BioPAX pathway converted from "Activation of ATR in response to replication stress" in the Reactome database.Activation of ATR in response to replication stressGenotoxic stress caused by DNA damage or stalled replication forks can lead to genomic instability. To guard against such instability, genotoxically-stressed cells activate checkpoint factors that halt or slow cell cycle progression. Among the pathways affected are DNA replication by reduction of replication origin firing, and mitosis by inhibiting activation of cyclin-dependent kinases (Cdks). A key factor involved in the response to stalled replication forks is the ATM- and rad3-related (ATR) kinase, a member of the phosphoinositide-3-kinase-related kinase (PIKK) family. Rather than responding to particular lesions in DNA, ATR and its binding partner ATRIP (ATR-interacting protein) sense replication fork stalling indirectly by associating with persistent ssDNA bound by RPA. These structures would be formed, for example, by dissociation of the replicative helicase from the leading or lagging strand DNA polymerase when the polymerase encounters a DNA lesion that blocks DNA synthesis. Along with phosphorylating the downstream transducer kinase Chk1 and the tumor suppressor p53, activated ATR modifies numerous factors that regulate cell cycle progression or the repair of DNA damage. The persistent ssDNA also stimulates recruitment of the RFC-like Rad17-Rfc2-5 alternative clamp-loading complex, which subsequently loads the Rad9-Hus1-Rad1 complex onto the DNA. The latter '9-1-1' complex serves to facilitate Chk1 binding to the stalled replication fork, where Chk1 is phosphorylated by ATR and thereby activated. Upon activation, Chk1 can phosphorylate additional substrates including the Cdc25 family of phosphatases (Cdc25A, Cdc25B, and Cdc25C). These enzymes catalyze the removal of inhibitory phosphate residues from cyclin-dependent kinases (Cdks), allowing their activation. In particular, Cdc25A primarily functions at the G1/S transition to dephosphorylate Cdk2 at Thr 14 and Tyr 15, thus positively regulating the Cdk2-cyclin E complex for S-phase entry. Cdc25A also has mitotic functions. Phosphorylation of Cdc25A at Ser125 by Chk1 leads to Cdc25A ubiquitination and degradation, thus inhibiting DNA replication origin firing. In contrast, Cdc25B and Cdc25C regulate the onset of mitosis through dephosphorylation and activation of Cdk1-cyclin B complexes. In response to replication stress, Chk1 phosphorylates Cdc25B and Cdc25C leading to Cdc25B/C complex formation with 14-3-3 proteins. As these complexes are sequestered in the cytoplasm, they are unable to activate the nuclear Cdk1-cyclin B complex for mitotic entry.<p>These events are outlined in the figure. Persistent single-stranded DNA associated with RPA binds claspin (A) and ATR:ATRIP (B), leading to claspin phosphorylation (C). In parallel, the same single-stranded DNA:RPA complex binds RAD17:RFC (D), enabling the loading of RAD9:HUS1:RAD1 (9-1-1) complex onto the DNA (E). The resulting complex of proteins can then repeatedly bind (F) and phosphorylate (G) CHK1, activating multiple copies of CHK1.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28LEFT-TO-RIGHTStalling of DNA replication fork and RPA bindingWhen a DNA replication fork encounters DNA lesions (e.g., cyclobutane pyrimidine dimers or alkylated bases) stalling of the replicative DNA polymerase may occur. This can lead to dissociation or 'uncoupling' of the DNA polymerase from the DNA helicase and generation of long regions of persistent ssDNA. Uncoupling can also occur in response to other genotoxic stresses such as reduced dNTP pools caused by hydroxyurea treatment which inhibits cellular ribonucleotide diphosphate reductase. The exposed ssDNA is bound by the single-stranded DNA binding protein RPA. The persistent nature of this RPA-ssDNA complex (as opposed to a more-transient complex found at an active replication fork) allows it to serve as a signal for replication stress that can be recognized by the ATR-ATRIP and Rad17-Rfc2-5 complexes.<p>RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28Persistent single-stranded DNAReactome DB_ID: 176104nucleoplasmGENE ONTOLOGYGO:0005654Reactome Database ID Release 73176104Database 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=176104ReactomeR-ALL-1761042Reactome 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-176104.2Reactomehttp://www.reactome.orgChEBI61120additional informationMIMI:0361RPA heterotrimerReactome DB_ID: 68462RPA1DNA 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; leading to recruit PRIMPOL on chromatin and stimulate its DNA primase activity (PubMed:24126761, PubMed:25550423, PubMed:28534480). Interacts with XPA; the interaction is direct and associates XPA with the RPA complex (PubMed:7700386, PubMed:9699634, PubMed:10563794). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).PTM DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).PTM Sumoylated on lysine residues Lys-449 and Lys-577, with Lys-449 being the major site. Sumoylation promotes recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. Desumoylated by SENP6.SIMILARITY Belongs to the replication factor A protein 1 family.Homo sapiensNCBI Taxonomy9606UniProtP276942EQUAL616EQUALReactome Database ID Release 7368461Database 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 7368459Database 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-68459.21RPA2DNA Replication factor A protein 2 (32kD)RPA32Replication protein A 32 kDa subunitRP-ARF-AReplication factor-A protein 2Reactome DB_ID: 68457UniProt: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.UniProtP159271EQUAL270EQUALReactome Database ID Release 7368457Database 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=68457ReactomeR-HSA-684572Reactome 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-68457.21Reactome Database ID Release 7368462Database 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=68462ReactomeR-HSA-684625Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68462.5RPA-ssDNA complexRPA complexed to ssDNAReactome DB_ID: 17629311Reactome Database ID Release 73176293Database 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=176293ReactomeR-HSA-1762931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176293.1Reactome Database ID Release 73176175Database 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=176175ReactomeR-HSA-1761752Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176175.215833913Pubmed2005Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpointByun, TSPacek, MYee, MCWalter, JCCimprich, KAGenes Dev 19:1040-528196638Pubmed1994Human replication protein A binds single-stranded DNA in two distinct complexesBlackwell, LJBorowiec, James AMol Cell Biol 14:3993-400112142537Pubmed2002Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defectsSogo, JMLopes, MFoiani, MScience 297:599-60210473346Pubmed1999Replication protein A (RPA): the eukaryotic SSB.Iftode, CDaniely, YBorowiec, James ACrit Rev Biochem Mol Biol 34:141-8010051570Pubmed1999Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damageRaderschall, EGolub, EIHaaf, TProc Natl Acad Sci U S A 96:1921-616387650Pubmed2006Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesionsLopes, MFoiani, MSogo, JMMol Cell 21:15-279242902Pubmed1997Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism.Wold, MSAnnu Rev Biochem 66:61-9212791985Pubmed2003Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexesZou, LElledge, SJScience 300:1542-810373362Pubmed1999Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strandCordeiro-Stone, MMakhov, AMZaritskaya, LSGriffith, JDJ Mol Biol 289:1207-18GENE ONTOLOGYGO:0006260gene ontology term for cellular processMIMI:0359LEFT-TO-RIGHTBinding of ATR-ATRIP to the RPA-ssDNA complexATR kinase activity is stimulated upon binding of the ATR-ATRIP complex to an RPA-ssDNA complex. ATR can subsequently phosphorylate and activate the checkpoint kinase Chk1, allowing further amplification of the checkpoint signal. The ATR and Chk1 kinases then modify a variety of factors that can lead to stabilization of stalled DNA replication forks, inhibition of origin firing, inhibition of cell cycle progression, mobilization of DNA repair factors, and induction of apoptosis. This checkpoint signaling mechanism is highly conserved in eukaryotes, and homologues of ATR and ATRIP are found in such organisms as S. cerevisiae (Mec1 and Ddc2, respectively), S. pombe (rad3 and rad26, respectively), and X. laevis (Xatr and Xatrip, respectively).<p>The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR protein without affecting ATR mRNA levels indicating that complex formation stabilizes the ATR protein. ATRIP is also a substrate for the ATR kinase, but modification of ATRIP does not significantly regulate the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.<p>While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest affinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28ATR:ATRIPATR-ATRIPATM- and rad3-related (ATR)ATR-interacting protein (ATRIP)Reactome DB_ID: 176269ATRIPATRIP 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 73176231Database 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-176231.11ATRSerine/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 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 73912443Database 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-912443.11Reactome Database ID Release 73176269Database 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-176269.1ComplexPortalCPX-3622ATR:ATRIP:RPA:ssDNA signaling complexATR-ATRIP-RPA-ssDNA signaling complexReactome DB_ID: 17628111Reactome Database ID Release 73176281Database 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=176281ReactomeR-HSA-1762811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176281.1Reactome Database ID Release 73176250Database 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=176250ReactomeR-HSA-1762502Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176250.215743907Pubmed2005ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylationBall, HLMyers, JSCortez, DMol Biol Cell 16:2372-818019001Pubmed1994Identification and characterization of new elements involved in checkpoint and feedback controls in fission yeastal-Khodairy, FFotou, ESheldrick, KSGriffiths, DJLehmann, ARCarr, AMMol Biol Cell 5:147-6010559981Pubmed1999A Rad3-Rad26 complex responds to DNA damage independently of other checkpoint proteinsEdwards, RJBentley, NJCarr, AMNat Cell Biol 1:393-815451423Pubmed2004ATR-dependent phosphorylation of ATRIP in response to genotoxic stressItakura, EUmeda, KSekoguchi, ETakata, HOhsumi, MMatsuura, ABiochem Biophys Res Commun 323:1197-20215371427Pubmed2004Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1Kumagai, AKim, SMDunphy, WGJ Biol Chem 279:49599-60812015327Pubmed2002The role of single-stranded DNA and polymerase alpha in establishing the ATR, Hus1 DNA replication checkpointYou, ZKong, LNewport, JJ Biol Chem 277:27088-9316407120Pubmed2006ATRIP associates with replication protein A-coated ssDNA through multiple interactionsNamiki, YZou, LProc Natl Acad Sci U S A 103:580-516327781Pubmed2006ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaksJazayeri, AFalck, JLukas, CBartek, JSmith, GCLukas, JJackson, SPNat Cell Biol 8:37-4510950868Pubmed2000The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast.Paciotti, VClerici, MLucchini, GLonghese, MPGenes Dev 14:2046-59LEFT-TO-RIGHTRecruitment of Rad17-RFC complex to DNAThe Rad17-RFC complex is involved in an early stage of the genotoxic stress response. The major function of the protein complex is to load the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA at sites of damage and/or stalled replication forks. This reaction is conceptually similar to the loading of the PCNA sliding clamp onto DNA by RFC. The association of the Rad17-RFC complex with ssDNA or gapped or primed DNA is significantly stimulated by RPA, but not by the heterologous E. coli SSB. Loading of the human 9-1-1 complex onto such DNA templates is also strongly stimulated by cognate RPA, but not yeast RPA. Although Rad17 and Rad9 are substrates of the ATR kinase activity, loading of the Rad17 and 9-1-1 complexes onto DNA occurs independent of ATR.<p>The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is slightly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.<p>The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.<p>Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28RAD17:RFCRad17-RFC complexReactome DB_ID: 176353RAD17Cell 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 733008665Database 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-3008665.11RFC2RFC40Activator 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 7368433Database 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-68433.21RFC5RFC36Activator 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 7368427Database 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-68427.21RFC4RFC37Activator 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 7368429Database 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-68429.21RFC3RFC38Activator 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 7368431Database 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-68431.21Reactome Database ID Release 73176353Database 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-176353.1Rad17-RFC complex bound to DNAReactome DB_ID: 17620411Reactome Database ID Release 73176204Database 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=176204ReactomeR-HSA-1762041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176204.1Reactome Database ID Release 73176101Database 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=176101ReactomeR-HSA-1761012Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176101.214624239Pubmed2003Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5' recessed DNAEllison, VStillman, BPLoS Biol 1:E3312578958Pubmed2003Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitroBermudez, VPLindsey-Boltz, LACesare, AJManiwa, YGriffith, JDHurwitz, JSancar, AProc Natl Acad Sci U S A 100:1633-815279787Pubmed2004Dial 9-1-1 for DNA damage: the Rad9-Hus1-Rad1 (9-1-1) clamp complexParrilla-Castellar, ERArlander, SJKarnitz, LDNA Repair (Amst) 3:1009-1414605214Pubmed2003Replication protein A-mediated recruitment and activation of Rad17 complexesZou, LLiu, DElledge, SJProc Natl Acad Sci U S A 100:13827-32LEFT-TO-RIGHTRecruitment of the 9-1-1 complex to DNARecruitment of the Rad9-Hus1-Rad1 complex to DNAThe 9-1-1 complex is a heterotrimeric ring-shaped structure that is loaded onto DNA by the Rad17-RFC complex. In vitro studies indicate that loading is preferred onto DNA substrates containing ssDNA gaps that presumably resemble structures found upon replication fork stalling and DNA polymerase/helicase uncoupling. The Rad17-RFC and 9-1-1 complexes are structurally similar to the RFC (replication factor C) clamp loader and PCNA sliding clamp, respectively, and similar mechanisms are thought to be used during loading of the 9-1-1 complex and PCNA. Upon loading, the 9-1-1 complex can recruit Chk1 onto sites of replication fork uncoupling or DNA damage.<p>The purified Rad17 and Rad9-Hus1-Rad1 (9-1-1) complexes can form a stable co-complex in the presence of ATP, using Rad17-Rad9 interactions. From computer modeling studies, the Rad17 subunit of the complex is also proposed to interact with the C-terminus of Rad1, p36 with the C-terminus of Hus1, and p38 with the C-terminus of Rad9. A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phosphorylated, perhaps suggesting that 9-1-1 may regulate the recruiment of additional ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:289-1-1 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'-&gt;5' double stranded DNA exonuclease activity (PubMed:9660799).SUBUNIT Component of the toroidal 9-1-1 (RAD9-RAD1-HUS1) complex, composed of RAD9A, RAD1 and HUS1 (PubMed:10846170, PubMed:10884395). The 9-1-1 complex associates with LIG1, POLB, FEN1, RAD17, HDAC1, RPA1 and RPA2 (PubMed:10846170, PubMed:10884395, PubMed:15314187, PubMed:15556996, PubMed:15871698, PubMed:15897895, PubMed:16216273). The 9-1-1 complex associates with the RAD17-RFC complex (PubMed:12578958). RAD1 interacts with POLB, FEN1, HUS1, HUS1B, RAD9A and RAD9B (PubMed:10359610, PubMed:10777662, PubMed:11944979, PubMed:14500360, PubMed:14611806, PubMed:15314187, PubMed:15556996, PubMed:16216273). Interacts with DNAJC7 (PubMed:11573955).TISSUE SPECIFICITY Expressed in testis, uterus, bladder, spleen, ovaries, lung, brain and muscle (at protein level).SIMILARITY Belongs to the rad1 family.UniProtO606711EQUAL282EQUALReactome Database ID Release 73176382Database 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-176382.11HUS1Reactome 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 73176374Database 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-176374.11Converted 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'-&gt;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 73176372Database 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 73176325Database 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 73176222Database 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-176222.11Reactome Database ID Release 73176312Database 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-176312.1Rad9-Hus1-Rad1 bound to DNAReactome DB_ID: 17625611Reactome Database ID Release 73176256Database 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=176256ReactomeR-HSA-1762561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176256.1ACTIVATIONGENE ONTOLOGYGO:0003689gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 73176122Database 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=176122Reactome Database ID Release 73176264Database 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=176264ReactomeR-HSA-1762642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176264.212237462Pubmed2002Molecular modeling-based analysis of interactions in the RFC-dependent clamp-loading processVenclovas, CColvin, METhelen, MPProtein Sci 11:2403-1614500360Pubmed2003Expression of mammalian paralogues of HRAD9 and Mrad9 checkpoint control genes in normal and cancerous testicular tissueHopkins, KMWang, XBerlin, AHang, HThaker, HMLieberman, HBCancer Res 63:5291-815210332Pubmed2004The PCNA-RFC families of DNA clamps and clamp loadersMajka, JBurgers, PMProg Nucleic Acid Res Mol Biol 78:227-6010777662Pubmed2000Physical interactions among human checkpoint control proteins HUS1p, RAD1p, and RAD9p, and implications for the regulation of cell cycle progressionHang, HLieberman, HBGenomics 65:24-338943031Pubmed1996A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control geneLieberman, HBHopkins, KMNass, MDemetrick, DDavey, SProc Natl Acad Sci U S A 93:13890-5LEFT-TO-RIGHTLoading of claspin onto DNA during replication origin firingClaspin is loaded onto DNA replication origins during replication initiation. Studies in Xenopus egg extracts indicate claspin loading requires the presence of Cdc45, a factor that promotes the initial unwinding of the origin DNA in the presence of Cdk2. This step is followed by RPA binding which is a prerequisite for recruitment of PCNA and DNA polymerases alpha and delta. As RPA is not required for claspin binding, it is postulated that claspin binds at the time of initial origin unwinding but prior to the initiation of DNA synthesis. Claspin would then continue to associate with replication fork machinery where it can serve as a checkpoint sensor protein. Even though associated with the replication fork, claspin is not an essential DNA replication factor.<p>Studies of Xenopus claspin indicate that it can physically associate with cognate Cdc45, DNA polymerase epsilon, RPA, RFC, and Rad17-RFC on chromatin. Studies of purified human claspin indicate that it binds with high affinity to branched (or forked) DNA structures that resemble stalled replication forks. Electron microscopy of these complexes indicates that claspin binds as a ring-like structure near the branch. The protein is hypothesized to encircle the DNA at these sites.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28CDK:DDK:MCM10:active pre-replicative complex:CDC45Reactome DB_ID: 68564CDC45Cdc45CDC45-related proteinPORC-PI-1Reactome DB_ID: 68563UniProt:O75419 CDC45CDC45CDC45LCDC45L2UNQ374/PRO710FUNCTION Required for initiation of chromosomal DNA replication.SUBUNIT Associated with ORC2. Interacts with HELB (PubMed:25933514).TISSUE SPECIFICITY Widely expressed, highest levels are found in adult testis and thymus and in fetal liver.DEVELOPMENTAL STAGE Transcript peaks at G1-S transition, but total protein remains constant throughout the cell cycle. Expressed in multiple tissues during embryogenesis, including neural crest-derived structures.SIMILARITY Belongs to the CDC45 family.UniProtO754191EQUAL566EQUALReactome Database ID Release 7368563Database 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=68563ReactomeR-HSA-685632Reactome 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-68563.21CDK:DDK:MCM10:active pre-replicative complexReactome DB_ID: 68561CDKReactome DB_ID: 68380cyclinReactome DB_ID: 68379Reactome Database ID Release 7368379Database 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=68379ReactomeR-HSA-683792Reactome 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-68379.2ChEBI360801CDK2Cdk2Cell division protein kinase 2 (EC 2.7.1.-)(p33 protein kinase)(CDK2)Cell division protein kinase 2 p33 protein kinaseReactome DB_ID: 68365UniProt:P24941 CDK2CDK2CDKN2FUNCTION Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21).SUBUNIT Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148).INDUCTION Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis.PTM Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.PTM Nitrosylated after treatment with nitric oxide (DETA-NO).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.UniProtP249411EQUAL298EQUALReactome Database ID Release 7368365Database 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=68365ReactomeR-HSA-683652Reactome 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-68365.21Reactome Database ID Release 7368380Database 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=68380ReactomeR-HSA-683801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68380.11DDKReactome DB_ID: 68388DBF4Dbf4Reactome DB_ID: 68387UniProt:Q9UBU7 DBF4DBF4ASKDBF4AZDBF1FUNCTION Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S phase. The complex CDC7-DBF4A selectively phosphorylates MCM2 subunit at 'Ser-40' and 'Ser-53' and then is involved in regulating the initiation of DNA replication during cell cycle.SUBUNIT Forms a complex with CDC7. Note that CDC7 forms distinct complex either with DBF4A or DBF4B. Such complexes are stable upon replication stress. Interacts with MEN1, MCM2, ORC2, ORC4 and ORC6. Interacts (via IBM motifs) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).TISSUE SPECIFICITY Highly expressed in testis and thymus. Expressed also in most cancer cells lines.INDUCTION Induced in G1 phase at low level, increased during G1-S phase and remain high during S and G2-M phase.PTM Phosphorylation increases its interaction with PSIP1.UniProtQ9UBU71EQUAL674EQUALReactome Database ID Release 7368387Database 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=68387ReactomeR-HSA-683872Reactome 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-68387.21CDC7Cdc7Cell division protein kinase 7Cell division cycle 7-related protein kinase (EC 2.7.1.-) (CDC7- related kinase) (HsCdc7) (huCdc7)Cell division cycle 7-related protein kinase CDC7- related kinaseHsCdc7huCdc7Reactome DB_ID: 51781UniProt:O00311 CDC7CDC7CDC7L1FUNCTION Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication. Can phosphorylates MCM2 and MCM3.SUBUNIT Forms a complex with either DBF4/DBF4A or DBF4B, leading to the activation of the kinase activity.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC7 subfamily.UniProtO003111EQUAL574EQUALReactome Database ID Release 7351781Database 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=51781ReactomeR-HSA-517811Reactome 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-51781.11Reactome Database ID Release 7368388Database 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=68388ReactomeR-HSA-683881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68388.11MCM10:active pre-replicative complexReactome DB_ID: 156564MCM10Mcm10Reactome DB_ID: 68403UniProt:Q7L590 MCM10MCM10PRO2249FUNCTION Acts as a replication initiation factor that brings together the MCM2-7 helicase and the DNA polymerase alpha/primase complex in order to initiate DNA replication. Additionally, plays a role in preventing DNA damage during replication. Key effector of the RBBP6 and ZBTB38-mediated regulation of DNA-replication and common fragile sites stability; acts as a direct target of transcriptional repression by ZBTB38 (PubMed:24726359).SUBUNIT Self-associates (By similarity). Interacts with ORC2. May interact with MCM2 and MCM6. Interacts with the DNA polymerase alpha subunit POLA1. Interacts with RECQL4; this interaction regulates RECQL4 unwinding activity. Interacts with WDHD1.DEVELOPMENTAL STAGE Expression is cell cycle regulated. Expression increases at the G1/S-boundary. Expression decreases in late M phase, remains low during G(1) phase, and starts to accumulate at the onset of S phase.DOMAIN Each zinc finger-like domain binds a zinc ion and is involved in both ssDNA and dsDNA binding, as is the OB-fold domain.DOMAIN The N-terminal domain mediates homodimerization.SIMILARITY Belongs to the MCM10 family.UniProtQ7L5901EQUAL875EQUALReactome Database ID Release 7368403Database 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=68403ReactomeR-HSA-684032Reactome 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-68403.21active pre-replicative complexReactome DB_ID: 156562MCM2-7Reactome DB_ID: 68558MCM5Mcm5DNA replication licensing factor MCM5CDC46 homologP1-CDC46Reactome DB_ID: 68551UniProt:P33992 MCM5MCM5CDC46FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity (By similarity). Interacts with MCMBP.SUBUNIT Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). Interacts with ANKRD17.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtP339921EQUAL734EQUALReactome Database ID Release 7368551Database 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=68551ReactomeR-HSA-685511Reactome 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-68551.11MCM6Mcm6DNA replication licensing factor MCM6P105MCMReactome DB_ID: 68553UniProt:Q14566 MCM6MCM6FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.SUBUNIT Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). May interact with MCM10. Interacts with TIPIN. Interacts with CDT1. Interacts with MCMBP. Interacts with DDI2 (PubMed:29290612).PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.POLYMORPHISM Intronic variations in MCM6 upstream from the LCT gene are associated with adult-type hypolactasia [MIM:223100] leading to lactose intolerance, or with lactase persistance. Lactose intolerance is a normal physiological phenomenon caused by developmental down-regulation of lactase activity during childhood or early adulthood. A non-coding variation in MCM6 affects the transcriptional regulation of the LCT gene resulting in down-regulation of lactase activity. However, the majority of Northern Europeans and some African populations have the ability to maintain lactase activity and digest lactose throughout life (lactase persistence).MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtQ145661EQUAL821EQUALReactome Database ID Release 7368553Database 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=68553ReactomeR-HSA-685531Reactome 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-68553.11MCM2Mcm2DNA replication licensing factor MCM2Nuclear protein BM28Reactome DB_ID: 68557UniProt:P49736 MCM2MCM2BM28CCNL1CDCL1KIAA0030FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for the entry in S phase and for cell division. Plays a role in terminally differentiated hair cells development of the cochlea and induces cells apoptosis.SUBUNIT Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). Interacts with DBF4 (By similarity). Interacts with KAT7. May interact with MCM10. Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891).PTM Phosphorylated on Ser-108 by ATR in proliferating cells. Ser-108 proliferation is increased by genotoxic agents. Ser-40 is mediated by the CDC7-DBF4 and CDC7-DBF4B complexes, while Ser-53 phosphorylation is only mediated by the CDC7-DBF4 complex. Phosphorylation by the CDC7-DBF4 complex during G1/S phase is required for the initiation of DNA replication.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtP497362EQUAL904EQUALReactome Database ID Release 7368557Database 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=68557ReactomeR-HSA-685571Reactome 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-68557.11MCM7Mcm7DNA replication licensing factor MCM7CDC47 homologP1.1-MCM3Reactome DB_ID: 68555UniProt:P33993 MCM7MCM7CDC47MCM2FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for S-phase checkpoint activation upon UV-induced damage.SUBUNIT Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). Interacts with the ATR-ATRIP complex and with RAD17. Interacts with TIPIN. Interacts with MCMBP. Interacts with ANKRD17. Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR (PubMed:28191891).PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtP339932EQUAL719EQUALReactome Database ID Release 7368555Database 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=68555ReactomeR-HSA-685551Reactome 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-68555.11MCM3Mcm3DNA replication licensing factor MCM3DNA polymerase alpha holoenzyme-associated protein P1RLF beta subunitP102 proteinP1-MCM3Reactome DB_ID: 68546UniProt:P25205 MCM3MCM3FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Required for DNA replication and cell proliferation.SUBUNIT Component of the MCM2-7 complex. The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). Associated with the replication-specific DNA polymerase alpha. Interacts with MCMBP. Interacts with ANKRD17. Interacts with MCM3AP isoform MCM3AP; this interaction leads to MCM3 acetylation (PubMed:9712829, PubMed:11258703, PubMed:12226073).PTM Acetylated by MCM3AP.PTM O-glycosylated (O-GlcNAcylated), in a cell cycle-dependent manner.MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtP252052EQUAL808EQUALReactome Database ID Release 7368546Database 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=68546ReactomeR-HSA-685461Reactome 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-68546.11MCM4Mcm4DNA replication licensing factor MCM4CDC21 homologP1-CDC21Reactome DB_ID: 68549UniProt:P33991 MCM4MCM4CDC21FUNCTION Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.SUBUNIT Component of the MCM2-7 complex (PubMed:9305914, PubMed:16899510). The complex forms a toroidal hexameric ring with the proposed subunit order MCM2-MCM6-MCM4-MCM7-MCM3-MCM5 (Probable). Interacts with MCMBP (PubMed:17296731).PTM Sumoylated; SUMO2 modified in response to stress caused by inhibition of proteasome activity (in vitro).MISCELLANEOUS Early fractionation of eukaryotic MCM proteins yielded a variety of dimeric, trimeric and tetrameric complexes with unclear biological significance. Specifically a MCM467 subcomplex is shown to have in vitro helicase activity which is inhibited by the MCM2 subunit. The MCM2-7 hexamer is the proposed physiological active complex.SIMILARITY Belongs to the MCM family.UniProtP339912EQUAL863EQUALReactome Database ID Release 7368549Database 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=68549ReactomeR-HSA-685491Reactome 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-68549.11Reactome Database ID Release 7368558Database 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=68558ReactomeR-HSA-685582Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68558.2ComplexPortalCPX-29401CDC6:ORC:origin complexReactome DB_ID: 68543ORC:origin of replicationReactome DB_ID: 68540ORC4Orc4Origin recognition complex subunit 4Reactome DB_ID: 68519UniProt:O43929 ORC4ORC4ORC4LFUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase (PubMed:12909626, PubMed:17716973). Interacts with DBF4 (By similarity). Interacts with POLQ (PubMed:24989122).SIMILARITY Belongs to the ORC4 family.UniProtO439291EQUAL436EQUALReactome Database ID Release 7368519Database 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=68519ReactomeR-HSA-685192Reactome 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-68519.21ORC3Orc3Origin recognition complex subunit 3Origin recognition complex subunit LatheoReactome DB_ID: 68513UniProt:Q9UBD5 ORC3ORC3LATHEOORC3LFUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.PTM Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.SIMILARITY Belongs to the ORC3 family.UniProtQ9UBD51EQUAL711EQUALReactome Database ID Release 7368513Database 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=68513ReactomeR-HSA-685132Reactome 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-68513.21ARSorigin of replicationoriginautonomously replicating sequenceReactome DB_ID: 68419Reactome Database ID Release 7368419Database 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=68419ReactomeR-ALL-684192Reactome 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-68419.2ChEBI611201ORC6Orc6Origin recognition complex subunit 6Reactome DB_ID: 68539UniProt:Q9Y5N6 ORC6ORC6ORC6LFUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Does not bind histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with DBF4 (By similarity).SIMILARITY Belongs to the ORC6 family.UniProtQ9Y5N61EQUAL252EQUALReactome Database ID Release 7368539Database 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=68539ReactomeR-HSA-685392Reactome 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-68539.21ORC5Orc5Origin recognition complex subunit 5Reactome DB_ID: 68516UniProt:O43913 ORC5ORC5ORC5LFUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase.TISSUE SPECIFICITY Abundant in spleen, ovary, prostate, testis, and colon mucosa.PTM Multi-mono-ubiquitinated by OBI1; ubiquitination is important for efficient DNA replication origin site activation. Ubiquitination levels are low in mitotic and early G1-phAse cells and are induced in late G1-/early S-phase, peaking in S-phase and decrease toward the end of the cell cycle.SIMILARITY Belongs to the ORC5 family.UniProtO439131EQUAL435EQUALReactome Database ID Release 7368516Database 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=68516ReactomeR-HSA-685162Reactome 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-68516.21ORC1Orc1Origin recognition complex subunit 1Replication control protein 1Reactome DB_ID: 68522UniProt:Q13415 ORC1ORC1ORC1LPARC1FUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase. Interacts with CDC6 and KAT7/HBO1. Interacts with LRWD1 predominantly during the G1 phase and with less affinity during mitosis, when phosphorylated.DEVELOPMENTAL STAGE Expression is cell-cycle regulated, it starts to accumulate in mid-G1 phase, reaches a peak at the G1/S boundary, and decreases to a basal level in S phase (at protein level).DOMAIN The BAH domain mediates binding to dimethylated histone H4 'Lys-20' (H4K20me2), which is enriched at replication origins.PTM Phosphorylated during mitosis.SIMILARITY Belongs to the ORC1 family.UniProtQ134151EQUAL861EQUALReactome Database ID Release 7368522Database 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=68522ReactomeR-HSA-685222Reactome 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-68522.21Orc2 associated with MCM8Reactome DB_ID: 176970ORC2Orc2Origin recognition complex subunit 2Reactome DB_ID: 68405UniProt:Q13416 ORC2ORC2ORC2LFUNCTION Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Binds histone H3 and H4 trimethylation marks H3K9me3, H3K20me3 and H4K27me3. Stabilizes LRWD1, by protecting it from ubiquitin-mediated proteasomal degradation. Also stabilizes ORC3.SUBUNIT Component of ORC, a complex composed of at least 6 subunits: ORC1, ORC2, ORC3, ORC4, ORC5 and ORC6. ORC is regulated in a cell-cycle dependent manner. It is sequentially assembled at the exit from anaphase of mitosis and disassembled as cells enter S phase (PubMed:12909626, PubMed:17716973). Interacts with DBF4 (By similarity). Interacts with MCM10 (PubMed:11095689). Interacts with LRWD1 throughout the cell cycle; this interaction, wich occurs only with non-ubiquitinated form of LRWD1, prevents LRWD1 ubiquitination and hence stabilizes the protein (PubMed:22645314). Interacts with POLQ (PubMed:24989122).SIMILARITY Belongs to the ORC2 family.UniProtQ134161EQUAL577EQUALReactome Database ID Release 7368405Database 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=68405ReactomeR-HSA-684052Reactome 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-68405.21MCM8DNA helicase MCM8MCM8_HUMANReactome DB_ID: 3006646UniProt:Q9UJA3 MCM8MCM8C20orf154FUNCTION Component of the MCM8-MCM9 complex, a complex involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR) (PubMed:23401855). Required for DNA resection by the MRE11-RAD50-NBN/NBS1 (MRN) complex by recruiting the MRN complex to the repair site and by promoting the complex nuclease activity (PubMed:26215093). Probably by regulating the localization of the MNR complex, indirectly regulates the recruitment of downstream effector RAD51 to DNA damage sites including DBSs and ICLs (PubMed:23401855). The MCM8-MCM9 complex is dispensable for DNA replication and S phase progression (PubMed:23401855). However, may play a non-essential for DNA replication: may be involved in the activation of the prereplicative complex (pre-RC) during G(1) phase by recruiting CDC6 to the origin recognition complex (ORC) (PubMed:15684404). Probably by regulating HR, plays a key role during gametogenesis (By similarity). Stabilizes MCM9 protein (PubMed:23401855, PubMed:26215093).SUBUNIT Component of the MCM8-MCM9 complex, which forms a hexamer composed of MCM8 and MCM9 (PubMed:23401855, PubMed:26300262). Interacts with the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Interacts with RAD51; the interaction recruits RAD51 to DNA damage sites (PubMed:23401855). Interacts with the MRN complex composed of MRE11, RAD50 and NBN/NBS1 (PubMed:26215093). Interacts with CDC6 and ORC2 (PubMed:15684404). Interacts with HROB; the interaction recruits the MCM8-MCM9 complex to DNA damage sites (PubMed:31467087).TISSUE SPECIFICITY Highest levels in placenta, lung and pancreas. Low levels in skeletal muscle and kidney. Expressed in various tumors with highest levels in colon and lung cancers.INDUCTION By E2F1.SIMILARITY Belongs to the MCM family.CAUTION Was initially thought to play a role in DNA replication (PubMed:15684404). However, it was later shown that it is mainly involved in homologous recombination repair (PubMed:23401855).UniProtQ9UJA31EQUAL840EQUALReactome Database ID Release 733006646Database 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=3006646ReactomeR-HSA-30066461Reactome 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-3006646.11Reactome Database ID Release 73176970Database 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=176970ReactomeR-HSA-1769701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176970.11Reactome Database ID Release 7368540Database 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=68540ReactomeR-HSA-685402Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68540.21CDC6Reactome DB_ID: 68542UniProt:Q99741 CDC6CDC6CDC18LFUNCTION Involved in the initiation of DNA replication. Also participates in checkpoint controls that ensure DNA replication is completed before mitosis is initiated.SUBUNIT Interacts with PCNA, ORC1, cyclin-CDK (PubMed:9566895). Interacts with HUWE1 (PubMed:17567951). Interacts with ANKRD17 (PubMed:23711367). Interacts with GRWD1; origin binding of GRWD1 is dependent on CDC6 (PubMed:25990725). Interacts with CDT1; are mutually dependent on one another for loading MCM complexes onto chromatin (PubMed:14672932). Interacts with TTC4 (PubMed:18320024).SIMILARITY Belongs to the CDC6/cdc18 family.UniProtQ997411EQUAL560EQUALReactome Database ID Release 7368542Database 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=68542ReactomeR-HSA-685422Reactome 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-68542.21Reactome Database ID Release 7368543Database 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=68543ReactomeR-HSA-685431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68543.11Reactome Database ID Release 73156562Database 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=156562ReactomeR-HSA-1565621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156562.11Reactome Database ID Release 73156564Database 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=156564ReactomeR-HSA-1565642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156564.21Reactome Database ID Release 7368561Database 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=68561ReactomeR-HSA-685612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68561.21Reactome Database ID Release 7368564Database 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=68564ReactomeR-HSA-685642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68564.2CLSPNClaspinReactome DB_ID: 176282UniProt:Q9HAW4 CLSPNCLSPNFUNCTION Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation. Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins. Can also bind specifically to branched DNA structures and may associate with S-phase chromatin following formation of the pre-replication complex (pre-RC). This may indicate a role for this protein as a sensor which monitors the integrity of DNA replication forks.SUBUNIT Interacts (phosphorylation-dependent) with CHEK1; regulates CLSPN function in checkpoint for DNA damage and replication. Interacts with ATR and RAD9A and these interactions are slightly reduced during checkpoint activation. Interacts with BRCA1 and this interaction increases during checkpoint activation. Interacts with TIMELESS.INDUCTION Expression peaks at S/G2 phases of the cell cycle.DOMAIN The C-terminus of the protein contains 3 potential CHEK1-binding motifs (CKB motifs). Potential phosphorylation sites within CKB motif 1 and CKB motif 2 are required for interaction with CHEK1.PTM Phosphorylated. Undergoes ATR-dependent phosphorylation by CHEK1 during activation of DNA replication or damage checkpoints. Phosphorylation by CSNK1G1/CK1 promotes CHEK1 binding.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) during G1 phase, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Following DNA damage, it is deubiquitinated by USP28 in G2 phase, preventing its degradation.SIMILARITY Belongs to the claspin family.UniProtQ9HAW41EQUAL1339EQUALReactome Database ID Release 73176282Database 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=176282ReactomeR-HSA-1762821Reactome 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-176282.1claspin bound to DNA replication forkCdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexReactome DB_ID: 17622911Reactome Database ID Release 73176229Database 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=176229ReactomeR-HSA-1762291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176229.1Reactome Database ID Release 73176318Database 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=176318ReactomeR-HSA-1763182Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176318.215226314Pubmed2004Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structuresSar, FLindsey-Boltz, LASubramanian, DCroteau, DLHutsell, SQGriffith, JDSancar, AJ Biol Chem 279:39289-9512620222Pubmed2003Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17Lee, JKumagai, ADunphy, WGMol Cell 11:329-4012545175Pubmed2003Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1Kumagai, ADunphy, WGNat Cell Biol 5:161-516148040Pubmed2005Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint responseLee, JGold, DAShevchenko, AnnaShevchenko, AndrejDunphy, WGMol Biol Cell 16:5269-8215279790Pubmed2004Claspin, a regulator of Chk1 in DNA replication stress pathwayChini, CCChen, JDNA Repair (Amst) 3:1033-711090622Pubmed2000Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extractsKumagai, ADunphy, WGMol Cell 6:839-49LEFT-TO-RIGHT2.7.11Activation of claspinClaspin is a replication fork-associated protein important for Chk1 activation. Claspin loads onto the fork during replication origin firing and travels with the fork during DNA synthesis. Upon fork uncoupling and ATR-ATRIP binding to persistent ssDNA, the activated ATR kinase phosphorylates claspin at two primary sites. Modification increases the affinity of claspin for Chk1. Studies of human or Xenopus claspin indicate that phosphorylation of both sites is essential for significant claspin-Chk1 association. Following claspin modification by ATR, Chk1 can be transiently recruited to the stalled replication fork for subsequent phosphorylation and activation by ATR. Activation of Chk1 allows modification of additional downstream targets, thus amplifying the checkpoint signal. While much of the mechanistic information concerning claspin action has been obtained using Xenopus laevis egg extracts and Xenopus claspin, factors with similar activity have been found in various eukaryotic species including S. cerevisiae (MRC1), S. pombe (mrc1), and humans.<p>Activated ATR phosphorylates human claspin on two sites, threonine 916 and serine 945.Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 29358ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 7329358Database 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=29358ReactomeR-ALL-293583Reactome 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-29358.3COMPOUNDC000022ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 113582ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 73113582Database 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=113582ReactomeR-ALL-1135823Reactome 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-113582.3COMPOUNDC000082Activated claspin bound to DNA replication forkCdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexReactome DB_ID: 176182p-T916,S945-CLSPNp-S945,T916-CLSPNActivated claspinReactome DB_ID: 176296945EQUALO-phospho-L-serineMODMOD:00046916EQUALO-phospho-L-threonineMODMOD:000471EQUAL1339EQUALReactome Database ID Release 73176296Database 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=176296ReactomeR-HSA-1762961Reactome 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-176296.111Reactome Database ID Release 73176182Database 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=176182ReactomeR-HSA-1761821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176182.1ACTIVATIONactiveUnit: #Protein5GENE ONTOLOGYGO:0004674Reactome Database ID Release 73176203Database 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=176203Reactome Database ID Release 73176298Database 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=176298ReactomeR-HSA-1762982Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176298.215707391Pubmed2005DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free systemClarke, CAClarke, PRBiochem J 388:705-12LEFT-TO-RIGHT2.7.11Recruitment and activation of Chk1Chk1 is a checkpoint kinase activated during genotoxic stress. Like ATR, Chk1 is essential for viability in mammals. Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. While the ATR and ATM pathways are distinct, there is interplay between the two. For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. The ATR and ATM pathways also have mechanistic similarities. Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53).Authored: Borowiec, JA, 2006-02-25 17:40:15Edited: D'Eustachio, P, 2006-02-25 17:41:28Chk1CHEK1Serine/threonine-protein kinase Chk1 (EC 2.7.1.-)Serine/threonine-protein kinase Chk1 Reactome DB_ID: 113826UniProt:O14757 CHEK1CHEK1CHK1FUNCTION Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.ACTIVITY REGULATION Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B.SUBUNIT Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ. Isoform 1 associates with isoform 2, the interaction is disrupted upon phosphorylation by ATR. Interacts with CDK5RAP3; antagonizes CHEK1 (PubMed:19223857).TISSUE SPECIFICITY Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.DOMAIN The autoinhibitory region (AIR) inhibits the activity of the kinase domain.PTM Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.PTM Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.UniProtO147571EQUAL476EQUALReactome Database ID Release 73113826Database 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=113826ReactomeR-HSA-1138261Reactome 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-113826.1phospho-Chk1p-S317,S345-CHEK1Serine/threonine-protein kinase Chk1 (EC 2.7.1.-) phosphorylatedSerine/threonine-protein kinase Chk1 Reactome DB_ID: 113838317EQUAL345EQUAL1EQUAL476EQUALReactome Database ID Release 73113838Database 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=113838ReactomeR-HSA-1138381Reactome 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-113838.1ACTIVATIONactiveUnit: #Protein5Reactome Database ID Release 73176116Database 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=176116ReactomeR-HSA-1761162Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176116.210859163Pubmed2000Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) miceTakai, HTominaga, KMotoyama, NMinamishima, YANagahama, HTsukiyama, TIkeda, KNakayama, KeikoNakanishi, MNakayama, Ken-ichiGenes Dev 14:1439-4711390642Pubmed2001ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1Zhao, HPiwnica-Worms, HMol Cell Biol 21:4129-3915190204Pubmed2004ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damageSorensen, CSSyljuasen, RGLukas, JBartek, JCell Cycle 3:941-510859164Pubmed2000Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.Liu, QGuntuku, SCui, XSMatsuoka, SCortez, DTamai, KLuo, GCarattini-Rivera, SDeMayo, FBradley, ADonehower, LAElledge, SJGenes Dev 14:1448-5912766152Pubmed2003Human claspin is required for replication checkpoint controlChini, CCChen, JJ Biol Chem 278:30057-6212781359Pubmed2003Chk1 and Chk2 kinases in checkpoint control and cancerBartek, JLukas, JCancer Cell 3:421-916431910Pubmed2006Rapid activation of ATR by ionizing radiation requires ATM and Mre11Myers, JSCortez, DJ Biol Chem15272308Pubmed2004Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanismUto, KInoue, DShimuta, KNakajo, NSagata, NEMBO J 23:3386-9615279789Pubmed2004Chk1 in the DNA damage response: conserved roles from yeasts to mammalsChen, YSanchez, YDNA Repair (Amst) 3:1025-3216360315Pubmed2006Rapid PIKK-Dependent Release of Chk1 from Chromatin Promotes the DNA-Damage Checkpoint ResponseSmits, VAReaper, PMJackson, SPCurr Biol 16:150-9LEFT-TO-RIGHT2.7.11Phosphorylation of Cdc25A at Ser-123 by Chk1Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk1, inhibiting Cdc25A.CDC25ACdc25AM-phase inducer phosphatase 1 (EC 3.1.3.48) (Dual specificity phosphatase Cdc25A)M-phase inducer phosphatase 1 Dual specificity phosphatase Cdc25AReactome DB_ID: 143487UniProt:P30304 CDC25ACDC25AFUNCTION Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro.ACTIVITY REGULATION Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation.SUBUNIT Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage. Interacts with PIM1. Interacts with CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495).DOMAIN The phosphodegron motif mediates interaction with specific F-box proteins when phosphorylated. Putative phosphorylation sites at Ser-79 and Ser-82 appear to be essential for this interaction.PTM Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-293 and Thr-507 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 may also promote ubiquitin-dependent proteolysis of CDC25A by the SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11. Phosphorylation by NEK11 is required for BTRC-mediated polyubiquitination and degradation. Phosphorylation by PIM1 leads to an increase in phosphatase activity. Phosphorylated by PLK3 following DNA damage, leading to promote its ubiquitination and degradation.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase leading to its degradation by the proteasome. Ubiquitinated by a SCF complex containing BTRC and FBXW11 during S phase leading to its degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads to its stabilization.SIMILARITY Belongs to the MPI phosphatase family.UniProtP303041EQUAL524EQUALReactome Database ID Release 73143487Database 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=143487ReactomeR-HSA-1434871Reactome 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-143487.1p-S123-CDC25Aphospho-Cdc25AReactome DB_ID: 143488123EQUAL1EQUAL524EQUALReactome Database ID Release 73143488Database 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=143488ReactomeR-HSA-1434881Reactome 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-143488.1ACTIVATIONReactome Database ID Release 73143490Database 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=143490Reactome Database ID Release 7369604Database 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=69604ReactomeR-HSA-696043Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69604.312399544Pubmed2002Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.Zhao, HWatkins, JLPiwnica-Worms, HProc Natl Acad Sci U S A 99:14795-800LEFT-TO-RIGHT2.7.11Phosphorylation of Cdc25C at Ser 216 by Chk1Phosphorylation of Cdc25C at Ser 216 results in both the inhibition of Cdc25C phosphatase activity and the creation of a 14-3-3 docking site (Peng et al. 1997).Authored: Matthews, L, 2003-08-05 01:10:00Edited: Matthews, L, 2006-07-10 19:19:59CDC25CCdc25CM-phase inducer phosphatase 3 (EC 3.1.3.48) (Dual specificity phosphatase Cdc25C)M-phase inducer phosphatase 3 Dual specificity phosphatase Cdc25CReactome DB_ID: 69741UniProt:P30307 CDC25CCDC25CFUNCTION Functions as a dosage-dependent inducer in mitotic control. Tyrosine protein phosphatase required for progression of the cell cycle. When phosphorylated, highly effective in activating G2 cells into prophase. Directly dephosphorylates CDK1 and activates its kinase activity.SUBUNIT Interacts with MAPK14 and 14-3-3 proteins. When phosphorylated on Ser-129 and/or Thr-130, interacts with PLK1.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpr; this interaction inactivates CDC25C phosphatase activity.DEVELOPMENTAL STAGE Expressed predominantly in G2 phase.PTM Phosphorylated by CHEK1 and MAPK14 at Ser-216. This phosphorylation creates a binding site for 14-3-3 protein and inhibits the phosphatase. Phosphorylated by PLK4. Phosphorylated by PLK1, leading to activate the phosphatase activity. Phosphorylation by PLK3 at Ser-191 promotes nuclear translocation. Ser-198 is a minor phosphorylation site. Was initially reported to be phosphorylated by PLK3 at Ser-216 (PubMed:10557092). However, such phosphorylation by PLK3 was not confirmed by other groups. Phosphorylation at Thr-48, Thr-67, Ser-122, Thr-130, Ser-168 and Ser-214 occurs at G2 and G2-M transition and is probably catalyzed by CDK1. Ser-168 phosphorylation levels are lower than those at the other 5 CDK1 sites. Phosphorylation by CDK1 leads to increased activity.SIMILARITY Belongs to the MPI phosphatase family.UniProtP303071EQUAL473EQUALReactome Database ID Release 7369741Database 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=69741ReactomeR-HSA-697411Reactome 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-69741.1p-S216-CDC25Cphosph-Cdc25C (Ser 216)M-phase inducer phosphatase 3 Dual specificity phosphatase Cdc25CReactome DB_ID: 156496216EQUAL1EQUAL473EQUALReactome Database ID Release 73156496Database 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=156496ReactomeR-HSA-1564961Reactome 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-156496.1ACTIVATIONReactome Database ID Release 73182636Database 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=182636Reactome Database ID Release 7375010Database 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=75010ReactomeR-HSA-750104Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75010.49278512Pubmed1997Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.Peng, CYGraves, PRThoma, RSWu, ZShaw, ASPiwnica-Worms, HScience 277:1501-5Reactome Database ID Release 73176187Database 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=176187ReactomeR-HSA-1761872Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176187.216314342Pubmed2005DNA damage checkpoints in mammalsNiida, HNakanishi, MMutagenesis15530773Pubmed2004The DNA damage response: sensing and signalingMcGowan, CHRussell, PCurr Opin Cell Biol 16:629-33