DNA Replication Pre-Initiation (Homo sapiens)

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12, 16, 26261, 412, 169, 15192, 8146, 7, 23, 2722, 236, 275, 1842246, 21, 27201, 46, 276, 11, 23, 2726nucleoplasmcytosolMCM4 UBB(77-152) MCM4 MCM3 ORC2 Cdt1:gemininE2F3 ORC2 POLE3 UBC(533-608) PSME2 RPA2 PSMC1 POLE p-MCM2-7Orc1:Orc4:Orc5:Orc3:Orc2:originORC2 PSMD13 Orc2:originorigin of replication MCM5 MCM3 ORC3 MCM6 ORC4 CDC6 DNA polymerasealpha:primase:DNApolymerasealpha:origincomplexORC6 MCM2 CDKUBC(77-152) PSMD3 MCM10 PSMD8 RPS27A(1-76) Orc4:Orc5:Orc3:Orc2:originorigin of replication POLE2 CDT1 ORC3 MCM2 ORC1 ORC3 UBC(305-380) MCM8GMNN Orc3:Orc2:originMCM2 ORC3 ORC3 ORC5 UBC(609-684) PSMA3 UBA52(1-76) RPA3 PSMB1 UBA52(1-76) MCM4 ORC4 PSMB5 origin of replication origin of replication origin of replication CDC6:ORC:origincomplexMCM7 CDC45 MCM6 PSMC4 POLE PRIM1 PSMA5 E2F1/2/3MCM5 POLE4 MCM6 ORC complex bound tooriginPSMB11 ORC3 PSME3 MCM3 Orc5:Orc3:Orc2:originorigin ofreplicationPOLA1 ORC5 UBC(533-608) ORC4 origin of replication MCM10:pre-replicative complexUBB(1-76) POLE3 CDC6 ORC2 MCM8 ORC1CDC6 PSMB3 ORC3 PRIM2 CDK2 MCM7 ORC4 E2F1 ORC2 ORC5 PSMC2 MCM2 ORC2 ORC2 DNA polymeraseepsilonCdt1:gemininUBC(609-684) CDK:DDK:MCM10:activepre-replicativecomplexORC:origin ofreplicationORC4 DBF4 ORC6 ORC6 MCM5 origin of replication MCM8 ORC4 MCM8 MCM6 DNA polymeraseepsilon:origincomplexCDC45MCM8 MCM5 MCM8 ORC4 ORC3 PSMD11 PSMA7 pre-replicativecomplexMCM3 UBC(457-532) ORC1 PSMB7 ORC6 MCM3 PSMD1 UBC(381-456) RPA2 ADPRPA3 CDK:DDK:MCM10:activepre-replicativecomplex:CDC45PSME4 origin of replication origin of replication GMNN UBC(77-152) MCM3 ORC1 MCM4 PSMB6 ORC6 POLE3 ORC5 MCM10 MCM2 MCM8 geminin:ubiquitincomplexMCM6 ORC2 POLE2 PSMD4 UBC(381-456) PSMD2 ORC6 CDC6 PSMC5 PSMB2 origin of replication ORC6 MCM4 UBC(229-304) CDC45 CDT1:CDC6:ORC:origincomplexMCM2 ORC3 POLE2 ATPORC6 ORC5 MCM7 RPA4 ORC2 origin of replication ORC2 CDT1 ORC1 origin of replication CDC6 CDT1 UBC(1-76) 26S proteasomePOLE4 MCM8 PSMB9 MCM5 CDC7 PSMD6 MCM10 MCM5 PRIM2 ORC1 POLA2 ORC3 CDK:DDK:MCM10:activepre-replicativecomplex:CDC45:RPA1-4UBB(153-228) PSMB4 DBF4 PSMA6 ORC5 CDK2 DDKPSMB8 RPS27A(1-76) POLA2 ORC4 PSMC6 ORC3 PSMD9 UBB(153-228) origin of replication ORC1 origin of replication cyclin ORC5 MCM6 RPA4 ORC4 MCM7 MCM4 UBC(457-532) MCM5 MCM10 UBC(305-380) ORC2 MCM2 CDT1 GMNNUBC(153-228) ORC1 ORC3 CDC6 CDT1PSME1 Pi ORC2 ORC2 MCM3 CDC6 UBB(77-152) ORC5 UBC(229-304) CDT1 CDT1CDC6RPA1-4cyclin MCM2 PSMA8 PSMA1 MCM7 PSMA4 DBF4 ORC6 CDC7 MCM7 PSMD5 PSMD10 CDK2 MCM4 UBB(1-76) CDC6 E2F2 ORC3 POLE UbMCM10PSMD7 MCM7 ORC1 ORC4 SHFM1 MCM10 ORC6 ORC5 PSMD14 ORC5 ORC2 CDC7 origin of replication ORC3ORC1 ORC5 DNA polymerasealpha:primaseCDC7 ORC5 MCM8 origin of replication MCM7 ORC1 MCM6 PSMD12 ORC4MCM6 PRIM1 GMNN ORC5POLE4 cyclin PSMC3 POLA1 MCM8 MCM5 ORC1 PSMB10 MCM2-7origin of replication MCM3 MCM10:activepre-replicativecomplexUBC(153-228) UBC(1-76) CDK2 ORC4 ORC6ORC3 RPA1 PSMA2 ORC5 DBF4 RPA1 cyclin ORC4 ORC2 PSMF1 MCM4 24, 256, 276, 27106, 23, 273, 176, 276, 27132, 86, 23, 276, 23, 2717


Description

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. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 69002
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Davey, Megan J, O'Donnell, Michael, Tye, Bik K

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. McGarry TJ, Kirschner MW.; ''Geminin, an inhibitor of DNA replication, is degraded during mitosis.''; PubMed Europe PMC
  2. 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.''; PubMed Europe PMC
  3. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC
  4. Wohlschlegel JA, Dwyer BT, Dhar SK, Cvetic C, Walter JC, Dutta A.; ''Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.''; PubMed Europe PMC
  5. Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A.; ''The human homolog of Saccharomyces cerevisiae CDC45.''; PubMed Europe PMC
  6. Vashee S, Simancek P, Challberg MD, Kelly TJ.; ''Assembly of the human origin recognition complex.''; PubMed Europe PMC
  7. 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.''; PubMed Europe PMC
  8. Jiang W, McDonald D, Hope TJ, Hunter T.; ''Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication.''; PubMed Europe PMC
  9. 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.''; PubMed Europe PMC
  10. Hubscher U, Maga G, Spadari S.; ''Eukaryotic DNA polymerases.''; PubMed Europe PMC
  11. 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.''; PubMed Europe PMC
  12. 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.''; PubMed Europe PMC
  13. Jiang W, Wells NJ, Hunter T.; ''Multistep regulation of DNA replication by Cdk phosphorylation of HsCdc6.''; PubMed Europe PMC
  14. 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.''; PubMed Europe PMC
  15. 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.''; PubMed Europe PMC
  16. Walter J, Newport J.; ''Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha.''; PubMed Europe PMC
  17. 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.''; PubMed Europe PMC
  18. Kukimoto I, Igaki H, Kanda T.; ''Human CDC45 protein binds to minichromosome maintenance 7 protein and the p70 subunit of DNA polymerase alpha.''; PubMed Europe PMC
  19. Herbig U, Marlar CA, Fanning E.; ''The Cdc6 nucleotide-binding site regulates its activity in DNA replication in human cells.''; PubMed Europe PMC
  20. 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.''; PubMed Europe PMC
  21. 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.''; PubMed Europe PMC
  22. Volkening M, Hoffmann I.; ''Involvement of human MCM8 in prereplication complex assembly by recruiting hcdc6 to chromatin.''; PubMed Europe PMC
  23. 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.''; PubMed Europe PMC
  24. 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.''; PubMed Europe PMC
  25. Li Y, Pursell ZF, Linn S.; ''Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon.''; PubMed Europe PMC
  26. Bell SP, Dutta A.; ''DNA replication in eukaryotic cells.''; PubMed Europe PMC
  27. Dhar SK, Delmolino L, Dutta A.; ''Architecture of the human origin recognition complex.''; PubMed Europe PMC

History

CompareRevisionActionTimeUserComment
101664view13:43, 1 November 2018DeSlOntology Term : 'DNA replication pathway' added !
101662view11:51, 1 November 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CDC45 ProteinO75419 (Uniprot-TrEMBL)
CDC45ProteinO75419 (Uniprot-TrEMBL)
CDC6 ProteinQ99741 (Uniprot-TrEMBL)
CDC6:ORC:origin complexComplexR-HSA-68543 (Reactome)
CDC6ProteinQ99741 (Uniprot-TrEMBL)
CDC7 ProteinO00311 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ComplexR-HSA-68568 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
ComplexR-HSA-68564 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
ComplexR-HSA-68561 (Reactome)
CDKComplexR-HSA-68380 (Reactome)
CDT1 ProteinQ9H211 (Uniprot-TrEMBL)
CDT1:CDC6:ORC:origin complexComplexR-HSA-68544 (Reactome)
CDT1ProteinQ9H211 (Uniprot-TrEMBL)
Cdt1:gemininComplexR-HSA-156502 (Reactome)
Cdt1:gemininComplexR-HSA-68537 (Reactome)
DBF4 ProteinQ9UBU7 (Uniprot-TrEMBL)
DDKComplexR-HSA-68388 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
ComplexR-HSA-68510 (Reactome)
DNA polymerase alpha:primaseComplexR-HSA-68507 (Reactome)
DNA polymerase

epsilon:origin

complex
ComplexR-HSA-68485 (Reactome)
DNA polymerase epsilonComplexR-HSA-68483 (Reactome)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1/2/3ComplexR-HSA-68640 (Reactome)
E2F2 ProteinQ14209 (Uniprot-TrEMBL)
E2F3 ProteinO00716 (Uniprot-TrEMBL)
GMNN ProteinO75496 (Uniprot-TrEMBL)
GMNNProteinO75496 (Uniprot-TrEMBL)
MCM10 ProteinQ7L590 (Uniprot-TrEMBL)
MCM10:active

pre-replicative

complex
ComplexR-HSA-156564 (Reactome)
MCM10:pre-replicative complexComplexR-HSA-68560 (Reactome)
MCM10ProteinQ7L590 (Uniprot-TrEMBL)
MCM2 ProteinP49736 (Uniprot-TrEMBL)
MCM2-7ComplexR-HSA-68558 (Reactome)
MCM3 ProteinP25205 (Uniprot-TrEMBL)
MCM4 ProteinP33991 (Uniprot-TrEMBL)
MCM5 ProteinP33992 (Uniprot-TrEMBL)
MCM6 ProteinQ14566 (Uniprot-TrEMBL)
MCM7 ProteinP33993 (Uniprot-TrEMBL)
MCM8 ProteinQ9UJA3 (Uniprot-TrEMBL)
MCM8ProteinQ9UJA3 (Uniprot-TrEMBL)
ORC complex bound to originComplexR-HSA-176958 (Reactome)
ORC1 ProteinQ13415 (Uniprot-TrEMBL)
ORC1ProteinQ13415 (Uniprot-TrEMBL)
ORC2 ProteinQ13416 (Uniprot-TrEMBL)
ORC3 ProteinQ9UBD5 (Uniprot-TrEMBL)
ORC3ProteinQ9UBD5 (Uniprot-TrEMBL)
ORC4 ProteinO43929 (Uniprot-TrEMBL)
ORC4ProteinO43929 (Uniprot-TrEMBL)
ORC5 ProteinO43913 (Uniprot-TrEMBL)
ORC5ProteinO43913 (Uniprot-TrEMBL)
ORC6 ProteinQ9Y5N6 (Uniprot-TrEMBL)
ORC6ProteinQ9Y5N6 (Uniprot-TrEMBL)
ORC:origin of replicationComplexR-HSA-68540 (Reactome)
Orc1:Orc4:Orc5:Orc3:Orc2:originComplexR-HSA-68592 (Reactome)
Orc2:originComplexR-HSA-68511 (Reactome)
Orc3:Orc2:originComplexR-HSA-68514 (Reactome)
Orc4:Orc5:Orc3:Orc2:originComplexR-HSA-68520 (Reactome)
Orc5:Orc3:Orc2:originComplexR-HSA-68517 (Reactome)
POLA1 ProteinP09884 (Uniprot-TrEMBL)
POLA2 ProteinQ14181 (Uniprot-TrEMBL)
POLE ProteinQ07864 (Uniprot-TrEMBL)
POLE2 ProteinP56282 (Uniprot-TrEMBL)
POLE3 ProteinQ9NRF9 (Uniprot-TrEMBL)
POLE4 ProteinQ9NR33 (Uniprot-TrEMBL)
PRIM1 ProteinP49642 (Uniprot-TrEMBL)
PRIM2 ProteinP49643 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
Pi MetaboliteCHEBI:18367 (ChEBI)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA1-4ComplexR-HSA-68567 (Reactome)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RPA4 ProteinQ13156 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
cyclin R-HSA-68379 (Reactome)
geminin:ubiquitin complexComplexR-HSA-68585 (Reactome)
origin of replicationR-ALL-68419 (Reactome)
origin of replication R-ALL-68419 (Reactome)
p-MCM2-7ComplexR-HSA-68569 (Reactome)
pre-replicative complexComplexR-HSA-68559 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-68825 (Reactome)
ADPArrowR-HSA-68954 (Reactome)
ATPR-HSA-68954 (Reactome)
CDC45R-HSA-68917 (Reactome)
CDC6:ORC:origin complexArrowR-HSA-68688 (Reactome)
CDC6:ORC:origin complexR-HSA-68826 (Reactome)
CDC6ArrowR-HSA-68637 (Reactome)
CDC6R-HSA-68688 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68914 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68916 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45:RPA1-4
ArrowR-HSA-68960 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
ArrowR-HSA-68917 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex:CDC45
R-HSA-68916 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
ArrowR-HSA-68918 (Reactome)
CDK:DDK:MCM10:active

pre-replicative

complex
R-HSA-68917 (Reactome)
CDKR-HSA-68918 (Reactome)
CDT1:CDC6:ORC:origin complexArrowR-HSA-68826 (Reactome)
CDT1:CDC6:ORC:origin complexR-HSA-68849 (Reactome)
CDT1ArrowR-HSA-68712 (Reactome)
CDT1ArrowR-HSA-68940 (Reactome)
CDT1R-HSA-68826 (Reactome)
CDT1R-HSA-69299 (Reactome)
Cdt1:gemininArrowR-HSA-69299 (Reactome)
Cdt1:gemininR-HSA-68712 (Reactome)
DDKR-HSA-68918 (Reactome)
DDKmim-catalysisR-HSA-68954 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
ArrowR-HSA-68914 (Reactome)
DNA polymerase alpha:primaseR-HSA-68914 (Reactome)
DNA polymerase

epsilon:origin

complex
ArrowR-HSA-68960 (Reactome)
DNA polymerase

epsilon:origin

complex
R-HSA-68914 (Reactome)
DNA polymerase epsilonR-HSA-68960 (Reactome)
E2F1/2/3ArrowR-HSA-68637 (Reactome)
GMNNR-HSA-69299 (Reactome)
MCM10:active

pre-replicative

complex
ArrowR-HSA-68940 (Reactome)
MCM10:active

pre-replicative

complex
R-HSA-68918 (Reactome)
MCM10:pre-replicative complexArrowR-HSA-68919 (Reactome)
MCM10:pre-replicative complexR-HSA-68940 (Reactome)
MCM10R-HSA-68919 (Reactome)
MCM2-7R-HSA-68849 (Reactome)
MCM2-7R-HSA-68954 (Reactome)
MCM8R-HSA-176973 (Reactome)
ORC complex bound to originArrowR-HSA-68615 (Reactome)
ORC complex bound to originR-HSA-176973 (Reactome)
ORC1R-HSA-68611 (Reactome)
ORC3R-HSA-68595 (Reactome)
ORC4R-HSA-68610 (Reactome)
ORC5R-HSA-68603 (Reactome)
ORC6R-HSA-68615 (Reactome)
ORC:origin of replicationArrowR-HSA-176973 (Reactome)
ORC:origin of replicationR-HSA-68688 (Reactome)
Orc1:Orc4:Orc5:Orc3:Orc2:originArrowR-HSA-68611 (Reactome)
Orc1:Orc4:Orc5:Orc3:Orc2:originR-HSA-68615 (Reactome)
Orc2:originR-HSA-68595 (Reactome)
Orc3:Orc2:originArrowR-HSA-68595 (Reactome)
Orc3:Orc2:originR-HSA-68603 (Reactome)
Orc4:Orc5:Orc3:Orc2:originArrowR-HSA-68610 (Reactome)
Orc4:Orc5:Orc3:Orc2:originR-HSA-68611 (Reactome)
Orc5:Orc3:Orc2:originArrowR-HSA-68603 (Reactome)
Orc5:Orc3:Orc2:originR-HSA-68610 (Reactome)
R-HSA-176973 (Reactome) 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.
R-HSA-68595 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68603 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68610 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68611 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68615 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68637 (Reactome) At the end of this reaction, 1 molecule of 'Cdc6' is present.



R-HSA-68688 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68712 (Reactome) 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.

This reaction takes place in the 'cytosol'.

R-HSA-68825 (Reactome) 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'.

R-HSA-68826 (Reactome) 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.

This reaction takes place in the 'nucleus'.

R-HSA-68849 (Reactome) 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.
R-HSA-68914 (Reactome) 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.
R-HSA-68916 (Reactome) 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.
R-HSA-68917 (Reactome) 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.
R-HSA-68918 (Reactome) 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'.

R-HSA-68919 (Reactome) 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).
R-HSA-68940 (Reactome) 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'.

R-HSA-68954 (Reactome) 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'.

R-HSA-68960 (Reactome) 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.



R-HSA-69299 (Reactome) 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'.

RPA1-4R-HSA-68916 (Reactome)
UbArrowR-HSA-68825 (Reactome)
UbR-HSA-68712 (Reactome)
geminin:ubiquitin complexArrowR-HSA-68712 (Reactome)
geminin:ubiquitin complexR-HSA-68825 (Reactome)
origin of replicationR-HSA-68960 (Reactome)
p-MCM2-7ArrowR-HSA-68954 (Reactome)
pre-replicative complexArrowR-HSA-68849 (Reactome)
pre-replicative complexR-HSA-68919 (Reactome)
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