Checkpoint Kinase 1 (CHEK1)

CHK1; Cell cycle checkpoint kinase; Serine/threonine-protein kinase Chk1

SPN	N054
HGNC	1925
MGI	1202065
PubMed	23844225
RGD	620545
UniProt	O14757
Wiki	CHEK1

Chk1 is a kinase that phosphorylates cdc25, an important phosphatase in cell cycle control, particularly for entry into mitosis. Cdc25, when phosphorylated on serine 216 by chk1 becomes bound by an adaptor protein in the cytoplasm. Therefore it is inhibited from removing the inhibiting phosphate from MPF (mitotic/maturation promoting factor) added by Wee1. Consequently, a cell is prevented from entering mitosis.CHK1 is expressed ubiquitously as an approximately 2.4-kb mRNA, with the most abundant expression in thymus, testis, small intestine, and colon. Antibodies against CHK1 recognized a 54-kD protein on immunoblots of mammalian cell extracts. However, the protein had altered mobility when isolated from cells treated with ionizing radiation (IR), indicating that CHK1 is modified in response to DNA damage.

Reference

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"The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites."
Genes Dev. 14:289-300(2000) [PubMed] [Europe PMC] [Abstract]

Erratum
Genes Dev. 14:750-750(2000)

"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint."
Genes Dev. 14:1448-1459(2000) [PubMed] [Europe PMC] [Abstract]

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Erratum
J. Biol. Chem. 277:35776-35777(2002)

"An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage."
Mol. Cell. Biol. 22:8552-8561(2002) [PubMed] [Europe PMC] [Abstract]

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Nat. Genet. 30:285-289(2002) [PubMed] [Europe PMC] [Abstract]

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"Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A."
Cancer Cell 3:247-258(2003) [PubMed] [Europe PMC] [Abstract]

"Human tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint."
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"SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase."
Genes Dev. 17:3062-3074(2003) [PubMed] [Europe PMC] [Abstract]

"Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on ser-317 in response to ionizing radiation."
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"Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents."
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"Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on ser-345."
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"Phosphorylation at serine 75 is required for UV-mediated degradation of human Cdc25A phosphatase at the S-phase checkpoint."
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"Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding."
Mol. Cell. Biol. 23:7488-7497(2003) [PubMed] [Europe PMC] [Abstract]

"Suppression of tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1."
Oncogene 22:5927-5937(2003) [PubMed] [Europe PMC] [Abstract]

"MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation."
Proc. Natl. Acad. Sci. U.S.A. 100:15387-15392(2003) [PubMed] [Europe PMC] [Abstract]

"The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways."
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"Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains."
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"Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase."
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Cancer Cell 7:193-204(2005) [PubMed] [Europe PMC] [Abstract]

"PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints."
Genes Dev. 19:1162-1174(2005) [PubMed] [Europe PMC] [Abstract]

"p53 C-terminal phosphorylation by CHK1 and CHK2 participates in the regulation of DNA-damage-induced C-terminal acetylation."
Mol. Biol. Cell 16:1684-1695(2005) [PubMed] [Europe PMC] [Abstract]

"Coupling of human circadian and cell cycles by the timeless protein."
Mol. Cell. Biol. 25:3109-3116(2005) [PubMed] [Europe PMC] [Abstract]

"The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair."
Nat. Cell Biol. 7:195-201(2005) [PubMed] [Europe PMC] [Abstract]

"DNA damage-induced mitotic catastrophe is mediated by the Chk1-dependent mitotic exit DNA damage checkpoint."
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"14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation."
EMBO J. 25:1207-1218(2006) [PubMed] [Europe PMC] [Abstract]

"Repeated phosphopeptide motifs in human Claspin are phosphorylated by Chk1 and mediate Claspin function."
J. Biol. Chem. 281:33276-33282(2006) [PubMed] [Europe PMC] [Abstract]

"Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage."
EMBO J. 26:2083-2093(2007) [PubMed] [Europe PMC] [Abstract]

"Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway."
Mol. Cell. Biol. 27:3098-3108(2007) [PubMed] [Europe PMC] [Abstract]

"Tryptic digestion of ubiquitin standards reveals an improved strategy for identifying ubiquitinated proteins by mass spectrometry."
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"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage."
Science 316:1160-1166(2007) [PubMed] [Europe PMC] [Abstract]

"Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3."
Cell 133:864-877(2008) [PubMed] [Europe PMC] [Abstract]

"Nek6 is involved in G2/M phase cell cycle arrest through DNA damage-induced phosphorylation."
Cell Cycle 7:2705-2709(2008) [PubMed] [Europe PMC] [Abstract]

"Chk1 and Claspin potentiate PCNA ubiquitination."
Genes Dev. 22:1147-1152(2008) [PubMed] [Europe PMC] [Abstract]

"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]

"The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage."
Oncogene 27:3977-3985(2008) [PubMed] [Europe PMC] [Abstract]

"A quantitative atlas of mitotic phosphorylation."
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]

"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]

"The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress."
Mol. Cell 35:442-453(2009) [PubMed] [Europe PMC] [Abstract]

"Large-scale proteomics analysis of the human kinome."
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]

"NEK11 regulates CDC25A degradation and the IR-induced G2/M checkpoint."
Nat. Cell Biol. 11:1247-1253(2009) [PubMed] [Europe PMC] [Abstract]

"Human FEM1B is required for Rad9 recruitment and CHK1 activation in response to replication stress."
Oncogene 28:1971-1981(2009) [PubMed] [Europe PMC] [Abstract]

"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]

"NEK11: linking CHK1 and CDC25A in DNA damage checkpoint signaling."
Cell Cycle 9:450-455(2010) [PubMed] [Europe PMC] [Abstract]

"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]

"Initial characterization of the human central proteome."
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]

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Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]

"The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation."
Cell 100:681-692(2000) [PubMed] [Europe PMC] [Abstract]

"Structural basis for Chk1 inhibition by UCN-01."
J. Biol. Chem. 277:46609-46615(2002) [PubMed] [Europe PMC] [Abstract]

"Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity."
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"Patterns of somatic mutation in human cancer genomes."
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]