 by AURKA is required for normal cell cycle progression from G2 to mitosis. Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR. Phosphorylation at Ser-988 by CHEK2 regulates mitotic spindle assembly.PTM Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.POLYMORPHISM There is evidence that the presence of the rare form of Gln-356-Arg and Leu-871-Pro polymorphisms may be associated with an increased risk for developing ovarian cancer.UniProtP38398988EQUAL1387EQUAL1423EQUAL1524EQUAL1547EQUAL1EQUAL1863EQUALReactome Database ID Release 705683800Database 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=5683800ReactomeR-HSA-56838001Reactome 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-5683800.11p-T714,T734-BARD1Reactome DB_ID: 5659846UniProt:Q99728 BARD1BARD1FUNCTION E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homo- and heterodimer. Heterodimer (RING-type zinc finger) with BRCA1. Heterodimer (via ANK repeats and BRCT domains) with CSTF1/CSTF-50. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts with UBXN1.PTM Processed during apoptosis. The homodimer is more susceptible to proteolytic cleavage than the BARD1/BRCA1 heterodimer.CAUTION It is uncertain whether Met-1 or Met-26 is the initiator.UniProtQ99728714EQUALO-phospho-L-threonineMODMOD:00047734EQUAL1EQUAL777EQUALReactome Database ID Release 705659846Database 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=5659846ReactomeR-HSA-56598461Reactome 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-5659846.11Reactome Database ID Release 705683809Database 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=5683809ReactomeR-HSA-56838091Reactome 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-5683809.11p-S327,T847,T859-RBBP8 homotetramerReactome DB_ID: 5684137p-S327,T847,T859-RBBP8Reactome DB_ID: 5684138UniProt:Q99708 RBBP8RBBP8CTIPFUNCTION 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. HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse. Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ). 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. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage (PubMed:10764811, PubMed:10910365, PubMed:15485915, PubMed:16581787, PubMed:16818604, PubMed:17965729, PubMed:19202191, PubMed:19759395, PubMed:20064462, PubMed:20829486). 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 SIRT6; the interaction deacetylates RBBP8 upon DNA damage (PubMed:20829486). 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:20829486, PubMed:23623683, PubMed:25349192, PubMed:26502057, PubMed:26807646, PubMed:27561354, PubMed:9535825, PubMed:9721205). Interacts with SAMHD1 (PubMed:28834754).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 Acetylated. Deacetylation by SIRT6 upon DNA damage promotes DNA end resection.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.UniProtQ99708327EQUAL847EQUAL859EQUAL1EQUAL897EQUALReactome Database ID Release 705684138Database 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=5684138ReactomeR-HSA-56841381Reactome 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-5684138.14Reactome Database ID Release 705684137Database 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=5684137ReactomeR-HSA-56841371Reactome 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-5684137.11Reactome Database ID Release 705685656Database 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=5685656ReactomeR-HSA-56856561Reactome 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-5685656.11DNA DSB with annealed 3' ssDNA overhangs and displaced flaps:p-MRN:p-S1981,Ac-K3016-ATM:KAT5Reactome DB_ID: 5686614p-S1981,Ac-K3016-ATMReactome DB_ID: 5693527UniProt:Q13315 ATMATMFUNCTION 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/H2AFX 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, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, 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). 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.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.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. Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase.PTM Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981. Acetylated in vitro by KAT5/TIP60.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.UniProtQ133151981EQUAL3016EQUAL1EQUAL3056EQUALReactome Database ID Release 705693527Database 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=5693527ReactomeR-HSA-56935271Reactome 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-5693527.11DNA DSB with annealed 3' ssDNA overhangs and displaced flaps:p-MRNReactome DB_ID: 5686620DNA DSB with annealed 3' overhanging ssDNA and flapsReactome DB_ID: 5686618Reactome Database ID Release 705686618Database 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=5686618ReactomeR-ALL-56866181Reactome 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-ALL-5686618.11p-MRNMRE11:RAD50:p-S343-NBNMRE11:RAD50:p-S343-NBS1Reactome DB_ID: 5682166RAD50Reactome DB_ID: 75160UniProt:Q92878 RAD50RAD50FUNCTION 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).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.UniProtQ928781EQUAL1312EQUALReactome Database ID Release 7075160Database 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=75160ReactomeR-HSA-751601Reactome 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-75160.11MRE11ADouble-strand break repair protein MRE11AMRE11 homolog 1Reactome DB_ID: 59544UniProt:P49959 MRE11MRE11HNGS1MRE11AFUNCTION 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).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.UniProtP499591EQUAL708EQUALReactome Database ID Release 7059544Database 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=59544ReactomeR-HSA-595441Reactome 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-59544.11p-S343-NBNphospho-NBS1Reactome DB_ID: 75237UniProt:O60934 NBNNBNNBSNBS1P95FUNCTION 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 H2AFX this requires phosphorylation of H2AFX 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).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.TISSUE SPECIFICITY Ubiquitous. Expressed at high levels in testis.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 H2AFX 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.UniProtO60934343EQUAL1EQUAL754EQUALReactome Database ID Release 7075237Database 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=75237ReactomeR-HSA-752371Reactome 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-75237.11Reactome Database ID Release 705682166Database 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=5682166ReactomeR-HSA-56821661Reactome 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-5682166.11Reactome Database ID Release 705686620Database 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=5686620ReactomeR-HSA-56866201Reactome 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-5686620.11KAT5Histone acetyltransferase KAT5KAT5_HUMANTip60Reactome DB_ID: 3321979UniProt:Q92993 KAT5KAT5HTATIPTIP60FUNCTION Catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:16387653, PubMed:19909775, PubMed:15196461). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:15196461). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:15196461). NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:15196461). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as ATM, NR1D2, RAN, FOXP3, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17360565, PubMed:17996965, PubMed:29040603, PubMed:30704899). Directly acetylates and activates ATM (PubMed:16141325). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Promotes FOXP3 acetylation and positively regulates its transcriptional repressor activity (PubMed:17360565). Acetylates RAN at 'Lys-134' (PubMed:29040603). 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).ACTIVITY REGULATION Acetyltransferase activity is promoted by phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B).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). HTATTIP/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC. 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 (By similarity). 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). Interacts with ZBTB49 (PubMed:25245946).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT.PTM (Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.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.PTM Ubiquitinated by MDM2, leading to its proteasome-dependent degradation.PTM Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase (PubMed:12468530). The phosphorylated form has a higher histone acetyltransferase activity (PubMed:12468530). Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase activity (PubMed:30704899). Phosphorylation at Ser-90 is a prerequisite for phosphorylation at Ser-86 by GSK3 (PubMed:30704899).PTM Autoacetylation at Lys-327 is required for proper function.SIMILARITY Belongs to the MYST (SAS/MOZ) family.UniProtQ929931EQUAL513EQUALReactome Database ID Release 703321979Database 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=3321979ReactomeR-HSA-33219791Reactome 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-3321979.11Reactome Database ID Release 705686614Database 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=5686614ReactomeR-HSA-56866141Reactome 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-5686614.11p-RPA heterotrimerReactome DB_ID: 5685169p-S33-RPA2Reactome DB_ID: 5685148UniProt:P15927 RPA2RPA2REPA2RPA32RPA34FUNCTION 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. Plays also 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.UniProtP1592733EQUAL1EQUAL270EQUALReactome Database ID Release 705685148Database 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=5685148ReactomeR-HSA-56851481Reactome 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-5685148.11RPA1DNA Replication factor A protein A1 (70kD)RPA70Replication protein A 70 kDa DNA-binding subunitRP-ARF-AReplication factor-A protein 1Single-stranded DNA-binding proteinReactome DB_ID: 68461UniProt:P27694 RPA1RPA1REPA1RPA70FUNCTION 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). Plays also 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 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 (PubMed:24126761). 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).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.UniProtP276942EQUAL616EQUALReactome Database ID Release 7068461Database 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=68461ReactomeR-HSA-684612Reactome 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-68461.21RPA3DNA Replication factor A protein 3 (14kD)RPA14Replication protein A 14 kDa subunitRP-ARF-AReplication factor-A protein 3Reactome DB_ID: 68459UniProt:P35244 RPA3RPA3REPA3RPA14FUNCTION 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). Plays also 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 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).UniProtP352441EQUAL121EQUALReactome Database ID Release 7068459Database 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=68459ReactomeR-HSA-684592Reactome 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-68459.21Reactome Database ID Release 705685169Database 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=5685169ReactomeR-HSA-56851692Reactome 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-5685169.21Reactome Database ID Release 705686615Database 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=5686615ReactomeR-HSA-56866151Reactome 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-5686615.11Reactome Database ID Release 705686619Database 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=5686619ReactomeR-HSA-56866191Reactome 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-5686619.11TOPBP1DNA topoisomerase 2-binding protein 1Reactome DB_ID: 5684878UniProt:Q92547 TOPBP1TOPBP1KIAA0259FUNCTION 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.UniProtQ925471EQUAL1522EQUALReactome Database ID Release 705684878Database 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=5684878ReactomeR-HSA-56848781Reactome 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-5684878.11Reactome Database ID Release 705686616Database 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=5686616ReactomeR-HSA-56866161Reactome 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-5686616.11Reactome Database ID Release 705686617Database 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=5686617ReactomeR-HSA-56866171Reactome 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-5686617.11Reactome Database ID Release 705686613Database 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=5686613ReactomeR-HSA-56866131Reactome 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-5686613.1SSB-dsDNA with inter-SSA deletionReactome DB_ID: 5686662Reactome Database ID Release 705686662Database 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=5686662ReactomeR-ALL-56866621Reactome 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-ALL-5686662.1FlapReactome DB_ID: 68454Reactome Database ID Release 7068454Database 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=68454ReactomeR-ALL-684541Reactome 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-ALL-68454.12ACTIVATIONERCC1:ERCC4ERCC1:XPF complexReactome DB_ID: 109943ERCC1ERCC1, DNA excision repair proteinDNA excision repair protein ERCC-1Reactome DB_ID: 54427UniProt:P07992 ERCC1ERCC1FUNCTION Isoform 1: Non-catalytic component of a structure-specific DNA repair endonuclease responsible for the 5'-incision during DNA repair. Responsible, in conjunction with SLX4, for the first step in the repair of interstrand cross-links (ICL). Participates in the processing of anaphase bridge-generating DNA structures, which consist in incompletely processed DNA lesions arising during S or G2 phase, and can result in cytokinesis failure. Also required for homology-directed repair (HDR) of DNA double-strand breaks, in conjunction with SLX4.SUBUNIT Heterodimer composed of ERCC1 isoform 1 and XPF/ERRC4.SIMILARITY Belongs to the ERCC1/RAD10/SWI10 family.UniProtP079921EQUAL297EQUALReactome Database ID Release 7054427Database 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=54427ReactomeR-HSA-544271Reactome 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-54427.11ERCC4XPF proteinDNA-repair protein complementing XP-F cell (Xeroderma pigmentosum group F complementing protein) (DNA excision repair protein ERCC-4)DNA-repair protein complementing XP-F cellXeroderma pigmentosum group F complementing proteinDNA excision repair protein ERCC-4Reactome DB_ID: 67445UniProt:Q92889 ERCC4ERCC4ERCC11XPFFUNCTION Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair. Involved in homologous recombination that assists in removing interstrand cross-link.SUBUNIT Heterodimer composed of ERCC1 and XPF/ERCC4. Interacts with SLX4/BTBD12; this interaction is direct and links the ERCC1-XPF/ERCC1 complex to SLX4, which may coordinate the action of the structure-specific endonuclease during DNA repair.SIMILARITY Belongs to the XPF family.UniProtQ928891EQUAL916EQUALReactome Database ID Release 7067445Database 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=67445ReactomeR-HSA-674451Reactome 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-67445.11Reactome Database ID Release 70109943Database 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=109943ReactomeR-HSA-1099432Reactome 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-109943.2GENE ONTOLOGYGO:0004520gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 705686658Database 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=5686658Reactome Database ID Release 705686657Database 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=5686657ReactomeR-HSA-56866571Reactome 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-5686657.118541667Pubmed2008ERCC1-XPF endonuclease facilitates DNA double-strand break repairAhmad, AnwaarRobinson, Andria RasileDuensing, Anettevan Drunen, EllenBeverloo, H BernaWeisberg, David BHasty, PaulHoeijmakers, Jan H JNiedernhofer, Laura JMol. Cell. Biol. 28:5082-9217962301Pubmed2008The ERCC1/XPF endonuclease is required for efficient single-strand annealing and gene conversion in mammalian cellsAl-Minawi, Ali ZSaleh-Gohari, NasrollahHelleday, ThomasNucleic Acids Res. 36:1-914734547Pubmed2004Physical and functional interaction between the XPF/ERCC1 endonuclease and hRad52Motycka, Teresa ABessho, TadayoshiPost, Sean MSung, PTomkinson, Alan EJ. Biol. Chem. 279:13634-9