BioPAX pathway converted from "Activation of the pre-replicative complex" in the Reactome database.

Activation of the pre-replicative complex

In 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 Mcm2-7

MCM10 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: 68403

nucleoplasmGO0005654

UniProt:Q7L590 MCM10

MCM10

PRO2249MCM10FUNCTION 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.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtQ7L590

Chain Coordinates

EQUAL

875

EQUAL

Reactome DB_ID: 68559

pre-replicative complex [nucleoplasm]

pre-replicative complex

preRC

Reactome DB_ID: 68544

CDT1:CDC6:ORC:origin complex [nucleoplasm]

CDT1:CDC6:ORC:origin complex

Reactome DB_ID: 68543

CDC6:ORC:origin complex [nucleoplasm]

CDC6:ORC:origin complex

Reactome DB_ID: 68542

UniProt:Q99741 CDC6

CDC6

CDC18LCDC6FUNCTION 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).SIMILARITY Belongs to the CDC6/cdc18 family.

UniProtQ99741

EQUAL

560

EQUAL

Reactome DB_ID: 68540

ORC:origin of replication [nucleoplasm]

ORC:origin of replication

Reactome DB_ID: 68519

UniProt:O43929 ORC4

ORC4

ORC4ORC4LFUNCTION 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.

UniProtO43929

EQUAL

436

EQUAL

Reactome DB_ID: 68516

UniProt:O43913 ORC5

ORC5

ORC5ORC5LFUNCTION 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.SIMILARITY Belongs to the ORC5 family.

UniProtO43913

EQUAL

435

EQUAL

Reactome DB_ID: 68513

UniProt:Q9UBD5 ORC3

ORC3

ORC3ORC3LLATHEOFUNCTION 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.SIMILARITY Belongs to the ORC3 family.

UniProtQ9UBD5

EQUAL

711

EQUAL

Reactome DB_ID: 176970

Orc2 associated with MCM8 [nucleoplasm]

Orc2 associated with MCM8

Reactome DB_ID: 3006646

UniProt:Q9UJA3 MCM8

MCM8

C20orf154MCM8FUNCTION 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).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).

UniProtQ9UJA3

EQUAL

840

EQUAL

Reactome DB_ID: 68405

UniProt:Q13416 ORC2

ORC2

ORC2LORC2FUNCTION 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.

UniProtQ13416

EQUAL

577

EQUAL

Reactome Database ID Release 70176970Database identifier. Use 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-176970

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176970.1

Reactome DB_ID: 68419

origin of replication [nucleoplasm]

origin of replication

ARSautonomously replicating sequenceorigin

Reactome DB_ID: 68539

UniProt:Q9Y5N6 ORC6

ORC6

ORC6ORC6LFUNCTION 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.

UniProtQ9Y5N6

EQUAL

252

EQUAL

Reactome DB_ID: 68522

UniProt:Q13415 ORC1

ORC1

ORC1ORC1LPARC1FUNCTION 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.

UniProtQ13415

EQUAL

861

EQUAL

Reactome Database ID Release 7068540Database identifier. Use 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-68540

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68540.2Reactome Database ID Release 7068543Database identifier. Use 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-68543

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68543.1

Reactome DB_ID: 68536

UniProt:Q9H211 CDT1

CDT1

CDT1FUNCTION 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.

UniProtQ9H211

EQUAL

546

EQUAL

Reactome Database ID Release 7068544Database identifier. Use 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-68544

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68544.1

Reactome DB_ID: 68558

MCM2-7 [nucleoplasm]

MCM2-7

Reactome DB_ID: 68549

UniProt:P33991 MCM4

MCM4

CDC21MCM4FUNCTION 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.

UniProtP33991

EQUAL

863

EQUAL

Reactome DB_ID: 68555

UniProt:P33993 MCM7

MCM7

MCM7CDC47MCM2FUNCTION 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.

UniProtP33993

EQUAL

719

EQUAL

Reactome DB_ID: 68553

UniProt:Q14566 MCM6

MCM6

MCM6FUNCTION 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.

UniProtQ14566

EQUAL

821

EQUAL

Reactome DB_ID: 68546

UniProt:P25205 MCM3

MCM3

MCM3FUNCTION 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.

UniProtP25205

EQUAL

808

EQUAL

Reactome DB_ID: 68551

UniProt:P33992 MCM5

MCM5

CDC46MCM5FUNCTION 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.

UniProtP33992

EQUAL

734

EQUAL

Reactome DB_ID: 68557

UniProt:P49736 MCM2

MCM2

CDCL1CCNL1BM28MCM2KIAA0030FUNCTION 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.

UniProtP49736

EQUAL

904

EQUAL

Reactome Database ID Release 7068558Database identifier. Use 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-68558

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68558.2Reactome Database ID Release 7068559Database identifier. Use 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-68559

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68559.1

Reactome DB_ID: 68560

MCM10:pre-replicative complex [nucleoplasm]

MCM10:pre-replicative complex

Reactome DB_ID: 68403

EQUAL

875

EQUAL

Reactome DB_ID: 68559

Reactome Database ID Release 7068560Database identifier. Use 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-68560

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68560.2Reactome Database ID Release 7068919Database identifier. Use 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-68919

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68919.29154825Pubmed1997A 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 17:3261-7115201046Pubmed2004Mcm10 and Cdc45 cooperate in origin activation in Saccharomyces cerevisiaeSawyer, SLCheng, IHChai, WTye, Bik KJ Mol Biol 340:195-20210783164Pubmed2000Mcm10 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 14:913-2611095689Pubmed2000The 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 28:4769-7712604790Pubmed2003The 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 100:2334-915494305Pubmed2004Mcm10 regulates the stability and chromatin association of DNA polymerase-alphaRicke, RMBielinsky, AKMol Cell 16:173-8511864598Pubmed2002Xenopus Mcm10 binds to origins of DNA replication after Mcm2-7 and stimulates origin binding of Cdc45.Wohlschlegel, JADhar, SKProkhorova, TADutta, AWalter, JCMol Cell 9:233-4011282021Pubmed2001Initiating DNA synthesis: from recruiting to activating the MCM complex.Lei, MTye, Bik KJ Cell Sci 114:1447-5414766746Pubmed2004Primer utilization by DNA polymerase alpha-primase is influenced by its interaction with Mcm10pFien, KCho, YSLee, JKRaychaudhuri, STappin, IHurwitz, JJ Biol Chem 279:16144-539745018Pubmed1998The essential schizosaccharomyces pombe cdc23 DNA replication gene shares structural and functional homology with the Saccharomyces cerevisiae DNA43 (MCM10) geneAves, SJTongue, NFoster, AJHart, EACurr Genet 34:164-71

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. This reaction takes place in the 'nucleus'.

Reactome DB_ID: 68560

Reactome DB_ID: 68536

EQUAL

546

EQUAL

Reactome DB_ID: 156564

MCM10:active pre-replicative complex [nucleoplasm]

MCM10:active pre-replicative complex

Reactome DB_ID: 156562

active pre-replicative complex [nucleoplasm]

active pre-replicative complex

Reactome DB_ID: 68558

Reactome DB_ID: 68543

Reactome Database ID Release 70156562Database identifier. Use 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-156562

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156562.1

Reactome DB_ID: 68403

EQUAL

875

EQUAL

Reactome Database ID Release 70156564Database identifier. Use 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-156564

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156564.2Reactome Database ID Release 7068940Database identifier. Use 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-68940

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68940.212045100Pubmed2002DNA replication in eukaryotic cells.Bell, SPDutta, AAnnu Rev Biochem 71:333-74

Cdt1 associates with geminin

At 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. This reaction takes place in the 'nucleoplasm'.

Reactome DB_ID: 68536

EQUAL

546

EQUAL

Reactome DB_ID: 113554

UniProt:O75496 GMNN

GMNN

GMNNFUNCTION Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle.FUNCTION Inhibits the transcriptional activity of a subset of Hox proteins, enrolling them in cell proliferative control.SUBUNIT Homotetramer. Interacts with CDT1; this inhibits binding of the MCM complex to origins of replication. The complex with CDT1 exists in two forms, a "permissive" heterotrimer and an "inhibitory" heterohexamer. Interacts (via coiled-coil domain) with IDAS (via coiled-coil domain); this targets GMNN to the nucleus. The heterodimer formed by GMNN and MCIDAS has much lower affinity for CDT1 than the GMNN homodimer. Interacts with a subset of Hox proteins, affinity increasing from anterior to posterior types, the strongest interaction being with HOXB1, HOXC9 and HOXD10. Interacts with LRWD1 from G1/S to mitosis.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.

UniProtO75496

EQUAL

209

EQUAL

Reactome DB_ID: 156502

Cdt1:geminin [nucleoplasm]

Cdt1:geminin

Reactome DB_ID: 68536

EQUAL

546

EQUAL

Reactome DB_ID: 113554

EQUAL

209

EQUAL

Reactome Database ID Release 70156502Database identifier. Use 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-156502

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-156502.1Reactome Database ID Release 7069299Database identifier. Use 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-69299

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69299.211125146Pubmed2000Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.Wohlschlegel, JADwyer, BTDhar, SKCvetic, CWalter, JCDutta, AScience 290:2309-12

CDK and DDK associate with the Mcm10:pre-replicative complex

At 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. This reaction takes place in the 'nucleus'.

Reactome DB_ID: 68380

CDK [nucleoplasm]

CDK

Reactome DB_ID: 68365

UniProt:P24941 CDK2

CDK2

CDK2CDKN2FUNCTION 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).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.

UniProtP24941

EQUAL

298

EQUAL

Reactome DB_ID: 68379

cyclin [nucleoplasm]

cyclin

Reactome Database ID Release 7068380Database identifier. Use 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-68380

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68380.1

Reactome DB_ID: 68388

DDK [nucleoplasm]

DDK

Reactome DB_ID: 68387

UniProt:Q9UBU7 DBF4

DBF4

DBF4ZDBF1DBF4AASKFUNCTION 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.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.

UniProtQ9UBU7

EQUAL

674

EQUAL

Reactome DB_ID: 51781

UniProt:O00311 CDC7

CDC7

CDC7L1CDC7FUNCTION 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.

UniProtO00311

EQUAL

574

EQUAL

Reactome Database ID Release 7068388Database identifier. Use 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-68388

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68388.1

Reactome DB_ID: 156564

Reactome DB_ID: 68561

CDK:DDK:MCM10:active pre-replicative complex [nucleoplasm]

CDK:DDK:MCM10:active pre-replicative complex

Reactome DB_ID: 68380

Reactome DB_ID: 68388

Reactome DB_ID: 156564

Reactome Database ID Release 7068561Database identifier. Use 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-68561

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68561.2Reactome Database ID Release 7068918Database identifier. Use 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-68918

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68918.310523313Pubmed1999Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.Jiang, WMcDonald, DHope, TJHunter, TonyEMBO J 18:5703-1310373557Pubmed1999A 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 19:5083-95

2.7.10

Mcm2-7 is phosphorylated by DDK

At 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. This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.

Reactome DB_ID: 68558

Reactome DB_ID: 29358

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 68569

p-MCM2-7 [nucleoplasm]

p-MCM2-7

Reactome DB_ID: 68558

Reactome DB_ID: 113550

phosphate(3-) [ChEBI:18367]

phosphate(3-)

ChEBI18367Reactome Database ID Release 7068569Database identifier. Use 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-68569

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68569.2

Reactome DB_ID: 113582

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 68388

GO0004713

GO molecular function

Reactome Database ID Release 7068401Database identifier. Use 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 7068954Database identifier. Use 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-68954

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-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 275:29042-52

Cdc45 associates with the pre-replicative complex at the origin

Once 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: 68561

Reactome DB_ID: 68563

UniProt:O75419 CDC45

CDC45

UNQ374/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.

UniProtO75419

EQUAL

566

EQUAL

Reactome DB_ID: 68564

CDK:DDK:MCM10:active pre-replicative complex:CDC45 [nucleoplasm]

CDK:DDK:MCM10:active pre-replicative complex:CDC45

Reactome DB_ID: 68561

Reactome DB_ID: 68563

EQUAL

566

EQUAL

Reactome Database ID Release 7068564Database identifier. Use 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-68564

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68564.2Reactome Database ID Release 7068917Database identifier. Use 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-68917

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68917.312438414Pubmed2002The 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 159:541-79554851Pubmed1998Formation of a preinitiation complex by S-phase cyclin CDK-dependent loading of Cdc45p onto chromatin.Zou, LStillman, BScience 280:593-611296242Pubmed2001Sld3, which interacts with Cdc45 (Sld4), functions for chromosomal DNA replication in Saccharomyces cerevisiae.Kamimura, YTak, YSSugino, AAraki, HEMBO J 20:2097-10710757793Pubmed2000Assembly 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 22:555-669335335Pubmed1997Components and dynamics of DNA replication complexes in S. cerevisiae: redistribution of MCM proteins and Cdc45p during S phase.Aparicio, OMWeinstein, DMBell, SPCell 91:59-697708676Pubmed1995Cell 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 92:2514-89660782Pubmed1998The human homolog of Saccharomyces cerevisiae CDC45.Saha, PThome, KCYamaguchi, RHou, ZWeremowicz, SDutta, AJ Biol Chem 273:18205-910790374Pubmed2000DNA synthesis at individual replication forks requires the essential initiation factor Cdc45p.Tercero, JALabib, KDiffley, JFEMBO J 19:2082-9310430907Pubmed1999Differential assembly of Cdc45p and DNA polymerases at early and late origins of DNA replication.Aparicio, OMStout, AMBell, SPProc Natl Acad Sci U S A 96:9130-510518787Pubmed1999Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha.Kukimoto, IIgaki, HKanda, TEur J Biochem 265:936-43

DNA Replication Factor A (RPA) associates with the pre-replicative complex at the origin

After 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: 68564

Reactome DB_ID: 68567

RPA1-4 [nucleoplasm]

RPA1-4

DNA Replication Factor ARFA

Reactome DB_ID: 68457

UniProt:P15927 RPA2

RPA2

RPA2REPA2RPA32RPA34FUNCTION 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.

UniProtP15927

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Reactome DB_ID: 68461

UniProt:P27694 RPA1

RPA1

RPA70RPA1REPA1FUNCTION As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism (PubMed:27723720, PubMed:27723717). Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage (PubMed:17765923). Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Plays also a role in base excision repair (BER) probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance (PubMed:17959650). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105).SUBUNIT Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3 (PubMed:27723720, PubMed:27723717). Also component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2 (PubMed:7760808, PubMed:19116208). The DNA-binding activity may reside exclusively on the RPA1 subunit. Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA) (PubMed:24332808). Interacts with RIPK1 (PubMed:16135809). Interacts with the polymerase alpha subunit POLA1/p180; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288). Interacts with RAD51 and SENP6 to regulate DNA repair (PubMed:20705237). Interacts with HELB; this interaction promotes HELB recruitment to chromatin following DNA damage (PubMed:22194613, PubMed:26774285). Interacts with PRIMPOL (PubMed:24126761). Interacts with XPA; the interaction is direct and associates XPA with the RPA complex (PubMed:7700386, PubMed:9699634, PubMed:10563794). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717).PTM DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).PTM Sumoylated on lysine residues Lys-449 and Lys-577, with Lys-449 being the major site. Sumoylation promotes recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. Desumoylated by SENP6.SIMILARITY Belongs to the replication factor A protein 1 family.

UniProtP27694

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616

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Reactome DB_ID: 68566

UniProt:Q13156 RPA4

RPA4

RPA4FUNCTION 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.

UniProtQ13156

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Reactome DB_ID: 68459

UniProt:P35244 RPA3

RPA3

RPA3REPA3RPA14FUNCTION 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).

UniProtP35244

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Reactome Database ID Release 7068567Database identifier. Use 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-68567

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68567.2

Reactome DB_ID: 68568

CDK:DDK:MCM10:active pre-replicative complex:CDC45:RPA1-4 [nucleoplasm]

CDK:DDK:MCM10:active pre-replicative complex:CDC45:RPA1-4

Reactome DB_ID: 68564

Reactome DB_ID: 68567

Reactome Database ID Release 7068568Database identifier. Use 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-68568

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68568.2Reactome Database ID Release 7068916Database identifier. Use 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-68916

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68916.210882098Pubmed2000Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.Walter, JNewport, JMol Cell 5:617-279242902Pubmed1997Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism.Wold, MSAnnu Rev Biochem 66:61-9210473346Pubmed1999Replication protein A (RPA): the eukaryotic SSB.Iftode, CDaniely, YBorowiec, James ACrit Rev Biochem Mol Biol 34:141-801311258Pubmed1992Interaction of DNA polymerase alpha-primase with cellular replication protein A and SV40 T antigen.Dornreiter, IErdile, LFGilbert, IUvon Winkler, DKelly, TJEMBO J 11:769-762200738Pubmed1990Cell-cycle-regulated phosphorylation of DNA replication factor A from human and yeast cells.Din, SBrill, SJFairman, MPStillman, BGenes Dev 4:968-77

DNA polymerase alpha:primase binds at the origin

DNA 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: 68507

DNA polymerase alpha:primase [nucleoplasm]

DNA polymerase alpha:primase

primosomeDNA Pol alpha:primase

Reactome DB_ID: 68495

UniProt:P49643 PRIM2

PRIM2

PRIM2PRIM2AFUNCTION DNA primase is the polymerase that synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication.SUBUNIT Heterodimer of a small subunit and a large subunit.SIMILARITY Belongs to the eukaryotic-type primase large subunit family.

UniProtP49643

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509

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Reactome DB_ID: 68497

UniProt:P49642 PRIM1

PRIM1

PRIM1FUNCTION DNA primase is the polymerase that synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication.SUBUNIT Heterodimer of a small subunit and a large subunit.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.

UniProtP49642

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420

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Reactome DB_ID: 68487

UniProt:P09884 POLA1

POLA1

POLA1POLAFUNCTION Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) 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 The DNA polymerase alpha complex is composed of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the small and the large primase subunits PRIM1 and PRIM2 respectively. Interacts with PARP1; this interaction functions as part of the control of replication fork progression. Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA. Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp.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 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.

UniProtP09884

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1462

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Reactome DB_ID: 68493

UniProt:Q14181 POLA2

POLA2

POLA2FUNCTION May play an essential role at the early stage of chromosomal DNA replication by coupling the polymerase alpha/primase complex to the cellular replication machinery.SUBUNIT DNA polymerase alpha:primase is a four subunit enzyme complex, which is assembled throughout the cell cycle, and consists of the two DNA polymerase subunits A and B, and the DNA primase large and small subunits. Subunit B binds to subunit A.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.

UniProtQ14181

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598

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Reactome Database ID Release 7068507Database identifier. Use 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-68507

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68507.1

Reactome DB_ID: 68485

DNA polymerase epsilon:origin complex [nucleoplasm]

DNA polymerase epsilon:origin complex

Reactome DB_ID: 68419

Reactome DB_ID: 68483

DNA polymerase epsilon [nucleoplasm]

DNA polymerase epsilon

Reactome DB_ID: 8866684

UniProt:Q9NR33 POLE4

POLE4

POLE4FUNCTION May play a role in allowing polymerase epsilon to carry out its replication and/or repair function.SUBUNIT Component of the epsilon DNA polymerase complex consisting of four subunits: POLE, POLE2, POLE3 and POLE4. Interaction with POLE3 is a prerequisite for further binding with POLE and POLE2.

UniProtQ9NR33

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Reactome DB_ID: 68482

UniProt:P56282 POLE2

POLE2

POLE2DPE2FUNCTION Participates in DNA repair and in chromosomal DNA replication.SUBUNIT Component of the epsilon DNA polymerase complex consisting of four subunits: POLE, 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.

UniProtP56282

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527

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Reactome DB_ID: 68473

UniProt:Q07864 POLE

POLE

POLE1POLEFUNCTION Participates in DNA repair and in chromosomal DNA replication.SUBUNIT Catalytic and central component of the epsilon DNA polymerase complex consisting of four subunits: POLE, 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 complexing subunits B and C. The C-terminus may also regulate the catalytic activities of the enzyme.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.

UniProtQ07864

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2286

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Reactome DB_ID: 8866685

UniProt:Q9NRF9 POLE3

POLE3

CHRAC17POLE3FUNCTION Forms a complex with DNA polymerase epsilon subunit CHRAC1 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome-remodeling activity of ISWI/SNF2H and ACF1.SUBUNIT Component of the epsilon DNA polymerase complex consisting of four subunits: POLE, 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.

UniProtQ9NRF9

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Reactome Database ID Release 7068483Database identifier. Use 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-68483

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68483.2Reactome Database ID Release 7068485Database identifier. Use 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-68485

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68485.1

Reactome DB_ID: 68510

DNA polymerase alpha:primase:DNA polymerase alpha:origin complex [nucleoplasm]

DNA polymerase alpha:primase:DNA polymerase alpha:origin complex

Reactome DB_ID: 68507

Reactome DB_ID: 68485

Reactome Database ID Release 7068510Database identifier. Use 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-68510

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68510.1Reactome Database ID Release 7068914Database identifier. Use 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-68914

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68914.48253737Pubmed1994Enzymatic characterization of the individual mammalian primase subunits reveals a biphasic mechanism for initiation of DNA replication.Copeland, WCWang, TSJ Biol Chem 268:26179-8911395402Pubmed2002DNA primases.Frick, DNRichardson, CCAnnu Rev Biochem 70:39-80

ACTIVATION

Reactome Database ID Release 7069385Database identifier. Use 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-69385

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69385.2

Reactome DB_ID: 68568

DNA polymerase epsilon binds at the origin

At 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.

Reactome DB_ID: 68419

Reactome DB_ID: 68483

Reactome DB_ID: 68485

Reactome Database ID Release 7068960Database identifier. Use 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-68960

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68960.3

ACTIVATION

Reactome Database ID Release 7068961Database identifier. Use 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-68961

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68961.2

Reactome DB_ID: 68568

Reactome Database ID Release 7068962Database identifier. Use 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-68962

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68962.310801458Pubmed2000ATPase switches controlling DNA replication initiation.Lee, DGBell, SPCurr Opin Cell Biol 12:280-510970868Pubmed2000Regulation of origin recognition complex conformation and ATPase activity: differential effects of single-stranded and double-stranded DNA binding.Lee, DGMakhov, AMKlemm, RDBell, SPEMBO J 19:4774-8211459976Pubmed2001ATP 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 276:26666-739765232Pubmed1998ORC5L, 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 270:1667-7111779870Pubmed2002Nuclear organization of DNA replication initiation proteins in mammalian cells.Fujita, MIshimi, YNakamura, HKiyono, TTsurumi, TJ Biol Chem 277:10354-6112169736Pubmed2002Orc6 involved in DNA replication, chromosome segregation, and cytokinesis.Prasanth, SGPrasanth, KVStillman, BScience 297:1026-319829972Pubmed1999The 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 273:32421-99038340Pubmed1997Coordinate binding of ATP and origin DNA regulates the ATPase activity of the origin recognition complex.Klemm, RDAustin, RJBell, SPCell 88:493-50211395502Pubmed2001Architecture of the human origin recognition complex.Dhar, SKDelmolino, LDutta, AJ Biol Chem 276:29067-7110402192Pubmed1999latheo 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 23:45-549353276Pubmed1997Identification of HsORC4, a member of the human origin of replication recognition complex.Quintana, DGHou, ZhThome, KCHendricks, MSaha, PDutta, AJ Biol Chem 272:28247-51