Cell cycle checkpoints (Homo sapiens)

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32139, 20, 3911, 2125, 441071041401, 3, 6, 27, 37...1730, 4819, 26, 2842383236332929815, 18, 31, 353221321316, 22, 43, 461, 27, 3732cytosolnucleoplasmphosph-Cdc25C (Ser 216)Mitotic checkpoint protein BUB3Rad17-RFC complexCOP1Cyclin E:Cdk2:p21/p27 complexhBUBR1:hBUB3:MAD2*:CDC20 complexRPA heterotrimerKinetochore:Mad1:MAD2* ComplexRad9-Hus1-Rad1 bound to DNAChk2Cyclin B1:phospho-Cdc2(Thr 161, Thr 14, Tyr 15)phospho-Wee1Cdc45:CDK:DDK:Mcm10:claspin:pre-replicative complexRad17-RFC complex bound to DNAWee1HsMad1MAD2*CDC20 complexCdc45:CDK:DDK:Mcm10:pre-replicative complexATPphosph-Cdc25C (Ser 216)ADPADPKinetochore:Mad1:MAD2 Complexp53 proteinADP14-3-3 proteinsATPADPCdc25AHsMAD2ATPp21Mdm2ADPRPA complexed to ssDNAp21/p27ATPRad9-Hus1-Rad1 complexATPADPMad1:kinetochore complexphosphorylated anaphase promoting complex (APC/C)ATR-ATRIP-RPA-ssDNA signaling complexCdc20ATPChk1/Ckk2(Cds1)phospho-Cdc25AKinetochore ComplexPersistent single-stranded DNAp53 tetramerCyclin B1:phospho-Cdc2 (Thr 14, Thr 161)Phospho-COP1(Ser-387):p53 complexphospho-Cdc25C:14-3-3 protein complexphospho-ATM (Ser 1981)ATPATPClaspinCdc25CADP26S proteasomeADPAmino AcidATPATPubiquitinated phospho-COP1(ser-387)ADPubiquitinphospho-Cdc25AMCC:APC/C complexADPATR-ATRIPphospho-Chk1Ubiquitinated Phospho-Cdc25Aphospho-MDM2Chk1ADPCyclin E:Cdk2 complexesATPCdc45:CDK:DDK:Mcm10:Activated claspin:pre-replicative complexATPphospho-COP1(Ser 387)phosho-COP1(ser-387)phospho-Chk2ADPMAD2*Cyclin B:Cdc2 complexp53 ser-15 phosphorylatedATPhBUBR1Cyclin B:phospho-Cdc2(Thr 14)Ubiquitin ligaseADP1416, 22, 234754, 15, 34, 452, 2412


Description

A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.<p>The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
117674view12:00, 22 May 2021EweitzModified title
114649view16:11, 25 January 2021ReactomeTeamReactome version 75
113097view11:16, 2 November 2020ReactomeTeamReactome version 74
112331view15:25, 9 October 2020ReactomeTeamReactome version 73
101230view11:12, 1 November 2018ReactomeTeamreactome version 66
100768view20:39, 31 October 2018ReactomeTeamreactome version 65
100312view19:16, 31 October 2018ReactomeTeamreactome version 64
99858view15:59, 31 October 2018ReactomeTeamreactome version 63
99415view14:35, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93868view13:42, 16 August 2017ReactomeTeamreactome version 61
93434view11:23, 9 August 2017ReactomeTeamreactome version 61
86525view09:20, 11 July 2016ReactomeTeamreactome version 56
83240view10:28, 18 November 2015ReactomeTeamVersion54
81345view12:52, 21 August 2015ReactomeTeamVersion53
76816view08:03, 17 July 2014ReactomeTeamFixed remaining interactions
76806view14:21, 16 July 2014ReactomeTeamFixed remaining interactions
76805view14:20, 16 July 2014ReactomeTeamFixed remaining interactions
76520view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75853view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75848view06:23, 11 June 2014Anwesha
75553view10:34, 10 June 2014ReactomeTeamReactome 48 Update
74908view13:43, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74552view08:35, 30 April 2014ReactomeTeamReactome46
69041view17:52, 8 July 2013MaintBotUpdated to 2013 gpml schema
44985view14:33, 6 October 2011MartijnVanIerselOntology Term : 'cell cycle checkpoint pathway' added !
42014view21:50, 4 March 2011MaintBotAutomatic update
39786view22:54, 18 January 2011KhanspersModified categories
39716view02:47, 14 January 2011AlexanderPicoAdded link to pathway
39714view02:35, 14 January 2011AlexanderPicoSpecify description
39703view02:08, 14 January 2011AlexanderPicoadded segmented line example
39702view01:54, 14 January 2011AlexanderPicoNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
14-3-3 proteins REACT_2548 (Reactome)
26S proteasome ComplexREACT_2353 (Reactome)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
ATR-ATRIP ComplexREACT_7002 (Reactome) The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR without affecting ATR mRNA levels indicating that complex formation stabilizes ATR. ATRIP is also a substrate for the ATR kinase, but this modification does not play a significant role in the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.
ATR-ATRIP-RPA-

ssDNA signaling complex

ComplexREACT_7037 (Reactome) While the ATR-ATRIP complex binds only poorly to RPA complexed with ssDNA lengths of 30 or 50 nt, binding is significantly enhanced in the presence of a 75 nt ssDNA molecule. Complex formation is primarily mediated by physical interaction between ATRIP and RPA. Multiple elements within the ATRIP molecule can bind to the RPA-ssDNA complex, including residues 1-107 (highest affinity), 218-390, and 390-791 (lowest afiinity). Although the full-length ATRIP is unable to bind ssDNA, an internal region (108-390) can weakly bind ssDNA when present in rabbit reticulocyte lysates. ATR can bind to the ssDNA directly independent of RPA, but this binding is inhibited by ATRIP. Upon binding, the ATR kinase becomes activated and can directly phosphorylate substrates such as Rad17.
Amino Acid REACT_2474 (Reactome)
COP1 ProteinQ8NHY2 (UniProt)
Cdc20 ProteinQ12834 (UniProt)
Cdc25A ProteinP30304 (UniProt)
Cdc25C ProteinP30307 (UniProt)
Cdc45:CDK:DDK:

Mcm10:Activated claspin:pre- replicative complex

ComplexREACT_7262 (Reactome)
Cdc45:CDK:DDK:

Mcm10:claspin:pre- replicative complex

ComplexREACT_7273 (Reactome)
Cdc45:CDK:DDK:

Mcm10:pre- replicative complex

ComplexREACT_4546 (Reactome)
Chk1 ProteinO14757 (UniProt)
Chk1/Ckk2(Cds1) REACT_5826 (Reactome)
Chk2 ProteinO96017-12 (UniProt)
Claspin ProteinQ9HAW4 (UniProt)
Cyclin B1:phospho-

Cdc2 (Thr 14, Thr 161)

ComplexREACT_6474 (Reactome)
Cyclin B1:phospho-

Cdc2(Thr 161, Thr 14, Tyr 15)

ComplexREACT_6704 (Reactome)
Cyclin B:Cdc2

complex

ComplexREACT_6447 (Reactome)
Cyclin B:phospho-

Cdc2(Thr 14)

ComplexREACT_6524 (Reactome)
Cyclin E:Cdk2

complexes

ComplexREACT_5247 (Reactome)
Cyclin E:Cdk2:

p21/p27 complex

ComplexREACT_3804 (Reactome)
HsMAD2 ProteinQ13257 (UniProt)
HsMad1 ProteinQ9Y6D9 (UniProt)
Kinetochore

Complex

REACT_5901 (Reactome)
Kinetochore:Mad1:

MAD2 Complex

ComplexREACT_4828 (Reactome) Mad2 binds to the Mad1:Kinetochore and undergoes a major conformational change within the complex to assume the form Mad2*.
Kinetochore:Mad1:

MAD2* Complex

ComplexREACT_5238 (Reactome)
MAD2* ProteinQ13257 (UniProt)
MAD2*CDC20

complex

ComplexREACT_2295 (Reactome) Activated Mad2 upon release from kinetochores binds and sequesters Cdc20 from activating the APC.
MCC:APC/C complex ComplexREACT_3955 (Reactome)
Mad1:kinetochore

complex

ComplexREACT_5632 (Reactome) The molecules that directly interact with Mad1 is unknown. However molecular genetic data has defined an assembly pathway consisting of CENP-I, HEC1, Mps1 that specifies the assembly of Mad1.
Mdm2 ProteinQ00987 (UniProt)
Mitotic checkpoint

protein BUB3

ProteinO43684 (UniProt)
Persistent single-

stranded DNA

REACT_7801 (Reactome)
Phospho-COP1(Ser-

387):p53 complex

ComplexREACT_21189 (Reactome)
RPA complexed to

ssDNA

ComplexREACT_7172 (Reactome) RPA associates with ssDNA in distinct complexes that can be distinguished by the length of ssDNA occluded by each RPA molecule. These complexes reflect the progressive association of distinct DNA-binding domains present in the RPA heterotrimeric structure. Binding is coupled to significant conformational changes within RPA that are observable at the microscopic level. Presumably, the different conformations of free and ssDNA-bound RPA allow the protein to selectively interact with factors such as ATR-ATRIP when bound to DNA.
RPA heterotrimer ComplexREACT_3427 (Reactome)
Rad17-RFC complex ComplexREACT_7804 (Reactome) The Rad17-RFC complex is a heteropentamer structurally similar to RFC. The Rad17-RFC complex contains the four smaller RFC subunits (Rfc2 [p37], Rfc3 [p36], Rfc4 [p40], and Rfc5 [p38]) and the 75 kDa Rad17 subunit in place of the Rfc1 [p140] subunit. The Rad17 complex contains a weak ATPase that is poorly stimulated by primed DNA. Along with binding the 9-1-1 complex and RPA, the Rad17-RFC complex interacts with human MCM7 protein. Each of these interactions is critical for Chk1 activation.

The Rad17 subunit is conserved evolutionarily with the protein showing 49% identity at the amino acid level with the S. pombe rad17 protein. Targeted deletion of the N-terminal region of mouse Rad17 leads to embryonic lethality, strongly suggesting that human Rad17 is also essential for long-term viability.

Rad17-RFC complex

bound to DNA

ComplexREACT_7502 (Reactome) Rad17-RFC complex associates with DNA substrates containing ssDNA regions including gapped or primed DNA in an ATP-independent reaction. Loading of the Rad9-Hus1-Rad1 (9-1-1) complex occurs preferentially on DNA substrates containing a 5' recessed end. This contrasts with the loading of PCNA by RFC which preferentially occurs on DNA with 3' recessed ends.
Rad9-Hus1-Rad1

bound to DNA

ComplexREACT_7267 (Reactome) A major known function of the 9-1-1 complex is to recruit Chk1 to stalled replication forks for activation by ATR. However, the presence of the 9-1-1 complex also alters the ability of Rad17 to become phoshorylated, perhaps suggesting that 9-1-1 may also serve to recruit a subset of ATR substrates. The 9-1-1 complex has also been found to interact with base excision repair factors human DNA polymerase beta, flap endonuclease FEN1, and the S. pombe MutY homolog (SpMYH), indicating that 9-1-1 also plays a direct role in DNA repair.
Rad9-Hus1-Rad1

complex

ComplexREACT_7593 (Reactome) The Rad9-Hus1-Rad1 (9-1-1) complex is a ring-shaped heterotrimeric complex. Under genotoxic stress conditions, it can be loaded onto DNA at sites of damage or stalled forks by the Rad17 complex.
Ubiquitin ligase REACT_4282 (Reactome)
Ubiquitinated

Phospho-Cdc25A

ComplexREACT_4164 (Reactome) A number of ubiquitin moeities are covalently added to the Cdc25A, which marks it for proteolytic degradation.
Wee1 ProteinP30291 (UniProt)
hBUBR1 ProteinO60566 (UniProt)
hBUBR1:hBUB3:

MAD2*:CDC20 complex

ComplexREACT_5836 (Reactome)
p21 ProteinP38936 (UniProt)
p21/p27 ProteinREACT_8306 (Reactome)
p53 protein ProteinP04637 (UniProt)
p53 ser-15

phosphorylated

ProteinP04637 (UniProt)
p53 tetramer ComplexREACT_20792 (Reactome)
phosho-COP1(ser-

387)

ProteinQ8NHY2 (UniProt)
phosph-Cdc25C (Ser

216)

ProteinP30307 (UniProt)
phospho-ATM (Ser

1981)

ProteinQ13315 (UniProt)
phospho-COP1(Ser

387)

ProteinQ8NHY2 (UniProt)
phospho-Cdc25A ProteinP30304 (UniProt)
phospho-Cdc25C:

14-3-3 protein complex

ComplexREACT_4474 (Reactome)
phospho-Chk1 ProteinO14757 (UniProt)
phospho-Chk2 ProteinO96017-12 (UniProt)
phospho-MDM2 ProteinQ00987 (UniProt)
phospho-Wee1 ProteinP30291 (UniProt)
phosphorylated

anaphase promoting complex (APC/C)

ComplexREACT_7058 (Reactome)
ubiquitin ProteinREACT_3316 (Reactome)
ubiquitinated

phospho-COP1(ser- 387)

ComplexREACT_21146 (Reactome)

Annotated Interactions

No annotated interactions

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