BioPAX pathway converted from "Activation of the pre-replicative complex" in the Reactome database.Activation of the pre-replicative complexActivation of the pre-replicative complexIn S. cerevisiae, two ORC subunits, Orc1 and Orc5, both bind ATP, and Orc1 in addition has ATPase activity. Both ATP binding and ATP hydrolysis appear to be essential functions in vivo. ATP binding by Orc1 is unaffected by the association of ORC with origin DNA (ARS) sequences, but ATP hydrolysis is ARS-dependent, being suppressed by associated double-stranded DNA and stimulated by associated single-stranded DNA. These data are consistent with the hypothesis that ORC functions as an ATPase switch, hydrolyzing bound ATP and changing state as DNA unwinds at the origin immediately before replication. It is attractive to speculate that ORC likewise functions as a switch as human pre-replicative complexes are activated, but human Orc proteins are not well enough characterized to allow the model to be critically tested. mRNAs encoding human orthologs of all six Orc proteins have been cloned, and ATP-binding amino acid sequence motifs have been identified in Orc1, Orc4, and Orc5. Interactions among proteins expressed from the cloned genes have been characterized, but the ATP-binding and hydrolyzing properties of these proteins and complexes of them have not been determined.Mcm10 associates with the pre-replicative complex, stabilizing Mcm2-7Mcm10 associates with the pre-replicative complex, stabilizing Mcm2-7MCM10 is required for human DNA replication. In S. cerevisiae, Mcm10, like Mcm2-7, is required for minichromosome maintenance, but Mcm10 has no sequence homology with these other proteins (Merchant et al., 1997). Genetic studies have demonstrated that Mcm10 is required for DNA replication in S. pombe (Aves et al., 1998) and S. cerevisiae cells (Homesley et al., 2000) and immunodepletion of XlMcm10 interferes with DNA replication in Xenopus egg extracts (Wohlschlegel et al., 2002). Human Mcm10 interacts with chromatin in G1 phase and then dissociates during G2 phase. In S. cerevisiae, Mcm10 has been shown to localize to origins during G1 (Ricke and Bielinsky, 2004), and it may stabilize the association of Mcm2-7 with the pre-replicative complex (Sawyer et al., 2004). This timing of association is consistent with studies that demonstrate that, in Xenopus egg extracts, Mcm10 is required for association of Cdc45, but not Mcm2-7 with chromatin. Biochemical evidence that Mcm10 plays a direct role in the activation of the pre-replicative complex includes the requirement for SpMcm10 in the phosphorylation of the Mcm2-7 complex by DDK (Lee et al., 2004) and the fact that SpMcm10 binds and stimulates DNA polymerase alpha activity (Fien et al., 2004).Reactome DB_ID: 685591nucleoplasmGO0005654pre-replicative complex [nucleoplasm]pre-replicative complexpreRCReactome DB_ID: 685441CDT1:CDC6:ORC:origin complex [nucleoplasm]CDT1:CDC6:ORC:origin complexReactome DB_ID: 685361UniProt:Q9H211 CDT1CDT1CDT1FUNCTION Required for both DNA replication and mitosis (PubMed:11125146, PubMed:22581055, PubMed:21856198, PubMed:14993212, PubMed:26842564). DNA replication licensing factor, required for pre-replication complex assembly. Cooperates with CDC6 and the origin recognition complex (ORC) during G1 phase of the cell cycle to promote the loading of the mini-chromosome maintenance (MCM) complex onto DNA to generate pre-replication complexes (pre-RC)(PubMed:14672932). Required also for mitosis by promoting stable kinetochore-microtubule attachments (PubMed:22581055). Potential oncogene (By similarity).SUBUNIT Interacts with GMNN; inhibits binding of the MCM complex to origins of replication (PubMed:11125146, PubMed:14672932, PubMed:14993212, PubMed:15257290). Interacts with CDC6; are mutually dependent on one another for loading MCM complexes onto chromatin (PubMed:14672932). Interacts with PCNA (PubMed:16861906). Interacts with LRWD1 during G1 phase and during mitosis (PubMed:22645314). Interacts with NDC80 subunit of the NDC80 complex; leading to kinetochore localization (PubMed:22581055). Interacts with GRWD1; origin binding of GRWD1 is dependent on CDT1 (PubMed:25990725). Interacts with KAT7 (PubMed:18832067). Interacts with ubiquitin-binding protein FAF1; the interaction is likely to promote CDT1 degradation (PubMed:26842564).DEVELOPMENTAL STAGE Present during G1 and early S phase of the cell cycle. Degraded during the late S, G2, and M phases.INDUCTION Induced by E2F transcription factors (PubMed:14990995).DOMAIN The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.PTM Two independent E3 ubiquitin ligase complexes, SCF(SKP2) and the DCX(DTL) complex, mediated CDT1 degradation in S phase. Ubiquitinated by the DCX(DTL) complex, in response to DNA damage, leading to its degradation. Ubiquitination by the DCX(DTL) complex is necessary to ensure proper cell cycle regulation and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Phosphorylation at Thr-29 by CDK2 targets CDT1 for ubiquitination by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). The interaction with GMNN protects it against ubiquitination. Deubiquitinated by USP37 (PubMed:27296872).PTM Phosphorylation by cyclin A-dependent kinases at Thr-29 targets CDT1 for ubiquitynation by SCF(SKP2) E3 ubiquitin ligase and subsequent degradation (PubMed:14993212). Phosphorylated at Thr-29 by MAPK8/JNK1, which blocks replication licensing in response to stress (PubMed:21856198). Binding to GMNN is not affected by phosphorylation.SIMILARITY Belongs to the Cdt1 family.Reactomehttp://www.reactome.orgHomo sapiensNCBI Taxonomy9606UniProtQ9H211Chain Coordinates1EQUAL546EQUALReactome DB_ID: 685431CDC6:ORC:origin complex [nucleoplasm]CDC6:ORC:origin complexReactome DB_ID: 685401ORC:origin of replication [nucleoplasm]ORC:origin of replicationReactome DB_ID: 685191UniProt:O43929 ORC4ORC4ORC4ORC4LFUNCTION 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 DB_ID: 685131UniProt:Q9UBD5 ORC3ORC3ORC3ORC3LLATHEOFUNCTION 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 DB_ID: 684191origin of replication [nucleoplasm]origin of replicationARSautonomously replicating sequenceoriginReactome DB_ID: 685391UniProt:Q9Y5N6 ORC6ORC6ORC6ORC6LFUNCTION 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 DB_ID: 685161UniProt:O43913 ORC5ORC5ORC5ORC5LFUNCTION 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 DB_ID: 685221UniProt:Q13415 ORC1ORC1ORC1ORC1LPARC1FUNCTION 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 DB_ID: 1769701Orc2 associated with MCM8 [nucleoplasm]Orc2 associated with MCM8Reactome DB_ID: 684051UniProt:Q13416 ORC2ORC2ORC2LORC2FUNCTION 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 DB_ID: 30066461UniProt:Q9UJA3 MCM8MCM8C20orf154MCM8FUNCTION 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 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-176970.1Reactome 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-68540.2Reactome DB_ID: 685421UniProt:Q99741 CDC6CDC6CDC18LCDC6FUNCTION 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 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-68543.1Reactome Database ID Release 7368544Database 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=68544ReactomeR-HSA-685441Reactome 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-68544.1Reactome DB_ID: 685581MCM2-7 [nucleoplasm]MCM2-7Reactome DB_ID: 685511UniProt:P33992 MCM5MCM5CDC46MCM5FUNCTION 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 DB_ID: 685531UniProt:Q14566 MCM6MCM6MCM6FUNCTION 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 DB_ID: 685571UniProt:P49736 MCM2MCM2CDCL1CCNL1BM28MCM2KIAA0030FUNCTION 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 DB_ID: 685551UniProt:P33993 MCM7MCM7MCM7CDC47MCM2FUNCTION 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 DB_ID: 685461UniProt:P25205 MCM3MCM3MCM3FUNCTION 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 DB_ID: 685491UniProt:P33991 MCM4MCM4CDC21MCM4FUNCTION 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 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-68558.2Reactome Database ID Release 7368559Database 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=68559ReactomeR-HSA-685591Reactome 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-68559.1Reactome DB_ID: 684031UniProt:Q7L590 MCM10MCM10PRO2249MCM10FUNCTION 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 DB_ID: 685601MCM10:pre-replicative complex [nucleoplasm]MCM10:pre-replicative complexReactome DB_ID: 685591Reactome DB_ID: 6840311EQUAL875EQUALReactome Database ID Release 7368560Database 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=68560ReactomeR-HSA-685602Reactome 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-68560.2Reactome Database ID Release 7368919Database 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=68919ReactomeR-HSA-689192Reactome 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-68919.29745018Pubmed1998The essential schizosaccharomyces pombe cdc23 DNA replication gene shares structural and functional homology with the Saccharomyces cerevisiae DNA43 (MCM10) geneAves, SJTongue, NFoster, AJHart, EACurr Genet 34:164-7112604790Pubmed2003The Cdc23 (Mcm10) protein is required for the phosphorylation of minichromosome maintenance complex by the Dfp1-Hsk1 kinaseLee, JKSeo, YSHurwitz, JProc Natl Acad Sci U S A 100:2334-911095689Pubmed2000The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase.Izumi, MYanagi, KMizuno, TYokoi, MKawasaki, YMoon, KYHurwitz, JYatagai, FHanaoka, FNucleic Acids Res 28:4769-779154825Pubmed1997A lesion in the DNA replication initiation factor Mcm10 induces pausing of elongation forks through chromosomal replication origins in Saccharomyces cerevisiaeMerchant, AMKawasaki, YChen, YLei, MTye, Bik KMol Cell Biol 17:3261-7111864598Pubmed2002Xenopus Mcm10 binds to origins of DNA replication after Mcm2-7 and stimulates origin binding of Cdc45.Wohlschlegel, JADhar, SKProkhorova, TADutta, AWalter, JCMol Cell 9:233-4014766746Pubmed2004Primer utilization by DNA polymerase alpha-primase is influenced by its interaction with Mcm10pFien, KCho, YSLee, JKRaychaudhuri, STappin, IHurwitz, JJ Biol Chem 279:16144-5311282021Pubmed2001Initiating DNA synthesis: from recruiting to activating the MCM complex.Lei, MTye, Bik KJ Cell Sci 114:1447-5410783164Pubmed2000Mcm10 and the MCM2-7 complex interact to initiate DNA synthesis and to release replication factors from origins.Homesley, LLei, MKawasaki, YSawyer, SChristensen, TTye, Bik KGenes Dev 14:913-2615494305Pubmed2004Mcm10 regulates the stability and chromatin association of DNA polymerase-alphaRicke, RMBielinsky, AKMol Cell 16:173-8515201046Pubmed2004Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiaeSawyer, SLCheng, IHChai, WTye, Bik KJ Mol Biol 340:195-202Cdt1 is displaced from the pre-replicative complex.Cdt1 is displaced from the pre-replicative complex.At the beginning of this reaction, 1 molecule of 'Mcm10:pre-replicative complex' is present. At the end of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', and 1 molecule of 'CDT1' are present.<br><br> This reaction takes place in the 'nucleus'.<br>Reactome DB_ID: 685601Reactome DB_ID: 6853611EQUAL546EQUALReactome DB_ID: 1565641MCM10:active pre-replicative complex [nucleoplasm]MCM10:active pre-replicative complexReactome DB_ID: 6840311EQUAL875EQUALReactome DB_ID: 1565621active pre-replicative complex [nucleoplasm]active pre-replicative complexReactome DB_ID: 685581Reactome DB_ID: 685431Reactome 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-156562.1Reactome 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-156564.2Reactome Database ID Release 7368940Database 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=68940ReactomeR-HSA-689402Reactome 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-68940.212045100Pubmed2002DNA replication in eukaryotic cells.Bell, SPDutta, AAnnu Rev Biochem 71:333-74Cdt1 associates with gemininCdt1 associates with gemininAt the beginning of this reaction, 1 molecule of 'geminin', and 1 molecule of 'CDT1' are present. At the end of this reaction, 1 molecule of 'Cdt1:geminin' is present.<br><br> This reaction takes place in the 'nucleoplasm'.<br>Reactome DB_ID: 6853611EQUAL546EQUALReactome DB_ID: 1135541UniProt:O75496 GMNNGMNNGMNNFUNCTION Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC) (PubMed:9635433, PubMed:14993212, PubMed:20129055, PubMed:24064211). It is degraded during the mitotic phase of the cell cycle (PubMed:9635433, PubMed:14993212, PubMed:24064211). Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle (PubMed:9635433, PubMed:14993212, PubMed:24064211). Inhibits histone acetyltransferase activity of KAT7/HBO1 in a CDT1-dependent manner, inhibiting histone H4 acetylation and DNA replication licensing (PubMed:20129055). Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control (PubMed:22615398).SUBUNIT Homotetramer (PubMed:15313623, PubMed:15260975, PubMed:15378034, PubMed:19906994). Interacts with CDT1; this inhibits binding of the MCM complex to origins of replication (PubMed:14993212, PubMed:21543332, PubMed:15260975, PubMed:19906994). The complex with CDT1 exists in two forms, a 'permissive' heterotrimer and an 'inhibitory' heterohexamer (PubMed:14993212, PubMed:15260975, PubMed:19906994). Interacts (via coiled-coil domain) with IDAS (via coiled-coil domain); this targets GMNN to the nucleus (PubMed:21543332). The heterodimer formed by GMNN and MCIDAS has much lower affinity for CDT1 than the GMNN homodimer (PubMed:24064211). Interacts with a subset of Hox proteins, affinity increasing from anterior to posterior types, the strongest interaction being with HOXB1, HOXC9 and HOXD10 (PubMed:22615398). Interacts with LRWD1 from G1/S to mitosis (PubMed:22645314).DEVELOPMENTAL STAGE Absent during G1 phase, accumulates during S, G2, and M phases, and disappears at the time of the metaphase-anaphase transition.PTM Phosphorylated during mitosis. Phosphorylation at Ser-184 by CK2 results in enhanced binding to Hox proteins and more potent inhibitory effect on Hox transcriptional activity.SIMILARITY Belongs to the geminin family.UniProtO754961EQUAL209EQUALReactome DB_ID: 1565021Cdt1:geminin [nucleoplasm]Cdt1:gemininReactome DB_ID: 6853611EQUAL546EQUALReactome DB_ID: 11355411EQUAL209EQUALReactome Database ID Release 73156502Database 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=156502ReactomeR-HSA-1565021Reactome 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-156502.1Reactome Database ID Release 7369299Database 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=69299ReactomeR-HSA-692992Reactome 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-69299.211125146Pubmed2000Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.Wohlschlegel, JADwyer, BTDhar, SKCvetic, CWalter, JCDutta, AScience 290:2309-12CDK and DDK associate with the Mcm10:pre-replicative complexCDK and DDK associate with the Mcm10:pre-replicative complexAt the beginning of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', 1 molecule of 'DDK', and 1 molecule of 'CDK' are present. At the end of this reaction, 1 molecule of 'CDK:DDK:Mcm10:pre-replicative complex' is present.<br><br> This reaction takes place in the 'nucleus'.<br>Reactome DB_ID: 683801CDK [nucleoplasm]CDKReactome DB_ID: 683791cyclin [nucleoplasm]cyclinReactome DB_ID: 683651UniProt:P24941 CDK2CDK2CDK2CDKN2FUNCTION 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 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-68380.1Reactome DB_ID: 683881DDK [nucleoplasm]DDKReactome DB_ID: 683871UniProt:Q9UBU7 DBF4DBF4DBF4ZDBF1DBF4AASKFUNCTION 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 DB_ID: 517811UniProt:O00311 CDC7CDC7CDC7L1CDC7FUNCTION 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 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-68388.1Reactome DB_ID: 1565641Reactome DB_ID: 685611CDK:DDK:MCM10:active pre-replicative complex [nucleoplasm]CDK:DDK:MCM10:active pre-replicative complexReactome DB_ID: 683801Reactome DB_ID: 683881Reactome DB_ID: 1565641Reactome 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-68561.2Reactome Database ID Release 7368918Database 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=68918ReactomeR-HSA-689183Reactome 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-68918.310373557Pubmed1999A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.Kumagai, HSato, NYamada, MMahony, DSeghezzi, WLees, EArai, KMasai, HMol Cell Biol 19:5083-9510523313Pubmed1999Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.Jiang, WMcDonald, DHope, TJHunter, TonyEMBO J 18:5703-132.7.10Mcm2-7 is phosphorylated by DDKMcm2-7 is phosphorylated by DDKAt the beginning of this reaction, 1 molecule of 'Mcm2-7 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phosphorylated Mcm2-7 complex', and 1 molecule of 'ADP' are present.<br><br> This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.<br>Reactome DB_ID: 685581Reactome DB_ID: 293581ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 1135821ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Reactome DB_ID: 685691p-MCM2-7 [nucleoplasm]p-MCM2-7Reactome DB_ID: 685581Reactome DB_ID: 1135501phosphate(3-) [ChEBI:18367]phosphate(3-)ChEBI18367Reactome Database ID Release 7368569Database 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=68569ReactomeR-HSA-685692Reactome 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-68569.2PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 68388GO0004713GO molecular functionReactome Database ID Release 7368401Database 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=68401Reactome Database ID Release 7368954Database 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=68954ReactomeR-HSA-689542Reactome 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-68954.210846177Pubmed2000Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a critical threonine residue of Cdc7 by Cdks.Masai, HMatsui, EYou, ZIshimi, YTamai, KArai, KJ Biol Chem 275:29042-52Cdc45 associates with the pre-replicative complex at the originCdc45 associates with the pre-replicative complex at the originOnce the Mcm2-7 complex has been assembled onto the origin of replication, the next step is the assembly of Cdc45, an essential replication protein, in late G1. The assembly of Cdc45 onto origins of replication forms a complex distinct from the pre-replicative complex, sometimes called the pre-initiation complex. The assembly of Cdc45 onto origins correlates with the time of initiation. Like the Mcm2-7 proteins, Cdc45 binds specifically to origins in the G1 phase of the cell cycle and then to non-origin DNA during S phase and is therefore thought to travel with the replication fork. Indeed, S. cerevisiae Cdc45 is required for DNA replication elongation as well as replication initiation. Cdc45 is required for the association of alpha DNA polymerase:primase with chromatin. Based on this observation and the observation that in S. cerevisiae, cCdc45 has been found in large complexes with some components of Mcm2-7 complex, it has been suggested that Cdc45 plays a scaffolding role at the replication fork, coupling Pol-alpha:primase to the replication fork through the helicase. Association of Cdc45 with origin DNA is regulated in the cell cycle and its association is dependent on the activity of cyclin-dependent kinases but not the Cdc7/Dbf4 kinase. In Xenopus egg extracts, association of Cdc45 with chromatin is dependent on Xmus101. TopBP1, the human homolog of Xmus1, is essential for DNA replication and interacts with DNA polymerase epsilon, one of the polymerases involved in replicating the genome. TopBP1 homologs have been found in S. cerevisiae and S. pombe. Sld3, an additional protein required for Cdc45 association with chromatin in S. cerevisiae and S. pombe, has no known human homolog.Reactome DB_ID: 685631UniProt:O75419 CDC45CDC45UNQ374/PRO710CDC45CDC45L2CDC45LFUNCTION 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 DB_ID: 685611Reactome DB_ID: 685641CDK:DDK:MCM10:active pre-replicative complex:CDC45 [nucleoplasm]CDK:DDK:MCM10:active pre-replicative complex:CDC45Reactome DB_ID: 6856311EQUAL566EQUALReactome DB_ID: 685611Reactome 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-68564.2Reactome Database ID Release 7368917Database 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=68917ReactomeR-HSA-689173Reactome 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-68917.310430907Pubmed1999Differential assembly of Cdc45p and DNA polymerases at early and late origins of DNA replication.Aparicio, OMStout, AMBell, SPProc Natl Acad Sci U S A 96:9130-59660782Pubmed1998The human homolog of Saccharomyces cerevisiae CDC45.Saha, PThome, KCYamaguchi, RHou, ZWeremowicz, SDutta, AJ Biol Chem 273:18205-99335335Pubmed1997Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase.Aparicio, OMWeinstein, DMBell, SPCell 91:59-6910790374Pubmed2000DNA synthesis at individual replication forks requires the essential initiation factor Cdc45p.Tercero, JALabib, KDiffley, JFEMBO J 19:2082-9311296242Pubmed2001Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae.Kamimura, YTak, YSSugino, AAraki, HEMBO J 20:2097-1079554851Pubmed1998Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin.Zou, LStillman, BScience 280:593-612438414Pubmed2002The Xenopus Xmus101 protein is required for the recruitment of Cdc45 to origins of DNA replication.Van Hatten, RATutter, AVHolway, AHKhederian, AMWalter, JCMichael, WMJ Cell Biol 159:541-710757793Pubmed2000Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase.Zou, LStillman, BMol Cell Biol 20:3086-9611756551Pubmed2001A DNA damage-regulated BRCT-containing protein, TopBP1, is required for cell survival.Yamane, KWu, XChen, JMol Cell Biol 22:555-6610518787Pubmed1999Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha.Kukimoto, IIgaki, HKanda, TEur J Biochem 265:936-437708676Pubmed1995Cell cycle-regulated nuclear import and export of Cdc47, a protein essential for initiation of DNA replication in budding yeast.Dalton, SWhitbread, LProc Natl Acad Sci U S A 92:2514-8DNA Replication Factor A (RPA) associates with the pre-replicative complex at the originDNA Replication Factor A (RPA) associates with the pre-replicative complex at the originAfter pre-RC assembly and Cdc45 association with the origin of replication, Replication Protein A (RPA) also associates with chromatin. RPA is a heterotrimeric complex containing p70, p34, and p11 subunits, and also is required for DNA recombination and DNA repair. The p70 subunit of RPA binds to the primase subunits of Pol alpha:primase. The p70 and p34 subunits of RPA are phosphorylated in a cell cycle-dependent manner. RPA is a single-strand DNA (ssDNA) binding protein and its association with chromatin at this stage suggests that DNA is partially unwound. This suggestion has been confirmed by detection of ssDNA in budding yeast origins of replication using chemical methods.Reactome DB_ID: 685671RPA1-4 [nucleoplasm]RPA1-4DNA Replication Factor ARFAReactome DB_ID: 684611UniProt:P27694 RPA1RPA1RPA70RPA1REPA1FUNCTION 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.UniProtP276942EQUAL616EQUALReactome DB_ID: 684591UniProt:P35244 RPA3RPA3RPA3REPA3RPA14FUNCTION 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 DB_ID: 685661UniProt:Q13156 RPA4RPA4RPA4FUNCTION 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 polymerase delta synthesis in the presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.SUBUNIT 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. Interacts with RPA1 and RPA3.TISSUE SPECIFICITY Preferentially expressed in placental and colon mucosa. Widely expressed at intermediate or lower levels.SIMILARITY Belongs to the replication factor A protein 2 family.UniProtQ131561EQUAL261EQUALReactome DB_ID: 684571UniProt:P15927 RPA2RPA2RPA2REPA2RPA32RPA34FUNCTION 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 7368567Database 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=68567ReactomeR-HSA-685672Reactome 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-68567.2Reactome DB_ID: 685641Reactome DB_ID: 685681CDK:DDK:MCM10:active pre-replicative complex:CDC45:RPA1-4 [nucleoplasm]CDK:DDK:MCM10:active pre-replicative complex:CDC45:RPA1-4Reactome DB_ID: 685671Reactome DB_ID: 685641Reactome Database ID Release 7368568Database 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=68568ReactomeR-HSA-685682Reactome 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-68568.2Reactome Database ID Release 7368916Database 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=68916ReactomeR-HSA-689162Reactome 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-68916.210882098Pubmed2000Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.Walter, JNewport, JMol Cell 5:617-2710473346Pubmed1999Replication protein A (RPA): the eukaryotic SSB.Iftode, CDaniely, YBorowiec, James ACrit Rev Biochem Mol Biol 34:141-802200738Pubmed1990Cell-cycle-regulated phosphorylation of DNA replication factor A from human and yeast cells.Din, SBrill, SJFairman, MPStillman, BGenes Dev 4:968-779242902Pubmed1997Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism.Wold, MSAnnu Rev Biochem 66:61-921311258Pubmed1992Interaction of DNA polymerase alpha-primase with cellular replication protein A and SV40 T antigen.Dornreiter, IErdile, LFGilbert, IUvon Winkler, DKelly, TJEMBO J 11:769-76DNA polymerase alpha:primase binds at the originDNA polymerase alpha:primase binds at the originDNA polymerase alpha:primase is comprised of four subunits, p180, p70, p58, and p49. The two primase subunits, p58 and p49, form a tight complex. The p49 subunit contains the DNA primase activity and one role of p58 appears to be tethering p49 to p180, the DNA polymerase catalytic subunit. The fourth subunit, p70, binds p180 and may tether the DNA polymerase alpha:primase complex to Cdc45.Reactome DB_ID: 685071DNA polymerase alpha:primase [nucleoplasm]DNA polymerase alpha:primaseprimosomeDNA Pol alpha:primaseReactome DB_ID: 96688121PRIM1:PRIM2 [nucleoplasm]PRIM1:PRIM2Primase heterodimerReactome DB_ID: 684951UniProt:P49643 PRIM2PRIM2PRIM2PRIM2AFUNCTION Regulatory subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which play an essential role in the initiation of DNA synthesis (PubMed:9705292, PubMed:17893144). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (PubMed:17893144). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity). In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit (PubMed:17893144). Stabilizes and modulates the activity of the catalytic subunit (By similarity).SUBUNIT Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex (PubMed:9705292, PubMed:17893144). Interacts via (C-terminus) with PRIM1 (PubMed:17893144). Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292). Within the complex, POLA1 directly interacts with PRIM2 (By similarity).SIMILARITY Belongs to the eukaryotic-type primase large subunit family.UniProtP496431EQUAL509EQUALReactome DB_ID: 684971UniProt:P49642 PRIM1PRIM1PRIM1FUNCTION Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which play an essential role in the initiation of DNA synthesis (PubMed:9268648, PubMed:9705292, PubMed:17893144). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (PubMed:17893144). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity). In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit (PubMed:17893144). Can add both ribo- and deoxynucleotides during elongation of the primers (By similarity). Binds single stranded DNA (By similarity).ACTIVITY REGULATION The presence of the regulatory subunit PRIM2/p58 accelerates the kinetics of initiation and primer extension.SUBUNIT Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex (PubMed:9705292, PubMed:17893144). Interacts with PRIM2 (via C-terminus) (PubMed:17893144). Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292). Within the complex, POLA1 directly interacts with PRIM2 (By similarity).MISCELLANEOUS The bound zinc ion is not a cofactor. It is bound to a zinc knuckle motif that may be involved in sequence recognition and the binding of ssDNA (By similarity).SIMILARITY Belongs to the eukaryotic-type primase small subunit family.UniProtP496421EQUAL420EQUALReactome Database ID Release 739668812Database 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=9668812ReactomeR-HSA-96688121Reactome 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-9668812.1Reactome DB_ID: 684871UniProt:P09884 POLA1POLA1POLA1POLAFUNCTION Catalytic subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, a regulatory subunit POLA2 and two primase subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. In the cytosol, responsible for a substantial proportion of the physiological concentration of cytosolic RNA:DNA hybrids, which are necessary to prevent spontaneous activation of type I interferon responses (PubMed:27019227).SUBUNIT Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292). Interacts with PARP1; this interaction functions as part of the control of replication fork progression (PubMed:9518481). Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA (PubMed:19608746). Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288).SUBUNIT (Microbial infection) Interacts with SV40 Large T antigen; this interaction allows viral DNA replication.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1/HHV-1 replication origin-binding protein UL9.DOMAIN The CysA-type zinc finger is required for PCNA-binding.DOMAIN The CysB motif binds 1 4Fe-4S cluster and is required for the formation of polymerase complexes.PTM A 165 kDa form is probably produced by proteolytic cleavage at Lys-124.MISCELLANEOUS In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.SIMILARITY Belongs to the DNA polymerase type-B family.UniProtP098841EQUAL1462EQUALReactome DB_ID: 684931UniProt:Q14181 POLA2POLA2POLA2FUNCTION Accessory subunit of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) which plays an essential role in the initiation of DNA synthesis (PubMed:9705292). During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1 (By similarity). The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands (By similarity). These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively (By similarity).SUBUNIT Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292). Within the complex, POLA1 directly interacts with PRIM2/p58 (By similarity).DOMAIN The N-terminal 240 amino acids are sufficient to mediate complex formation.PTM Phosphorylated in a cell cycle-dependent manner, in G2/M phase.SIMILARITY Belongs to the DNA polymerase alpha subunit B family.UniProtQ141811EQUAL598EQUALReactome Database ID Release 7368507Database 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=68507ReactomeR-HSA-685072Reactome 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-68507.2Reactome DB_ID: 684851DNA polymerase epsilon:origin complex [nucleoplasm]DNA polymerase epsilon:origin complexReactome DB_ID: 684831DNA polymerase epsilon [nucleoplasm]DNA polymerase epsilonReactome DB_ID: 88666841UniProt:Q9NR33 POLE4POLE4POLE4FUNCTION Accessory component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in DNA repair and in chromosomal DNA replication (By similarity).SUBUNIT Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interaction with POLE3 is a prerequisite for further binding with POLE and POLE2.UniProtQ9NR332EQUAL117EQUALReactome DB_ID: 684731UniProt:Q07864 POLEPOLEPOLE1POLEFUNCTION Catalytic component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in chromosomal DNA replication (By similarity). Required during synthesis of the leading DNA strands at the replication fork, binds at/or near replication origins and moves along DNA with the replication fork (By similarity). Has 3'-5' proofreading exonuclease activity that corrects errors arising during DNA replication (By similarity). Involved in DNA synthesis during DNA repair (PubMed:20227374, PubMed:27573199). Along with DNA polymerase POLD1 and DNA polymerase POLK, has a role in excision repair (NER) synthesis following UV irradiation (PubMed:20227374).SUBUNIT Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interacts with RAD17 and TOPBP1.DOMAIN The DNA polymerase activity domain resides in the N-terminal half of the protein, while the C-terminus is necessary for maintenance of the complex.DOMAIN The CysA-type zinc finger is required for PCNA-binding.DOMAIN The CysB motif binds 1 4Fe-4S cluster and is required for the formation of polymerase complexes.SIMILARITY Belongs to the DNA polymerase type-B family.UniProtQ078641EQUAL2286EQUALReactome DB_ID: 88666851UniProt:Q9NRF9 POLE3POLE3CHRAC17POLE3FUNCTION Accessory component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in DNA repair and in chromosomal DNA replication (By similarity). Forms a complex with CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1 (PubMed:10801849).SUBUNIT Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4. Interaction with POLE4 is a prerequisite for further binding with POLE and POLE2. Interacts with CHRAC1. Together with CHRAC1, ACF1 and ISWI/SNF2H proteins, it forms the ISWI chromatin-remodeling complex, CHRAC.TISSUE SPECIFICITY Expressed in all tissues tested, including, heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.UniProtQ9NRF92EQUAL147EQUALReactome DB_ID: 684821UniProt:P56282 POLE2POLE2POLE2DPE2FUNCTION Accessory component of the DNA polymerase epsilon complex (PubMed:10801849). Participates in DNA repair and in chromosomal DNA replication (By similarity).SUBUNIT Component of the DNA polymerase epsilon complex consisting of four subunits: the catalytic subunit POLE and the accessory subunits POLE2, POLE3 and POLE4.MISCELLANEOUS In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.SIMILARITY Belongs to the DNA polymerase epsilon subunit B family.UniProtP562821EQUAL527EQUALReactome Database ID Release 7368483Database 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=68483ReactomeR-HSA-684832Reactome 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-68483.2Reactome DB_ID: 684191Reactome Database ID Release 7368485Database 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=68485ReactomeR-HSA-684851Reactome 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-68485.1Reactome DB_ID: 685101DNA polymerase alpha:primase:DNA polymerase alpha:origin complex [nucleoplasm]DNA polymerase alpha:primase:DNA polymerase alpha:origin complexReactome DB_ID: 685071Reactome DB_ID: 684851Reactome Database ID Release 7368510Database 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=68510ReactomeR-HSA-685101Reactome 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-68510.1Reactome Database ID Release 7368914Database 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=68914ReactomeR-HSA-689144Reactome 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-68914.411395402Pubmed2002DNA primases.Frick, DNRichardson, CCAnnu Rev Biochem 70:39-808253737Pubmed1994Enzymatic characterization of the individual mammalian primase subunits reveals a biphasic mechanism for initiation of DNA replication.Copeland, WCWang, TSJ Biol Chem 268:26179-89ACTIVATIONReactome Database ID Release 7369385Database 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=69385ReactomeR-HSA-693852Reactome 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-69385.2Reactome DB_ID: 68568DNA polymerase epsilon binds at the originDNA polymerase epsilon binds at the originAt the beginning of this reaction, 1 molecule of 'origin of replication', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon:origin complex' is present.<br><br> <br>Reactome DB_ID: 684831Reactome DB_ID: 684191Reactome DB_ID: 684851Reactome Database ID Release 7368960Database 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=68960ReactomeR-HSA-689603Reactome 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-68960.3ACTIVATIONReactome Database ID Release 7368961Database 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=68961ReactomeR-HSA-689612Reactome 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-68961.2Reactome DB_ID: 68568Reactome Database ID Release 7368962Database 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=68962ReactomeR-HSA-689623Reactome 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-68962.310801458Pubmed2000ATPase switches controlling DNA replication initiation.Lee, DGBell, SPCurr Opin Cell Biol 12:280-59765232Pubmed1998ORC5L, a new member of the human origin recognition complex, is deleted in uterine leiomyomas and malignant myeloid diseases.Quintana, DGThome, KCHou, ZHLigon, AHMorton, CCDutta, AJ Biol Chem 273:27137-457502077Pubmed1996Conserved initiator proteins in eukaryotes.Gavin, KAHidaka, MStillman, BScience 270:1667-719353276Pubmed1997Identification of HsORC4, a member of the human origin of replication recognition complex.Quintana, DGHou, ZhThome, KCHendricks, MSaha, PDutta, AJ Biol Chem 272:28247-5110970868Pubmed2000Regulation of origin recognition complex conformation and ATPase activity: differential effects of single-stranded and double-stranded DNA binding.Lee, DGMakhov, AMKlemm, RDBell, SPEMBO J 19:4774-829038340Pubmed1997Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex.Klemm, RDAustin, RJBell, SPCell 88:493-5029829972Pubmed1999The Orc4p and Orc5p subunits of the Xenopus and human origin recognition complex are related to Orc1p and Cdc6p.Tugal, TZou-Yang, XHGavin, KPappin, DCanas, BKobayashi, RHunt, TStillman, BJ Biol Chem 273:32421-910402192Pubmed1999latheo encodes a subunit of the origin recognition complex and disrupts neuronal proliferation and adult olfactory memory when mutant.Pinto, SQuintana, DGSmith, PMihalek, RMHou, ZHBoynton, SJones, CJHendricks, MVelinzon, KWohlschlegel, JAAustin, RJLane, WSTully, TDutta, ANeuron 23:45-5411395502Pubmed2001Architecture of the human origin recognition complex.Dhar, SKDelmolino, LDutta, AJ Biol Chem 276:29067-7112169736Pubmed2002Orc6 involved in DNA replication, chromosome segregation, and cytokinesis.Prasanth, SGPrasanth, KVStillman, BScience 297:1026-3111459976Pubmed2001ATP bound to the origin recognition complex is important for preRC formation.Klemm, RDBell, SPProc Natl Acad Sci U S A 98:8361-711323433Pubmed2001Assembly of the human origin recognition complex.Vashee, SSimancek, PChallberg, MDKelly, TJJ Biol Chem 276:26666-7311779870Pubmed2002Nuclear organization of DNA replication initiation proteins in mammalian cells.Fujita, MIshimi, YNakamura, HKiyono, TTsurumi, TJ Biol Chem 277:10354-61