Although, DNA replication occurs in the S phase of the cell cycle, the formation of the DNA replication pre-initiation complex begins during G1 phase.
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Reactome-Converter
Pathway is converted from Reactome ID: 69002
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Reactome version: 75
Reactome Author
Reactome Author: Davey, Megan J, O'Donnell, Michael, Tye, Bik K
Méndez J, Stillman B.; ''Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis.''; PubMedEurope PMCScholia
Kumagai H, Sato N, Yamada M, Mahony D, Seghezzi W, Lees E, Arai K, Masai H.; ''A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells.''; PubMedEurope PMCScholia
Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A.; ''Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.''; PubMedEurope PMCScholia
Walter J, Newport J.; ''Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.''; PubMedEurope PMCScholia
Masai H, Matsui E, You Z, Ishimi Y, Tamai K, Arai K.; ''Human Cdc7-related kinase complex. In vitro phosphorylation of MCM by concerted actions of Cdks and Cdc7 and that of a criticial threonine residue of Cdc7 bY Cdks.''; PubMedEurope PMCScholia
McGarry TJ, Kirschner MW.; ''Geminin, an inhibitor of DNA replication, is degraded during mitosis.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Herbig U, Marlar CA, Fanning E.; ''The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells.''; PubMedEurope PMCScholia
Izumi M, Yanagi K, Mizuno T, Yokoi M, Kawasaki Y, Moon KY, Hurwitz J, Yatagai F, Hanaoka F.; ''The human homolog of Saccharomyces cerevisiae Mcm10 interacts with replication factors and dissociates from nuclease-resistant nuclear structures in G(2) phase.''; PubMedEurope PMCScholia
Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A.; ''The human homolog of Saccharomyces cerevisiae CDC45.''; PubMedEurope PMCScholia
Quintana DG, Thome KC, Hou ZH, Ligon AH, Morton CC, Dutta A.; ''ORC5L, a new member of the human origin recognition complex, is deleted in uterine leiomyomas and malignant myeloid diseases.''; PubMedEurope PMCScholia
Dhar SK, Delmolino L, Dutta A.; ''Architecture of the human origin recognition complex.''; PubMedEurope PMCScholia
Jiang W, McDonald D, Hope TJ, Hunter T.; ''Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.''; PubMedEurope PMCScholia
Ritzi M, Baack M, Musahl C, Romanowski P, Laskey RA, Knippers R.; ''Human minichromosome maintenance proteins and human origin recognition complex 2 protein on chromatin.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Zou L, Stillman B.; ''Assembly of a complex containing Cdc45p, replication protein A, and Mcm2p at replication origins controlled by S-phase cyclin-dependent kinases and Cdc7p-Dbf4p kinase.''; PubMedEurope PMCScholia
Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS.; ''Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.''; PubMedEurope PMCScholia
Ohtani K, Tsujimoto A, Ikeda M, Nakamura M.; ''Regulation of cell growth-dependent expression of mammalian CDC6 gene by the cell cycle transcription factor E2F.''; PubMedEurope PMCScholia
Li Y, Pursell ZF, Linn S.; ''Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.''; PubMedEurope PMCScholia
Kukimoto I, Igaki H, Kanda T.; ''Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha.''; PubMedEurope PMCScholia
Li Y, Asahara H, Patel VS, Zhou S, Linn S.; ''Purification, cDNA cloning, and gene mapping of the small subunit of human DNA polymerase epsilon.''; PubMedEurope PMCScholia
Zhang Y, Baranovskiy AG, Tahirov TH, Pavlov YI.; ''The C-terminal domain of the DNA polymerase catalytic subunit regulates the primase and polymerase activities of the human DNA polymerase α-primase complex.''; PubMedEurope PMCScholia
Jiang W, Wells NJ, Hunter T.; ''Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.''; PubMedEurope PMCScholia
Vashee S, Simancek P, Challberg MD, Kelly TJ.; ''Assembly of the human origin recognition complex.''; PubMedEurope PMCScholia
Li CJ, DePamphilis ML.; ''Mammalian Orc1 protein is selectively released from chromatin and ubiquitinated during the S-to-M transition in the cell division cycle.''; PubMedEurope PMCScholia
Volkening M, Hoffmann I.; ''Involvement of human MCM8 in prereplication complex assembly by recruiting hcdc6 to chromatin.''; PubMedEurope PMCScholia
The MCM2-7 complex, an essential component of the pre-replication complex, recruits CDC6 and CDT1 proteins to the origin. MCM8, another member of the MCM family has been found to bind to chromatin during early G1 phase. MCM8 interacts specifically with the ORC2 protein.
At the beginning of this reaction, 1 molecule of 'Orc2:origin', and 1 molecule of 'Orc3' are present. At the end of this reaction, 1 molecule of 'Orc3:Orc2:origin' is present.
At the beginning of this reaction, 1 molecule of 'Orc3:Orc2:origin', and 1 molecule of 'Orc5' are present. At the end of this reaction, 1 molecule of 'Orc5:Orc3:Orc2:origin' is present.
At the beginning of this reaction, 1 molecule of 'Orc4', and 1 molecule of 'Orc5:Orc3:Orc2:origin' are present. At the end of this reaction, 1 molecule of 'Orc4:Orc5:Orc3:Orc2:origin' is present.
At the beginning of this reaction, 1 molecule of 'Orc4:Orc5:Orc3:Orc2:origin', and 1 molecule of 'Orc1' are present. At the end of this reaction, 1 molecule of 'Orc1:Orc4:Orc5:Orc3:Orc2:origin' is present.
At the beginning of this reaction, 1 molecule of 'Orc1:Orc4:Orc5:Orc3:Orc2:origin', and 1 molecule of 'Orc6' are present. At the end of this reaction, 1 molecule of 'ORC complex bound to origin' is present.
At the beginning of this reaction, 1 molecule of 'ORC:origin', and 1 molecule of 'CDC6' are present. At the end of this reaction, 1 molecule of 'CDC6:ORC:origin complex' is present.
At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'Cdt1:geminin' are present. At the end of this reaction, 1 molecule of 'geminin:ubiquitin complex', and 1 molecule of 'Cdt1' are present.
At the beginning of this reaction, 1 molecule of 'geminin:ubiquitin complex' is present. At the end of this reaction, 1 molecule of 'ubiquitin' is present.
This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.
At the beginning of this reaction, 1 molecule of 'CDT1', and 1 molecule of 'CDC6:ORC:origin complex' are present. At the end of this reaction, 1 molecule of 'CDT1:CDC6:ORC:origin complex' is present.
Genetic studies in S. cerevisiae indicate that wild-type Cdc6 function is required for correctly timed loading of Mcm2-7 onto ORC. Biochemical studies indicate that the human and Xenopus Cdc6 proteins likewise are required for Mcm2-7 loading, and that they are ATPase switches. Specifically, Cdc6 may function as a clamp loader, assembling Mcm2-7 onto DNA in an ATP-dependent reaction. All known Cdc6 proteins have the Walker A and Walker B sequence motifs characteristic of the AAA+ superfamily of ATPases. As expected for an AAA+ protein, human Cdc6 binds and slowly hydrolyzes ATP in vitro. ATP hydrolysis was disrupted by mutations of the Walker B motif, while both binding and hydrolysis were disrupted by Walker A mutations. Microinjection of either mutant protein into HeLa cells blocked their progression through S phase. Both wild-type and mutant proteins can dimerize in vitro, and studies with Xenopus egg extracts suggest that Cdc6 functions in vivo as a dimer or larger multimer. In Xenopus extracts depleted of Cdc6 and reconstituted with either mutant protein, recruitment of Mcm2-7 to chromatin failed.
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.
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.
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.
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.
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).
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.
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'.
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.
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.
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DataNodes
pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complexalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexpre-replicative
complexAnnotated Interactions
pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complex:CDC45pre-replicative
complexpre-replicative
complexalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexepsilon:origin
complexpre-replicative
complexpre-replicative
complexThis reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'cytosol'.
This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.
This reaction takes place in the 'nucleoplasm'.