S Phase (Homo sapiens)

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62315, 35, 406023, 26194834, 4339589606062305514, 24, 435230, 454750622950, 5138, 40, 5422, 61134, 16, 20, 21, 33...211, 24, 43, 536031, 32, 37, 40, 44...4, 18, 30, 33, 4676, 59, 6210, 12283631, 5613, 4313913, 17, 24, 422714, 24nucleoplasm2xAcK-SMC3 UBC(305-380) PSMD2 UBC(381-456) PRIM1 p-Y342-PTK6PDS5A UBA52(1-76) PSME2 SKP1 ORC4 PRIM2 ATPPRIM2 MCM7 CCNA2 RFC4 MCM6 origin of replication dTTPCDT1 Sister Chromosomal Arm SKP2 CDKN1A PSMF1 GINS1WAPAL Replication Fork POLA1 MCM4 p-T160-CDK2 CDC6 RFC5 CDC25AORC2 RNA primer RFC5 POLD2 UBC(77-152) UBA52(1-76) CDK2 RFC3 PCNA CDKN1AWAPAL POLA1 p-T286-CCND1 PSMA7 PSMB11 UBA52(1-76) CDC45GINS3 p-T187-CDKN1B PRIM1 RPS27A(1-76) PSMC1 CCNA:CDK2MCM5 p-Y15-CDK2 Okazaki fragmentCUL1:SKP1:SKP2GINS1 CAKphospho(T286)-CyclinD1:Cdk4DNA primer cyclin CDKN1A,CDKN1BORC3 PDS5B ORC1 UBB(1-76) UBC(533-608) UBC(533-608) RFCHeteropentamer:RNAprimer-DNAprimer:originduplexPOLA1 CDCA5 DNA primer POLA2 POLE2 DNA polymerasealpha:primase:DNApolymerasealpha:origincomplexPOLD1 multi-ubiquitinatedphospho-(T286)Cyclin D1PSMD11 CDK4 PSME2 CDK2 CCNA1 CDT1 POLD1 DNA primer CUL1 p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))POLD4 UBC(77-152) UBC(1-76) UBB(1-76) ADP2xAcK-SMC3 PSMB1 ATP CCNE1 POLE CDK7 UBC(457-532) CCNH MCM8PRIM1 POLA2 p-T187-CDKN1B Cdc25 A/Bphospho(T286)-CyclinD1:Cdk4PSMB2 PDS5B GINS4 UBC(153-228) p-S,T-ORC1CCNA1 p-T160-CDK2 CCNA2 UBC(381-456) UBC(229-304) dGTPCDCA5CDK2 origin of replication PCNA CUL1 CDKN1A PSMD5 2xAcK-SMC3 RFC1 ORC6 CCNE1 ESCO1 RFC4 CCNA1 PSMD7 PSMB4 SMC1A 26S proteasomePOLD4 PCNA homotrimerCCNA1 p-CDC6RNA primer-DNAprimer:originduplex:PCNAPOLE CoA-SHATPCKS1BGINS1 Sister Centromere p-T187-CDKN1B ATPCCND1 PSMB4 UBC(609-684) CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))p-T286-CCND1UBC(457-532) UBC(533-608) CCNA2 POLD1 PSMA5 PDS5A UBB(77-152) PRIM1 CCNA2 RPA3 UBB(77-152) POLD2 PSMD10 PSMF1 FZR1 PSMA2 UBC(1-76) SisterCentromeres:Ac-Cohesin:PDS5:CDCA5:WAPALRPA3 RNA primer DNA polymeraseepsilonPCNA POLA1 CDKN1B RPS27A(1-76) CKS1B UBC(457-532) UBB(1-76) PCNA DNA primer PSMD3 NTPUBC(153-228) CDC6 UBB(1-76) PSMB3 UBB(153-228) POLD2 p-CDC6POLD1 RPA1 PDS5A CDC25A RFCHeteropentamer:RNAprimer-DNAprimer:originduplex:PCNAhomotrimerPOLE2 CCND1:CDK4PRIM2 origin of replication STAG2 RFC2 UBC(1-76) UBC(381-456) WAPAL Processivecomplex:Okazakifragments:RemainingFlapOkazaki fragment MCM7 CCNA1 origin of replication CCNA STAG1 PSMB8 RPS27A(1-76) PCNA ESCO2 PSMB7 UBC(305-380) CDK2 ORC2 CDKN1B PSMA3 ADPubiquitinated Orc1MCM6 PSMD7 SisterChromosomalArms:Ac-Cohesin:PDS5:CDCA5:WAPALCCNA Cyclin E RPA1 DNA Polymerase deltatetramerCCNAPDS5A RFC2 glycogen synthasekinase-3 betaRB1 PRIM1 CDK2origin of replication PRIM2 Processivecomplex:nicked DNAfrom adjacentOkazaki fragmentsCDK2 PCNA origin of replication 26S proteasomeADPGINS3 ATPUMPPSMA1 PDS5A PRIM2 ADPUBC(457-532) CTP RNA primer CDK4 p-T160-CDK2 PRIM2 MCM3 MCM7 PSMB8 UBA52(1-76) PSMA6 UBC(1-76) PRIM1 UBC(457-532) PSMA4 POLD4 PSME3 WAPAL SKP1 POLA1 PiRNA primer:originduplex:DNApolymerasealpha:primasecomplexMCM6 p-T286-CCND1 UBC(229-304) PDS5B UBB(153-228) p-FZR1 CDK4 CCNA UBC(153-228) RFC3 MCM6 p-T187-CDKN1B UBB(1-76) CDK4 PSMD1 PSMD4 MCM5 CDC6MCM2 UBB(153-228) UBA52(1-76) PSMA5 UBB(1-76) MCM2 RFC HeteropentamerPOLA1 POLA2 DNA primer DNA primer ATPPOLD2 p-S130-CDKN1A DNA polymerasealpha:primasePOLA1 Flap Okazaki fragment PSMB7 Processivecomplex:Okazakifragment:Flap:RPAheterotrimer:dna2PCNA UBB(153-228) DNA2RPS27A(1-76) PRIM1 MCM4 UBC(381-456) PSMD4 CyclinA:Cdk2:p21/p27complexPOLA2 SMC1A origin of replication PSMC2 PSMC4 PRIM1 MCM2-7CCND1 UBC(229-304) UBC(77-152) pre-replicativecomplex(Orc1-minus)DNA2 Sister Centromere MCM7 POLA1 RNA primer POLD3 ADPORC1 POLD3 p-RB1 RNA primer PSMD13 PSMB3 POLA2 PRIM2 p-T286-CCND1 PSMB10 POLA2 GINS4SMC3 UBB(153-228) origin of replication POLD4 Replication ForkORC4 PSMD6 PRIM1 UBC(77-152) CDKDNA primer CKS1B CDKN1A origin of replication ADPRAD21 CDK2 PRIM2 UBC(609-684) POLA1 PSMD1 POLD3 CDK2 UBC(153-228) UBB(77-152) PSMA6 Flap Processivecomplex:Okazakifragment:Flap:RPAheterotrimerCCNA POLA1 ATPPOLD3 PDS5B PSMB5 Processive complexATPUBC(229-304) STAG2 RFC3 POLA2 UBC(609-684) RNA primer Okazaki fragment UBC(533-608) MCM4 CDK4 PSME1 MCM8 Cyclin E POLD3 GINS2 RNA primer PSMA3 UBC(609-684) SMC3 PSMA7 UBC(381-456) p-S130-CDKN1A CDC25B RPA3 POLD1 Sister Chromosomal Arm origin of replication UBC(305-380) MCM3CDK2 Ac-Cohesin:PDS5:WAPAL:Chromosomal ArmdATPOkazaki fragment ATPUBC(609-684) Cyclin E UBB(153-228) p-S130-CDKN1A UBB(153-228) CCNA1 POLD1 PSMB9 CCNA2 p-S130-CDKN1A CDKN1A PSMA4 RAD21 RNA primer MYC PCNA RPA2 PSMA1 PRIM1 Sister Centromere origin of replication RFC1 POLA2 PDS5B CCNA2 PSMD8 PSMC1 PRIM2 PSMB6 PSMC5 UBC(305-380) POLA1 PSMC5 PSMD8 MCM3 POLA1 DNA primer UBC(381-456) MCM5 PSME1 DNA primer PSMC3 GINS4 SMC1A PDS5B ADPPSMD2 MCM2 CyclinA:Cdk2:phospho-p27/p21 complexPSMD6 ligated okazakifragmentSTAG1 PRIM1 H2OPSMC6 UBC(533-608) MCM3 MCM2 UbiquitinCDCA5 UBB(77-152) UBC(153-228) UBC(229-304) GMPCohesin:PDS5:WAPAL:Chromosomal ArmMCM8 PSMB2 PCNA SKP1 CDK2 origin of replication RFC4 POLA1 UBC(381-456) DNA primer Unwinding complex atreplication forkESCOPOLD1 CDK2 UBC(305-380) PSMD11 p-Y342-PTK6 UBC(533-608) CDKN1BPSMD12 Mcm4,6,7 complexORC1 RPA1 origin of replication POLD4 CDK2 Okazaki fragment UbCyclinA:phospho-Cdk2(Tyr15)dCTPCDKN1B POLA2 CCNA2 CCNA:p-T160-CDK2POLD2 UBC(457-532) UBC(229-304) PSMA2 RNA primer MAX CDKN1B RNA primer WAPAL UBC(305-380) CKS1B RNA primer POLD1 CDK2 UBB(77-152) POLA2 RAD21 MCM2CCNA1 PSMC3 POLD3 UBC(1-76) POLD4 POLA2 ATPSister ChromosomalArmMCM4 POLA1 STAG2 POLD2 STAG2 UBC(533-608) POLD2 MCM6 Ac-CoAWEE1RNA primer AMPCDKN1B CCNA2 CyclinE/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinUBC(457-532) CUL1 UBC(1-76) Flap RNA primer-DNAprimer:originduplexPSMD3 POLD4 PSMD10 PSMB6 PSMD9 CyclinE/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BPOLD4 p-T187-CDKN1B anaphase-promotingcomplex (APC)SMC1A MCM5MCM4 p-Y88-CDKN1B ORC5 Unwound forkSTAG1 GINS complexPRIM1 SKP2 SKP1 UBA52(1-76) ubiquitinated Cdc6STAG1 RPA2 UBB(1-76) FEN1RAD21 Cyclin E GTP CDK4 PSMD14 p-S130-CDKN1A CDKN1AGINS2origin of replication PSMD9 CUL1:SKP1:SKP2:CKS1BSMC1A CCNA CCND1 RFC1 PSMC4 CCNE1 MYC:MAXRFC2 CyclinA:Cdk2:phosphorylated substrate complexCyclinE/A:CDK2:CDKN1A,CDKN1BSTAG1 POLD3 CyclinE/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1BRPA2 UTP LIG1Sister CentromerePOLA2 ubiquitinated Orc1PSMD14 Mitotic Prometaphaseorigin of replication PRIM2 Ubiquitin ligasePSME3 RPS27A(1-76) CCNA2 SMC1A CUL1 CDC6 RPS27A(1-76) Processivecomplex:Okazakifragment complexPOLD2 PSMB5 PDS5A STAG2 PSMC2 GINS3MCM7 UBA52(1-76) PRIM2 ORC5 CDC45 ADPUBC(1-76) PRIM2 Sister Chromosomal Arm UBB(77-152) DNA primer POLD3 ATPUBC(153-228) STAG1 STAG2 p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))POLA2 UBC(77-152) PRIM1 PSME4 RAD21 ORC3 Cyclin E PSMC6 POLA2 PSMB1 PSMD12 UBC(77-152) Cyclin E/A:CDK2Remaining Flap PSMA8 RPA heterotrimerPCNA UBC(229-304) CCNA1 PSMB10 pre-replicativecomplexUBC(305-380) PRIM1 Cohesin:PDS5:WAPAL:CentromereCDK2 PSMD13 CDKN1BMCM5 UBC(609-684) 2xAcK-SMC3 RAD21 CCND1 PRIM2 ADPCyclinA:Cdk2:substratecomplexUBB(77-152) PSMD5 CCNA:CDK2SKP2 CDKN1B RFC5 MNAT1 Processivecomplex:Okazakifragment:FlapSKP2 CMPWAPAL UBC(153-228) Ac-Cohesin:PDS5:WAPAL:CentromereRPS27A(1-76) PSMB9 p-T286-CCND1UBC(77-152) UBC(609-684) MCM3 MitoticTelophase/CytokinesisORC6 GINS2 Okazaki fragment minus Flap CCNA1 PRIM2 6050254149, 576055419850129


Description

DNA synthesis occurs in the S phase, or the synthesis phase, of the cell cycle. The cell duplicates its hereditary material, and two copies of the chromosome are formed. As DNA replication continues, the E type cyclins shared by the G1 and S phases, are destroyed and the levels of the mitotic cyclins rise. View original pathway at:Reactome.

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
118522view10:10, 28 May 2021EweitzOntology Term : 'S phase pathway' added !
115059view17:00, 25 January 2021ReactomeTeamReactome version 75
113503view11:58, 2 November 2020ReactomeTeamReactome version 74
112703view16:10, 9 October 2020ReactomeTeamReactome version 73
101618view11:48, 1 November 2018ReactomeTeamreactome version 66
101154view21:34, 31 October 2018ReactomeTeamreactome version 65
100681view20:07, 31 October 2018ReactomeTeamreactome version 64
100231view16:52, 31 October 2018ReactomeTeamreactome version 63
99783view15:18, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99337view12:47, 31 October 2018ReactomeTeamreactome version 62
93537view11:26, 9 August 2017ReactomeTeamreactome version 61
86636view09:22, 11 July 2016ReactomeTeamreactome version 56
83395view11:07, 18 November 2015ReactomeTeamVersion54
81589view13:07, 21 August 2015ReactomeTeamVersion53
77049view08:35, 17 July 2014ReactomeTeamFixed remaining interactions
76754view12:11, 16 July 2014ReactomeTeamFixed remaining interactions
76079view10:14, 11 June 2014ReactomeTeamRe-fixing comment source
75789view11:32, 10 June 2014ReactomeTeamReactome 48 Update
75139view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74786view08:52, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-177750 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
2xAcK-SMC3 ProteinQ9UQE7 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-Cohesin:PDS5:WAPAL:CentromereComplexR-HSA-2473149 (Reactome)
Ac-Cohesin:PDS5:WAPAL:Chromosomal ArmComplexR-HSA-2473153 (Reactome)
CAKComplexR-HSA-69221 (Reactome)
CCNA R-HSA-75202 (Reactome)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:CDK2ComplexR-HSA-141608 (Reactome)
CCNA:CDK2ComplexR-HSA-187501 (Reactome)
CCNA:p-T160-CDK2ComplexR-HSA-187952 (Reactome)
CCNAComplexR-HSA-170089 (Reactome)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND1:CDK4ComplexR-HSA-113844 (Reactome)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNH ProteinP51946 (Uniprot-TrEMBL)
CDC25A ProteinP30304 (Uniprot-TrEMBL)
CDC25AProteinP30304 (Uniprot-TrEMBL)
CDC25B ProteinP30305 (Uniprot-TrEMBL)
CDC45 ProteinO75419 (Uniprot-TrEMBL)
CDC45ProteinO75419 (Uniprot-TrEMBL)
CDC6 ProteinQ99741 (Uniprot-TrEMBL)
CDC6ProteinQ99741 (Uniprot-TrEMBL)
CDCA5 ProteinQ96FF9 (Uniprot-TrEMBL)
CDCA5ProteinQ96FF9 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDK7 ProteinP50613 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A,CDKN1BComplexR-HSA-182558 (Reactome)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848419 (Reactome)
CDKN1BProteinP46527 (Uniprot-TrEMBL)
CDKComplexR-HSA-68380 (Reactome)
CDT1 ProteinQ9H211 (Uniprot-TrEMBL)
CKS1B ProteinP61024 (Uniprot-TrEMBL)
CKS1BProteinP61024 (Uniprot-TrEMBL)
CMPMetaboliteCHEBI:17361 (ChEBI)
CTP MetaboliteCHEBI:17677 (ChEBI)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
CUL1:SKP1:SKP2:CKS1BComplexR-HSA-187547 (Reactome)
CUL1:SKP1:SKP2ComplexR-HSA-187541 (Reactome)
Cdc25 A/BComplexR-HSA-187904 (Reactome)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
Cohesin:PDS5:WAPAL:CentromereComplexR-HSA-2545177 (Reactome)
Cohesin:PDS5:WAPAL:Chromosomal ArmComplexR-HSA-2545179 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ComplexR-HSA-187926 (Reactome)
Cyclin A:Cdk2:phospho-p27/p21 complexComplexR-HSA-187912 (Reactome)
Cyclin A:Cdk2:phosphorylated substrate complexComplexR-HSA-187965 (Reactome)
Cyclin

A:Cdk2:substrate

complex
ComplexR-HSA-187947 (Reactome)
Cyclin

A:phospho-Cdk2(Tyr

15)
ComplexR-HSA-187907 (Reactome)
Cyclin E/A:CDK2:CDKN1A,CDKN1BComplexR-HSA-187516 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinComplexR-HSA-187568 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BComplexR-HSA-187565 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1BComplexR-HSA-187522 (Reactome)
Cyclin E R-HSA-187493 (Reactome)
Cyclin E/A:CDK2ComplexR-HSA-187496 (Reactome)
DNA Polymerase delta tetramerComplexR-HSA-68450 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
ComplexR-HSA-68510 (Reactome)
DNA polymerase alpha:primaseComplexR-HSA-68507 (Reactome)
DNA polymerase epsilonComplexR-HSA-68483 (Reactome)
DNA primer R-NUL-68424 (Reactome)
DNA2 ProteinP51530 (Uniprot-TrEMBL)
DNA2ProteinP51530 (Uniprot-TrEMBL)
ESCO1 ProteinQ5FWF5 (Uniprot-TrEMBL)
ESCO2 ProteinQ56NI9 (Uniprot-TrEMBL)
ESCOComplexR-HSA-2468046 (Reactome)
FEN1ProteinP39748 (Uniprot-TrEMBL)
FZR1 ProteinQ9UM11 (Uniprot-TrEMBL)
Flap R-NUL-68454 (Reactome)
GINS complexComplexR-HSA-176952 (Reactome)
GINS1 ProteinQ14691 (Uniprot-TrEMBL)
GINS1ProteinQ14691 (Uniprot-TrEMBL)
GINS2 ProteinQ9Y248 (Uniprot-TrEMBL)
GINS2ProteinQ9Y248 (Uniprot-TrEMBL)
GINS3 ProteinQ9BRX5 (Uniprot-TrEMBL)
GINS3ProteinQ9BRX5 (Uniprot-TrEMBL)
GINS4 ProteinQ9BRT9 (Uniprot-TrEMBL)
GINS4ProteinQ9BRT9 (Uniprot-TrEMBL)
GMPMetaboliteCHEBI:17345 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
LIG1ProteinP18858 (Uniprot-TrEMBL)
MAX ProteinP61244 (Uniprot-TrEMBL)
MCM2 ProteinP49736 (Uniprot-TrEMBL)
MCM2-7ComplexR-HSA-68558 (Reactome)
MCM2ProteinP49736 (Uniprot-TrEMBL)
MCM3 ProteinP25205 (Uniprot-TrEMBL)
MCM3ProteinP25205 (Uniprot-TrEMBL)
MCM4 ProteinP33991 (Uniprot-TrEMBL)
MCM5 ProteinP33992 (Uniprot-TrEMBL)
MCM5ProteinP33992 (Uniprot-TrEMBL)
MCM6 ProteinQ14566 (Uniprot-TrEMBL)
MCM7 ProteinP33993 (Uniprot-TrEMBL)
MCM8 ProteinQ9UJA3 (Uniprot-TrEMBL)
MCM8ProteinQ9UJA3 (Uniprot-TrEMBL)
MNAT1 ProteinP51948 (Uniprot-TrEMBL)
MYC ProteinP01106 (Uniprot-TrEMBL)
MYC:MAXComplexR-HSA-188378 (Reactome)
Mcm4,6,7 complexComplexR-HSA-69018 (Reactome)
Mitotic Telophase/CytokinesisPathwayR-HSA-68884 (Reactome) In this final phase of mitosis, new membranes are formed around two sets of chromatids and two daughter cells are formed. The chromosomes and the spindle fibers disperse, and the fiber ring around the center of the cell, composed of actin, contracts, pinching the cell into two daughter cells.
Mitotic PrometaphasePathwayR-HSA-68877 (Reactome) The dissolution of the nuclear membrane marks the beginning of the prometaphase. Kinetochores are created when proteins attach to the centromeres. Microtubules then attach at the kinetochores, and the chromosomes begin to move to the metaphase plate.
NTPComplexR-ALL-30595 (Reactome)
ORC1 ProteinQ13415 (Uniprot-TrEMBL)
ORC2 ProteinQ13416 (Uniprot-TrEMBL)
ORC3 ProteinQ9UBD5 (Uniprot-TrEMBL)
ORC4 ProteinO43929 (Uniprot-TrEMBL)
ORC5 ProteinO43913 (Uniprot-TrEMBL)
ORC6 ProteinQ9Y5N6 (Uniprot-TrEMBL)
Okazaki fragment R-NUL-68452 (Reactome)
Okazaki fragment minus Flap R-NUL-68469 (Reactome)
Okazaki fragmentR-NUL-68452 (Reactome)
PCNA ProteinP12004 (Uniprot-TrEMBL)
PCNA homotrimerComplexR-HSA-68440 (Reactome)
PDS5A ProteinQ29RF7 (Uniprot-TrEMBL)
PDS5B ProteinQ9NTI5 (Uniprot-TrEMBL)
POLA1 ProteinP09884 (Uniprot-TrEMBL)
POLA2 ProteinQ14181 (Uniprot-TrEMBL)
POLD1 ProteinP28340 (Uniprot-TrEMBL)
POLD2 ProteinP49005 (Uniprot-TrEMBL)
POLD3 ProteinQ15054 (Uniprot-TrEMBL)
POLD4 ProteinQ9HCU8 (Uniprot-TrEMBL)
POLE ProteinQ07864 (Uniprot-TrEMBL)
POLE2 ProteinP56282 (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)
PiMetaboliteCHEBI:18367 (ChEBI)
Processive

complex:Okazaki

fragment complex
ComplexR-HSA-68453 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer:dna2
ComplexR-HSA-68466 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer
ComplexR-HSA-68463 (Reactome)
Processive

complex:Okazaki

fragment:Flap
ComplexR-HSA-68455 (Reactome)
Processive

complex:Okazaki fragments:Remaining

Flap
ComplexR-HSA-68468 (Reactome)
Processive

complex:nicked DNA from adjacent

Okazaki fragments
ComplexR-HSA-68470 (Reactome)
Processive complexComplexR-HSA-68451 (Reactome)
RAD21 ProteinO60216 (Uniprot-TrEMBL)
RB1 ProteinP06400 (Uniprot-TrEMBL)
RFC

Heteropentamer:RNA primer-DNA primer:origin duplex:PCNA

homotrimer
ComplexR-HSA-68471 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:origin

duplex
ComplexR-HSA-68437 (Reactome)
RFC HeteropentamerComplexR-HSA-68436 (Reactome)
RFC1 ProteinP35251 (Uniprot-TrEMBL)
RFC2 ProteinP35250 (Uniprot-TrEMBL)
RFC3 ProteinP40938 (Uniprot-TrEMBL)
RFC4 ProteinP35249 (Uniprot-TrEMBL)
RFC5 ProteinP40937 (Uniprot-TrEMBL)
RNA primer R-NUL-68422 (Reactome)
RNA primer-DNA

primer:origin

duplex:PCNA
ComplexR-HSA-68441 (Reactome)
RNA primer-DNA

primer:origin

duplex
ComplexR-HSA-68425 (Reactome)
RNA primer:origin

duplex:DNA polymerase alpha:primase

complex
ComplexR-HSA-68423 (Reactome)
RPA heterotrimerComplexR-HSA-68462 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Remaining Flap R-NUL-68467 (Reactome)
Replication Fork R-NUL-169515 (Reactome)
Replication ForkR-NUL-169515 (Reactome)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SKP2 ProteinQ13309 (Uniprot-TrEMBL)
SMC1A ProteinQ14683 (Uniprot-TrEMBL)
SMC3 ProteinQ9UQE7 (Uniprot-TrEMBL)
STAG1 ProteinQ8WVM7 (Uniprot-TrEMBL)
STAG2 ProteinQ8N3U4 (Uniprot-TrEMBL)
Sister Centromeres:Ac-Cohesin:PDS5:CDCA5:WAPALComplexR-HSA-1638799 (Reactome)
Sister

Chromosomal

Arms:Ac-Cohesin:PDS5:CDCA5:WAPAL
ComplexR-HSA-1638802 (Reactome)
Sister Centromere R-NUL-1638792 (Reactome)
Sister CentromereR-NUL-1638792 (Reactome)
Sister Chromosomal ArmR-NUL-1638790 (Reactome)
Sister Chromosomal Arm R-NUL-1638790 (Reactome)
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)
UMPMetaboliteCHEBI:16695 (ChEBI)
UTP MetaboliteCHEBI:15713 (ChEBI)
UbComplexR-HSA-113595 (Reactome)
Ubiquitin ligaseR-HSA-69593 (Reactome)
UbiquitinComplexR-HSA-68524 (Reactome)
Unwinding complex at replication forkComplexR-HSA-176949 (Reactome)
Unwound forkR-NUL-169509 (Reactome)
WAPAL ProteinQ7Z5K2 (Uniprot-TrEMBL)
WEE1ProteinP30291 (Uniprot-TrEMBL)
anaphase-promoting complex (APC)R-HSA-69007 (Reactome)
cyclin R-HSA-68379 (Reactome)
dATPMetaboliteCHEBI:16284 (ChEBI)
dCTPMetaboliteCHEBI:16311 (ChEBI)
dGTPMetaboliteCHEBI:16497 (ChEBI)
dTTPMetaboliteCHEBI:18077 (ChEBI)
glycogen synthase kinase-3 betaR-NUL-75818 (Reactome)
ligated okazaki fragmentR-NUL-69172 (Reactome)
multi-ubiquitinated

phospho-(T286)

Cyclin D1
ComplexR-HSA-177997 (Reactome)
origin of replication R-NUL-68419 (Reactome)
p-CDC6ProteinQ99741 (Uniprot-TrEMBL)
p-FZR1 ProteinQ9UM11 (Uniprot-TrEMBL)
p-RB1 ProteinP06400 (Uniprot-TrEMBL) The pRB C-terminus contains a cluster of seven candidate in vivo cdk phosphorylation sites (residues 795, 807, 811, 821, and 826) and is phosphorylated in vitro by cyclin A, cyclin E, and cyclin D-associated kinases.
p-S,T-ORC1ProteinQ13415 (Uniprot-TrEMBL)
p-S130-CDKN1A ProteinP38936 (Uniprot-TrEMBL)
p-T160-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-T187-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-T286-CCND1 ProteinP24385 (Uniprot-TrEMBL)
p-T286-CCND1ProteinP24385 (Uniprot-TrEMBL)
p-Y15-CDK2 ProteinP24941 (Uniprot-TrEMBL)
p-Y342-PTK6 ProteinQ13882 (Uniprot-TrEMBL)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848415 (Reactome)
p-Y342-PTK6ProteinQ13882 (Uniprot-TrEMBL)
p-Y88-CDKN1B ProteinP46527 (Uniprot-TrEMBL)
p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848441 (Reactome)
phospho(T286)-Cyclin D1:Cdk4ComplexR-HSA-75812 (Reactome)
phospho(T286)-Cyclin D1:Cdk4ComplexR-HSA-75814 (Reactome)
pre-replicative

complex

(Orc1-minus)
ComplexR-HSA-157563 (Reactome)
pre-replicative complexComplexR-HSA-68559 (Reactome)
ubiquitinated Cdc6ComplexR-HSA-68570 (Reactome)
ubiquitinated Orc1ComplexR-HSA-113570 (Reactome)
ubiquitinated Orc1ComplexR-HSA-68586 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-187574 (Reactome)
26S proteasomemim-catalysisR-HSA-68948 (Reactome)
26S proteasomemim-catalysisR-HSA-69016 (Reactome)
26S proteasomemim-catalysisR-HSA-75825 (Reactome)
ADPArrowR-HSA-174164 (Reactome)
ADPArrowR-HSA-187520 (Reactome)
ADPArrowR-HSA-187948 (Reactome)
ADPArrowR-HSA-187949 (Reactome)
ADPArrowR-HSA-68944 (Reactome)
ADPArrowR-HSA-69005 (Reactome)
ADPArrowR-HSA-69063 (Reactome)
ADPArrowR-HSA-75820 (Reactome)
ADPArrowR-HSA-8848436 (Reactome)
AMPArrowR-HSA-69144 (Reactome)
ATPR-HSA-174164 (Reactome)
ATPR-HSA-187520 (Reactome)
ATPR-HSA-187948 (Reactome)
ATPR-HSA-187949 (Reactome)
ATPR-HSA-68944 (Reactome)
ATPR-HSA-69005 (Reactome)
ATPR-HSA-69015 (Reactome)
ATPR-HSA-69063 (Reactome)
ATPR-HSA-75820 (Reactome)
ATPR-HSA-8848436 (Reactome)
Ac-CoAR-HSA-2468039 (Reactome)
Ac-CoAR-HSA-2473152 (Reactome)
Ac-Cohesin:PDS5:WAPAL:CentromereArrowR-HSA-2473152 (Reactome)
Ac-Cohesin:PDS5:WAPAL:CentromereR-HSA-2473151 (Reactome)
Ac-Cohesin:PDS5:WAPAL:Chromosomal ArmArrowR-HSA-2468039 (Reactome)
Ac-Cohesin:PDS5:WAPAL:Chromosomal ArmR-HSA-2468041 (Reactome)
CAKmim-catalysisR-HSA-187949 (Reactome)
CCNA:CDK2ArrowR-HSA-174054 (Reactome)
CCNA:CDK2ArrowR-HSA-174110 (Reactome)
CCNA:CDK2ArrowR-HSA-174273 (Reactome)
CCNA:CDK2R-HSA-174164 (Reactome)
CCNA:CDK2R-HSA-174273 (Reactome)
CCNA:CDK2R-HSA-187934 (Reactome)
CCNA:CDK2R-HSA-187949 (Reactome)
CCNA:p-T160-CDK2ArrowR-HSA-187949 (Reactome)
CCNAR-HSA-174054 (Reactome)
CCND1:CDK4R-HSA-75820 (Reactome)
CDC25AArrowR-HSA-188345 (Reactome)
CDC45R-HSA-176942 (Reactome)
CDC6R-HSA-69005 (Reactome)
CDCA5R-HSA-2468041 (Reactome)
CDCA5R-HSA-2473151 (Reactome)
CDK2R-HSA-174054 (Reactome)
CDKN1A,CDKN1BR-HSA-187934 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-187934 (Reactome)
CDKN1AArrowR-HSA-187828 (Reactome)
CDKN1AR-HSA-187828 (Reactome)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))R-HSA-8848414 (Reactome)
CDKN1BArrowR-HSA-187506 (Reactome)
CDKN1BR-HSA-187506 (Reactome)
CDKmim-catalysisR-HSA-69005 (Reactome)
CKS1BR-HSA-187545 (Reactome)
CMPArrowR-HSA-69144 (Reactome)
CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187545 (Reactome)
CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187574 (Reactome)
CUL1:SKP1:SKP2:CKS1BR-HSA-187552 (Reactome)
CUL1:SKP1:SKP2R-HSA-187545 (Reactome)
Cdc25 A/Bmim-catalysisR-HSA-174110 (Reactome)
CoA-SHArrowR-HSA-2468039 (Reactome)
CoA-SHArrowR-HSA-2473152 (Reactome)
Cohesin:PDS5:WAPAL:CentromereR-HSA-2473152 (Reactome)
Cohesin:PDS5:WAPAL:Chromosomal ArmR-HSA-2468039 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
ArrowR-HSA-187934 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
R-HSA-187916 (Reactome)
Cyclin

A:Cdk2:p21/p27

complex
mim-catalysisR-HSA-187916 (Reactome)
Cyclin A:Cdk2:phospho-p27/p21 complexArrowR-HSA-187916 (Reactome)
Cyclin A:Cdk2:phosphorylated substrate complexArrowR-HSA-187948 (Reactome)
Cyclin

A:Cdk2:substrate

complex
R-HSA-187948 (Reactome)
Cyclin

A:Cdk2:substrate

complex
mim-catalysisR-HSA-187948 (Reactome)
Cyclin

A:Cdk2:substrate

complex
mim-catalysisR-HSA-68944 (Reactome)
Cyclin

A:phospho-Cdk2(Tyr

15)
ArrowR-HSA-174164 (Reactome)
Cyclin

A:phospho-Cdk2(Tyr

15)
R-HSA-174110 (Reactome)
Cyclin E/A:CDK2:CDKN1A,CDKN1BR-HSA-187520 (Reactome)
Cyclin E/A:CDK2:CDKN1A,CDKN1Bmim-catalysisR-HSA-187520 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinArrowR-HSA-187575 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinR-HSA-187574 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1B:3xubiquitinmim-catalysisR-HSA-187575 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BArrowR-HSA-187552 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1B:CUL1:SKP1:SKP2:CKS1BR-HSA-187575 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1BArrowR-HSA-187520 (Reactome)
Cyclin E/A:CDK2:p-S130-CDKN1A,p-T187-CDKN1BR-HSA-187552 (Reactome)
Cyclin E/A:CDK2ArrowR-HSA-187574 (Reactome)
DNA Polymerase delta tetramerR-HSA-69074 (Reactome)
DNA Polymerase delta tetramerR-HSA-69098 (Reactome)
DNA Polymerase delta tetramermim-catalysisR-HSA-69116 (Reactome)
DNA polymerase

alpha:primase:DNA polymerase alpha:origin

complex
R-HSA-68913 (Reactome)
DNA polymerase alpha:primasemim-catalysisR-HSA-68913 (Reactome)
DNA polymerase alpha:primasemim-catalysisR-HSA-68950 (Reactome)
DNA polymerase epsilonArrowR-HSA-68913 (Reactome)
DNA2ArrowR-HSA-69144 (Reactome)
DNA2R-HSA-69142 (Reactome)
ESCOmim-catalysisR-HSA-2468039 (Reactome)
ESCOmim-catalysisR-HSA-2473152 (Reactome)
FEN1mim-catalysisR-HSA-69152 (Reactome)
GINS complexArrowR-HSA-176956 (Reactome)
GINS complexR-HSA-176942 (Reactome)
GINS1R-HSA-176956 (Reactome)
GINS2R-HSA-176956 (Reactome)
GINS3R-HSA-176956 (Reactome)
GINS4R-HSA-176956 (Reactome)
GMPArrowR-HSA-69144 (Reactome)
H2OR-HSA-174110 (Reactome)
LIG1mim-catalysisR-HSA-69173 (Reactome)
MCM2-7R-HSA-176942 (Reactome)
MCM2-7R-HSA-69019 (Reactome)
MCM2-7mim-catalysisR-HSA-169468 (Reactome)
MCM2ArrowR-HSA-69019 (Reactome)
MCM3ArrowR-HSA-69019 (Reactome)
MCM5ArrowR-HSA-69019 (Reactome)
MCM8mim-catalysisR-HSA-169461 (Reactome)
MYC:MAXArrowR-HSA-188345 (Reactome)
Mcm4,6,7 complexArrowR-HSA-69019 (Reactome)
NTPR-HSA-68913 (Reactome)
Okazaki fragmentR-HSA-69173 (Reactome)
PCNA homotrimerR-HSA-69063 (Reactome)
PiArrowR-HSA-174110 (Reactome)
Processive

complex:Okazaki

fragment complex
ArrowR-HSA-69116 (Reactome)
Processive

complex:Okazaki

fragment complex
R-HSA-69127 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer:dna2
ArrowR-HSA-69142 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer:dna2
R-HSA-69144 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer
ArrowR-HSA-69140 (Reactome)
Processive

complex:Okazaki fragment:Flap:RPA

heterotrimer
R-HSA-69142 (Reactome)
Processive

complex:Okazaki

fragment:Flap
ArrowR-HSA-69127 (Reactome)
Processive

complex:Okazaki

fragment:Flap
R-HSA-69140 (Reactome)
Processive

complex:Okazaki fragments:Remaining

Flap
ArrowR-HSA-69144 (Reactome)
Processive

complex:Okazaki fragments:Remaining

Flap
R-HSA-69152 (Reactome)
Processive

complex:nicked DNA from adjacent

Okazaki fragments
ArrowR-HSA-69152 (Reactome)
Processive complexArrowR-HSA-69074 (Reactome)
Processive complexArrowR-HSA-69098 (Reactome)
Processive complexR-HSA-69116 (Reactome)
R-HSA-169461 (Reactome) The MCM2-7 related protein, MCM8, is required to replicate chromosomal DNA in Xenopus egg extracts. MCM8 binds chromatin upon initiation of DNA synthesis. It may function as an helicase in the elongation step.
R-HSA-169468 (Reactome) In budding yeast, all MCM proteins have been proved to be essential for elongation. The active form of this protein complex may be a heterohexamer. A subcomplex of MCM proteins consisting fo MCM4,6, and -7 has a weak helicase activity that may contribute to DNA unwinding.
R-HSA-174054 (Reactome) During G1 phase of the cell cycle, cyclin A is synthesized and associates with Cdk2.
R-HSA-174110 (Reactome) Cdc25A, and probably Cdc25B, regulate the entry into S phase cell cycle by removing inhibitory phosphates from the Cdk2 subunit of Cyclin A:Cdk2.
R-HSA-174164 (Reactome) The CDK activity of the Cyclin A:Cdk2 complex is inhibited by phosphorylation at Tyr 15, presumably by the Wee1 kinase.
R-HSA-174273 (Reactome) After forming in the cytoplasm, the Cyclin A:Cdk2 complexes are translocated to the nucleus.
R-HSA-176942 (Reactome) By applying the chromatin immunoprecipitation technique to paused forks, certain proteins like DNA pol alpha, DNA pol delta, DNA pol epsilon, MCM2-7, CDC45, GINS and MCM10 were identified. By uncoupling a helicase at the site using a polymerase inhibitor, MCM2-7, GINS complex and CDC45 alone were found to be enriched at the paused fork suggesting these proteins may form a part of an "unwindosome" at the replicating fork.
R-HSA-176956 (Reactome) At the beginning of this reaction, 1 molecule of 'PSF3p', 1 molecule of 'SLD5P', 1 molecule of 'PSF2p', and 1 molecule of 'PSF1p' are present. At the end of this reaction, 1 molecule of 'GINS complex' is present.

This reaction takes place in the 'nucleus'.

R-HSA-187506 (Reactome) p27 translocates to the nucleoplasm where it associates with CyclinE:Cdk2 complexes. Localization of p27 to the nucleus is necessary to inhibit Cdk activation by Cdk-activating kinase.
R-HSA-187520 (Reactome) The interaction between the Skp2 subunit of the SCF(Skp2) complex and p27 is dependent upon Cdk2:Cyclin A/E mediated phosphorylation of p27 at Thr 187 (Carrano et al, 1999; Tsvetkov et al, 1999). There is evidence that Cyclin A/B:Cdk1 can also bind and phosphorylate p27 on Thr 187 (Nakayama et al., 2004). This phosphorylation is also essential for the subsequent ubiquitination of p27.
R-HSA-187545 (Reactome) The accessory protein, Cks1 promotes efficient interaction between phosphorylated p27 and the SCF (Skp2) complex (Ganoth et al., 2001; Spruck et al., 2001). Cks1 binds to Skp2 in the leucine-rich repeat (LRR) domain and C-terminal tail (Hao et al., 2005). The phosphorylated Thr187 side chain of p27 associates with a phosphate binding site on Cks1, and the side chain containing Glu185 is positioned in the interface between Skp2 and Cks1 where it interacts with both (Hao et al., 2005).
R-HSA-187552 (Reactome) The association of Cks1 with both Skp2 and phosphorylated p27 promotes a tight interaction between p27 and the SCF complex (Hao et al., 2005).
R-HSA-187574 (Reactome) Following ubiquitination by the SCF(Skp2):Cks1 complex, phospho-p27/p21 is degraded by the 26S proteasome.
R-HSA-187575 (Reactome) Once in tight contact with the SCF (Skp2):Cks1 complex, phosphorylated p27/p21 is ubiquitinated.
R-HSA-187828 (Reactome) p21 associates with and inhibits Cyclin:Cdk complexes in the nucleus.
R-HSA-187916 (Reactome) Recognition of p27 by SCF(Skp2) and the subsequent ubiquitination of p27 is dependent upon Cyclin E/A:Cdk2-mediated phosphorylation of p27 at Thr 187 (Montagnoli et al., 1999). p21 is also phosphorylated at a specific site (Ser130) by Cyclin E/A:Cdk2, stimulating its ubiquitination. Unlike p27, however, p21 ubiquitination can take place in the absence of phosphorylation, although with less efficiency (Bornstein et al.,2003).
R-HSA-187934 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006).
R-HSA-187948 (Reactome) Active Cyclin A:Cdk2 complexes phosphorylate and inactivate proteins required for maintaining the G1/S phase including: Cdh1, RB1, p21 and p27. All this creates auto-amplification loops that render Cdk2 increasingly more active. In G2, Cdk2, in association with cyclin A, phosphorylates E2F1 and E2F3 resulting in the inactivation and possibly degradation of these two transcription factors (Dynlacht et al., 1994; Krek et al., 1994).
R-HSA-187949 (Reactome) Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995).
R-HSA-188345 (Reactome) The Myc/Max heterodimer binds to elements in the cdc25A gene and activates transcription in mid to late G1.
R-HSA-2468039 (Reactome) Acetyltransferases ESCO1 and ESCO2 are homologs of the S. cerevisiae acetyltransferase Eco1, essential for viability in yeast. ESCO1 and ESCO2 share sequence homology in the C-terminal region, consisting of a H2C2 zinc finger motif and an acetyltransferase domain (Hou and Zou 2005). Both ESCO1 and ESCO2 acetylate the cohesin subunit SMC3 on two lysine residues, K105 and K106 (Zhang et al. 2008), an important step in the establishment of sister-chromatid cohesion during the S-phase of the cell cycle. These dual acetylations on SMC3 are deacetylated by HDAC8 after the cohesin removal from chromatin for the dissociation and recycling of cohesin subunits (Deardorff et al. 2012). ESCO1 and ESCO2 differ in their N-termini, which are necessary for chromatin binding, and may perform distinct functions in sister chromatid cohesion (Hou and Zou 2005), as suggested by the study of Esco2 knockout mice (Whelan et al. 2012).
R-HSA-2468041 (Reactome) CDCA5 (Sororin) is essential for the establishment of sister chromatid cohesion in mammalian cells (Rankin et al. 2005) in the S-phase of the cell cycle (Nishiyama et al. 2010). Several factors contribute to the recruitment of CDCA5 to chromatin-associated cohesin: DNA replication (i.e. presence of two sister chromatids), association of cohesin complex with PDS5, and acetylation of the SMC3 cohesin subunit by ESCO1/ESCO2 acetyltransferases. Experiments in which a recombinant tagged mouse CDCA5 was expressed in human HeLa cell line showed that CDCA5 starts to accumulate on chromatin in S-phase and dissociates from chromosomal arms in prophase (Nishiyama et al. 2010).

CDCA5 is essential for the establishment of chromosomal cohesion only in the presence of WAPAL, suggesting that the key role of CDCA5 (Sororin) is to antagonize WAPAL. Both CDCA5 and WAPAL contain an FGF (phenylalanine-glycine-phenylalanine) motif that is essential for PDS5 binding and is also essential for CDCA5 function in cohesion establishment. Indeed, CDCA5 is able to displace WAPAL from PDS5:WAPAL heterodimers in vitro. In vivo experiments in Xenopus egg extracts suggest that CDCA5 rearranges the topology of cohesin associated proteins so that WAPAL is no longer able to inhibit sister chromatid cohesion but remains associated with cohesin (Nishiyama et al. 2010).
R-HSA-2473151 (Reactome) CDCA5 (Sororin) is essential for the establishment of sister chromatid cohesion at centromeres. Experiments in which a recombinant tagged mouse CDCA5 was expressed in human HeLa cell line showed that CDCA5 starts to accumulate on chromatin in S-phase and dissociates from centromeres in anaphase (Nishiyama et al. 2010).
R-HSA-2473152 (Reactome) Acetyltransferases ESCO1 and ESCO2 are homologs of the S. cerevisiae acetyltransferase Eco1, essential for viability in yeast. ESCO1 and ESCO2 share sequence homology in the C-terminal region, consisting of a H2C2 zinc finger motif and an acetyltransferase domain (Hou and Zou 2005). Both ESCO1 and ESCO2 acetylate the cohesin subunit SMC3 on two lysine residues, K105 and K106 (Zhang et al. 2008), an important step in the establishment of sister-chromatid cohesion during the S-phase of the cell cycle. Divergent N-termini of ESCO1 and ESCO2, necessary for chromatin binding, suggest that ESCO1 and ESCO2 may perform distinct functions in sister chromatid cohesion (Hou and Zou 2005). Several studies suggest that ESCO2 may be predominantly involved in acetylation of the SMC3 subunit of centromeric cohesin. A conditional targeting of Esco2 locus in mice leads to pre-implantational loss of homozygous Esco2 -/- embryos at the eight-cell stage. Prometaphase chromosomes isolated from two-cell stage Esco2 knockout embryos show marked cohesion defect at centromeres (Whelan et al. 2012). ESCO2 protein appears in the S-phase (Hou and Zou 2005, Whelan et al. 2012) and in mouse embryonic fibroblasts Esco2 predominantly localizes to pericentric heterochromatin (Whelan et al. 2012). Mutations in the ESCO2 gene (Vega et al. 2005) that impair ESCO2 acetyltransferase activity (Gordillo et al. 2008) are the cause of the Roberts syndrome, an autosomal recessive disorder characterized by craniofacial and limb abnormalities, and intellectual disability. Metaphase chromosomes of Roberts syndrome patients exhibit loss of cohesion at heterochromatic regions of centromeres and the Y chromosome, with a characteristic 'railroad track appearance' (Van den Berg and Francke 1993, Vega et al. 2005).
R-HSA-68913 (Reactome) At the beginning of this reaction, 1 molecule of 'DNA polymerase alpha:primase:DNA polymerase alpha:origin complex', and 1 molecule of 'NTP' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon', and 1 molecule of 'RNA primer:origin duplex:DNA polymerase alpha:primase complex' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed RNA polymerase activity' of 'DNA polymerase alpha:primase'.

R-HSA-68944 (Reactome) At the beginning of this reaction, 1 molecule of 'ATP', and 1 molecule of 'pre-replicative complex' are present. At the end of this reaction, 1 molecule of 'phosphorylated Orc1', 1 molecule of 'pre-replicative complex (Orc1-minus)', and 1 molecule of 'ADP' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'Cyclin A:Cdk2 complex'.

R-HSA-68946 (Reactome) At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'phosphorylated Orc1' are present. At the end of this reaction, 1 molecule of 'ubiquitinated Orc1' is present.

This reaction takes place in the 'nucleus'.

R-HSA-68947 (Reactome) In this reaction, 1 molecule of 'ubiquitinated Orc1' is translocated from nucleoplasm to cytosol.

This movement of the molecule occurs through the 'nuclear pore'.

R-HSA-68948 (Reactome) At the beginning of this reaction, 1 molecule of 'ubiquitinated Orc1' 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-68950 (Reactome) At the beginning of this reaction, 1 molecule of 'dTTP', 1 molecule of 'dGTP', 1 molecule of 'dATP', 1 molecule of 'RNA primer:origin duplex:DNA polymerase alpha:primase complex', and 1 molecule of 'dCTP' are present. At the end of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present.

This reaction takes place in the 'nucleus' and is mediated by the 'DNA-directed DNA polymerase activity' of 'DNA polymerase alpha:primase'.

R-HSA-69005 (Reactome) At the beginning of this reaction, 1 molecule of 'CDC6', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'phosphorylated Cdc6' are present.

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

R-HSA-69006 (Reactome) In this reaction, 1 molecule of 'phosphorylated Cdc6' is translocated from nucleoplasm to cytosol.

This movement of the molecule occurs through the 'nuclear pore'.

R-HSA-69015 (Reactome) At the beginning of this reaction, 1 molecule of 'phosphorylated Cdc6', 1 molecule of 'ubiquitin', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ubiquitinated Cdc6' is present.

This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of 'anaphase-promoting complex (APC)'.

R-HSA-69016 (Reactome) At the beginning of this reaction, 1 molecule of 'ubiquitinated Cdc6' 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-69019 (Reactome) At the start of the elongation phase of DNA replication, the Mcm2-7 complex may re-arrange to function as the replicative helicase associated with the replication fork. In general, a replicative helicase is associated with the replication fork and unwinds DNA ahead of the polymerase. In yeast, the Mcm proteins associate with origin DNA in G1 phase and then exit the origin upon replication initiation, consistent with moving out of the origin with the replication fork. The Mcm2-7 complex is a ring-shaped hexamer. Complexes of Mcm4, Mcm6 and Mcm7 proteins from humans or S. pombe display a modest ATP-dependent helicase activity in vitro. Consistent with the hypothesis that eukaryotic Mcm complexes function as helicases, an archaeal Mcm homolog is a ring-shaped double hexamer that has a processive DNA unwinding activity. Mcm proteins may have additional functions during elongation, as uninterrupted function of all six is required for replication fork progression in budding yeast. Mcm4,6,7 helicase activity may be negatively regulated in two ways. Mcm2, Mcm4, Mcm6, and Mcm7 also form a stable complex which, however, has no helicase activity, suggesting that Mcm2 inhibits DNA unwinding by Mcm4,6,7. In addition, phosphorylation of human Mcm4,6,7 complex by CDK inhibits its helicase activity.
R-HSA-69053 (Reactome) Once the RNA-DNA primer is synthesized, replication factor C (RFC) initiates a reaction called "polymerase switching"; pol delta, the processive enzyme replaces pol alpha, the priming enzyme. RFC binds to the 3'-end of the RNA-DNA primer on the Primosome, to displace the pol alpha primase complex. The binding of RFC triggers the binding of the primer recognition complex.
R-HSA-69063 (Reactome) The binding of the primer recognition complex involves the loading of proliferating cell nuclear antigen (PCNA). Replication Factor C transiently opens the PCNA toroid in an ATP-dependent reaction, and then allows PCNA to re-close around the double helix adjacent to the primer terminus. This leads to the formation of the "sliding clamp".
R-HSA-69068 (Reactome) Replication factor C is proposed to dissociate from PCNA following sliding clamp formation, and the DNA toroid alone tethers pol delta to the DNA.
R-HSA-69074 (Reactome) The loading of proliferating cell nuclear antigen (PCNA) leads to recruitment of pol delta. Human PCNA is a homotrimer of 36 kDa subunits that form a toroidal structure. The loading of PCNA by RFC is a key event in the transition from the priming mode to the extension mode of DNA synthesis. The processive complex is composed of the pol delta holoenzyme and PCNA.
R-HSA-69098 (Reactome) Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex. Polymerase delta possesses polymerization and proofreading activities, which increases the overall fidelity of DNA replication. The pol delta holoenzyme is a heterotetrameric complex that contains p125, p66, p50, and p12 subunits, in human cells.
R-HSA-69116 (Reactome) After RFC initiates the assembly of the primer recognition complex, the complex of pol delta and PCNA is responsible for incorporating the additional nucleotides prior to the position of the next downstream initiator RNA primer. On the lagging strand, short discontinuous segments of DNA, called Okazaki fragments, are synthesized on RNA primers. The average length of the Okazaki fragments is 100 nucleotides. Polymerase switching is a key event that allows the processive synthesis of DNA by the pol delta and PCNA complex.
R-HSA-69127 (Reactome) When the polymerase delta:PCNA complex reaches a downstream Okazaki fragment, strand displacement synthesis occurs. The primer containing 5'-terminus of the downstream Okazaki fragment is folded into a single-stranded flap.
R-HSA-69140 (Reactome) The first step in the removal of the flap intermediate is the binding of Replication Protein A (RPA) to the long flap structure. RPA is a eukaryotic single-stranded DNA binding protein.
R-HSA-69142 (Reactome) After RPA binds the long flap, it recruits the Dna2 endonuclease. Dna2 endonuclease removes most of the flap, but the job of complete removal of the flap is then completed by FEN-1.
R-HSA-69144 (Reactome) The Dna2 endonuclease removes the initiator RNA along with several downstream deoxyribonucleotides. The cleavage of the single-stranded RNA substrate results in the disassembly of RPA and Dna2. The current data for the role of the Dna2 endonuclease has been derived from studies with yeast and Xenopus Dna2.
R-HSA-69152 (Reactome) The remaining flap, which is too short to support RPA binding, is then processed by FEN-1. There is evidence that binding of RPA to the displaced end of the RNA-containing Okazaki fragment prevents FEN-1 from accessing the substrate. FEN-1 is a structure-specific endonuclease that cleaves near the base of the flap at a position one nucleotide into the annealed region. Biochemical studies have shown that the preferred substrate for FEN-1 consists of a one-nucleotide 3'-tail on the upstream primer in addition to the 5'-flap of the downstream primer.
R-HSA-69173 (Reactome) Removal of the flap by FEN-1 leads to the generation of a nick between the 3'-end of the upstream Okazaki fragment and the 5'-end of the downstream Okazaki fragment. DNA ligase I then seals the nicks between adjacent processed Okazaki fragments to generate intact double-stranded DNA.
R-HSA-75820 (Reactome) At the beginning of this reaction, 1 molecule of 'Cyclin D1:Cdk4', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phospho(T286)-Cyclin D1:Cdk4', and 1 molecule of 'ADP' are present.

This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'glycogen synthase kinase-3 beta'.

R-HSA-75822 (Reactome) In this reaction, 1 molecule of 'phospho(T286)-Cyclin D1:Cdk4' is translocated from nucleoplasm to cytosol.

This reaction takes place in the 'nuclear envelope'.

R-HSA-75823 (Reactome) In this reaction, 1 molecule of 'phospho(T286)-Cyclin D1' is translocated from nucleoplasm to cytosol.

This reaction takes place in the 'nuclear envelope'.

R-HSA-75824 (Reactome) Cyclin D is targeted for degradation by multi-ubiquitination.
R-HSA-75825 (Reactome) Phosphorylated Cyclin D1 is degraded during S phase by the 26S proteasome allowing for efficient DNA synthesis.
R-HSA-8848414 (Reactome) Activated PTK6 (BRK) binds to CDKN1B (p27KIP1) that is in a complex with CDK4 and cyclin D1 (CCND1). Since PTK6 increases cyclin E1 (CCNE1) levels downstream of ERBB2 while decreasing CDKN1B levels, PTK6 probably also associates with CDKN1B bound to the complex of CCNE1 and CDK2 (Xiang et al. 2008).
R-HSA-8848436 (Reactome) PTK6 (BRK) phosphorylates CDKN1B (p27KIP1) bound to the complex of CDK4 and CCND1 (cyclin D1) on tyrosine residue Y88 and possibly other tyrosines (e.g. Y89) (Patel et al. 2015). Based on the finding that PTK6 promotes ERBB2-induced increase in cyclin E1 (CCNE1) levels and decrease in CDKN1B levels (Xiang et al. 2008), and supported by the analogy with other SRC family kinases that phosphorylate CDKN1B (Grimmler et al. 2007), PTK6 is likely to also phosphorylate CDKN1B bound to the complex of CCNE1 and CDK2. Phosphorylation of CDKN1B (p27KIP1) on tyrosine residue Y88 by SRC family kinases dislodges the 3-10 helix of CDKN1B from the active site of CDK2 or CDK4, thus converting CDKN1B from a bound inhibitor to a bound non-inhibitor (Grimmler et al. 2007, Ray et al. 2009).
RFC

Heteropentamer:RNA primer-DNA primer:origin duplex:PCNA

homotrimer
ArrowR-HSA-69063 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:origin duplex:PCNA

homotrimer
R-HSA-69068 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:origin

duplex
ArrowR-HSA-69053 (Reactome)
RFC

Heteropentamer:RNA primer-DNA primer:origin

duplex
R-HSA-69063 (Reactome)
RFC HeteropentamerArrowR-HSA-69068 (Reactome)
RFC HeteropentamerR-HSA-69053 (Reactome)
RNA primer-DNA

primer:origin

duplex:PCNA
ArrowR-HSA-69068 (Reactome)
RNA primer-DNA

primer:origin

duplex:PCNA
R-HSA-69074 (Reactome)
RNA primer-DNA

primer:origin

duplex:PCNA
R-HSA-69098 (Reactome)
RNA primer-DNA

primer:origin

duplex
ArrowR-HSA-68950 (Reactome)
RNA primer-DNA

primer:origin

duplex
R-HSA-69053 (Reactome)
RNA primer:origin

duplex:DNA polymerase alpha:primase

complex
ArrowR-HSA-68913 (Reactome)
RNA primer:origin

duplex:DNA polymerase alpha:primase

complex
R-HSA-68950 (Reactome)
RPA heterotrimerArrowR-HSA-69144 (Reactome)
RPA heterotrimerR-HSA-69140 (Reactome)
Replication ForkR-HSA-169461 (Reactome)
Replication ForkR-HSA-169468 (Reactome)
Replication ForkR-HSA-176942 (Reactome)
Sister Centromeres:Ac-Cohesin:PDS5:CDCA5:WAPALArrowR-HSA-2473151 (Reactome)
Sister

Chromosomal

Arms:Ac-Cohesin:PDS5:CDCA5:WAPAL
ArrowR-HSA-2468041 (Reactome)
Sister CentromereR-HSA-2473151 (Reactome)
Sister Chromosomal ArmR-HSA-2468041 (Reactome)
UMPArrowR-HSA-69144 (Reactome)
UbArrowR-HSA-68948 (Reactome)
UbArrowR-HSA-69016 (Reactome)
UbArrowR-HSA-75825 (Reactome)
UbR-HSA-69015 (Reactome)
UbR-HSA-75824 (Reactome)
Ubiquitin ligasemim-catalysisR-HSA-75824 (Reactome)
UbiquitinArrowR-HSA-187574 (Reactome)
UbiquitinR-HSA-187575 (Reactome)
UbiquitinR-HSA-68946 (Reactome)
Unwinding complex at replication forkArrowR-HSA-176942 (Reactome)
Unwound forkArrowR-HSA-169461 (Reactome)
Unwound forkArrowR-HSA-169468 (Reactome)
WEE1mim-catalysisR-HSA-174164 (Reactome)
anaphase-promoting complex (APC)mim-catalysisR-HSA-69015 (Reactome)
dATPR-HSA-68950 (Reactome)
dCTPR-HSA-68950 (Reactome)
dGTPR-HSA-68950 (Reactome)
dTTPR-HSA-68950 (Reactome)
glycogen synthase kinase-3 betamim-catalysisR-HSA-75820 (Reactome)
ligated okazaki fragmentArrowR-HSA-69173 (Reactome)
multi-ubiquitinated

phospho-(T286)

Cyclin D1
ArrowR-HSA-75824 (Reactome)
multi-ubiquitinated

phospho-(T286)

Cyclin D1
R-HSA-75825 (Reactome)
p-CDC6ArrowR-HSA-69005 (Reactome)
p-CDC6ArrowR-HSA-69006 (Reactome)
p-CDC6R-HSA-69006 (Reactome)
p-CDC6R-HSA-69015 (Reactome)
p-S,T-ORC1ArrowR-HSA-68944 (Reactome)
p-S,T-ORC1R-HSA-68946 (Reactome)
p-T286-CCND1ArrowR-HSA-75823 (Reactome)
p-T286-CCND1R-HSA-75823 (Reactome)
p-T286-CCND1R-HSA-75824 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ArrowR-HSA-8848414 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))R-HSA-8848436 (Reactome)
p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))mim-catalysisR-HSA-8848436 (Reactome)
p-Y342-PTK6ArrowR-HSA-8848436 (Reactome)
p-Y342-PTK6R-HSA-8848414 (Reactome)
p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ArrowR-HSA-8848436 (Reactome)
phospho(T286)-Cyclin D1:Cdk4ArrowR-HSA-75820 (Reactome)
phospho(T286)-Cyclin D1:Cdk4ArrowR-HSA-75822 (Reactome)
phospho(T286)-Cyclin D1:Cdk4R-HSA-75822 (Reactome)
pre-replicative

complex

(Orc1-minus)
ArrowR-HSA-68944 (Reactome)
pre-replicative complexR-HSA-68944 (Reactome)
ubiquitinated Cdc6ArrowR-HSA-69015 (Reactome)
ubiquitinated Cdc6R-HSA-69016 (Reactome)
ubiquitinated Orc1ArrowR-HSA-68946 (Reactome)
ubiquitinated Orc1ArrowR-HSA-68947 (Reactome)
ubiquitinated Orc1R-HSA-68947 (Reactome)
ubiquitinated Orc1R-HSA-68948 (Reactome)
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