Description: Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 3, mRNA. RefSeq Summary (NM_001274): The protein encoded by this gene belongs to the Ser/Thr protein kinase family. It is required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. This protein acts to integrate signals from ATM and ATR, two cell cycle proteins involved in DNA damage responses, that also associate with chromatin in meiotic prophase I. Phosphorylation of CDC25A protein phosphatase by this protein is required for cells to delay cell cycle progression in response to double-strand DNA breaks. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2011]. Transcript (Including UTRs) Position: hg19 chr11:125,496,251-125,527,042 Size: 30,792 Total Exon Count: 13 Strand: + Coding Region Position: hg19 chr11:125,496,664-125,525,215 Size: 28,552 Coding Exon Count: 12
ID:CHK1_HUMAN DESCRIPTION: RecName: Full=Serine/threonine-protein kinase Chk1; EC=2.7.11.1; AltName: Full=CHK1 checkpoint homolog; AltName: Full=Cell cycle checkpoint kinase; AltName: Full=Checkpoint kinase-1; FUNCTION: Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser- 124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell- cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest. FUNCTION: Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication. Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B. SUBUNIT: Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ. Isoform 1 associates with isoform 2, the interaction is disrupted upon phosphorylation by ATR. INTERACTION: P38398:BRCA1; NbExp=3; IntAct=EBI-974488, EBI-349905; P30307:CDC25C; NbExp=2; IntAct=EBI-974488, EBI-974439; Q9HAW4:CLSPN; NbExp=5; IntAct=EBI-974488, EBI-1369377; Q06609:RAD51; NbExp=3; IntAct=EBI-974488, EBI-297202; Q9UNS1:TIMELESS; NbExp=2; IntAct=EBI-974488, EBI-2212315; SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cytoplasm, cytoskeleton, centrosome. Note=Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B. TISSUE SPECIFICITY: Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon. DOMAIN: The autoinhibitory region (AIR) inhibits the activity of the kinase domain. PTM: Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity. PTM: Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/chek1/";
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Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): CHEK1 CDC HuGE Published Literature: CHEK1 Positive Disease Associations: colorectal cancer Related Studies:
colorectal cancer Kim, C. J. et al. 2007, Chk1 frameshift mutation in sporadic and hereditary non-polyposis colorectal cancers with microsatellite instability, Eur J Surg Oncol 2007.
[PubMed 17408908]
These results suggest that the Chk1 gene is a target of genomic instability in MSI-positive colorectal cancers and that the Chk1 framshift mutations might be involved in colorectal tumourigenesis through a defect in response to DNA damage in a subset of sporadic colorectal cancers and HNPCCs.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O14757
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000077 DNA damage checkpoint GO:0006260 DNA replication GO:0006281 DNA repair GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0006975 DNA damage induced protein phosphorylation GO:0007049 cell cycle GO:0010569 regulation of double-strand break repair via homologous recombination GO:0010767 regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage GO:0016310 phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0035407 histone H3-T11 phosphorylation GO:0035556 intracellular signal transduction GO:0045787 positive regulation of cell cycle GO:0045839 negative regulation of mitotic nuclear division GO:0046602 regulation of mitotic centrosome separation GO:0048096 chromatin-mediated maintenance of transcription GO:0070317 negative regulation of G0 to G1 transition GO:0071260 cellular response to mechanical stimulus GO:0072425 signal transduction involved in G2 DNA damage checkpoint GO:0090399 replicative senescence GO:1901796 regulation of signal transduction by p53 class mediator GO:2000615 regulation of histone H3-K9 acetylation
LF208415 - JP 2014500723-A/15918: Polycomb-Associated Non-Coding RNAs. AK300082 - Homo sapiens cDNA FLJ56409 complete cds, highly similar to Serine/threonine-protein kinase Chk1 (EC 2.7.11.1). JF289264 - Homo sapiens cell-line HEK-293 Chk1-S variant (CHEK1) mRNA, complete cds, alternatively spliced. BC004202 - Homo sapiens CHK1 checkpoint homolog (S. pombe), mRNA (cDNA clone MGC:3717 IMAGE:3530606), complete cds. AK299783 - Homo sapiens cDNA FLJ51635 complete cds, highly similar to Serine/threonine-protein kinase Chk1 (EC 2.7.11.1). AK293143 - Homo sapiens cDNA FLJ59449 complete cds, highly similar to Serine/threonine-protein kinase Chk1 (EC 2.7.11.1). AK292549 - Homo sapiens cDNA FLJ75501 complete cds, highly similar to Homo sapiens CHK1 checkpoint homolog (S. pombe) (CHEK1), mRNA. BC017575 - Homo sapiens CHK1 checkpoint homolog (S. pombe), mRNA (cDNA clone MGC:24475 IMAGE:4091997), complete cds. JD458820 - Sequence 439844 from Patent EP1572962. JD334079 - Sequence 315103 from Patent EP1572962. JD516132 - Sequence 497156 from Patent EP1572962. LF376023 - JP 2014500723-A/183526: Polycomb-Associated Non-Coding RNAs. AF016582 - Homo sapiens checkpoint kinase Chk1 (CHK1) mRNA, complete cds. AB527508 - Synthetic construct DNA, clone: pF1KB5824, Homo sapiens CHEK1 gene for CHK1 checkpoint homolog, without stop codon, in Flexi system. DQ892907 - Synthetic construct clone IMAGE:100005537; FLH190728.01X; RZPDo839D0576D CHK1 checkpoint homolog (S. pombe) (CHEK1) gene, encodes complete protein. DQ896142 - Synthetic construct Homo sapiens clone IMAGE:100010602; FLH190724.01L; RZPDo839D0566D CHK1 checkpoint homolog (S. pombe) (CHEK1) gene, encodes complete protein. AB451345 - Homo sapiens CHEK1 mRNA for CHK1 checkpoint homolog, partial cds, clone: FLJ08006AAAF. AF032874 - Homo sapiens protein kinase (CHK1) mRNA, partial cds. AB451222 - Homo sapiens CHEK1 mRNA for CHK1 checkpoint homolog, complete cds, clone: FLJ08006AAAN. LF376020 - JP 2014500723-A/183523: Polycomb-Associated Non-Coding RNAs. JD407795 - Sequence 388819 from Patent EP1572962. JD214756 - Sequence 195780 from Patent EP1572962. JD264082 - Sequence 245106 from Patent EP1572962. JD358637 - Sequence 339661 from Patent EP1572962. JD563826 - Sequence 544850 from Patent EP1572962. JD483789 - Sequence 464813 from Patent EP1572962. JD501369 - Sequence 482393 from Patent EP1572962. LF376019 - JP 2014500723-A/183522: Polycomb-Associated Non-Coding RNAs. LF376018 - JP 2014500723-A/183521: Polycomb-Associated Non-Coding RNAs. MA443992 - JP 2018138019-A/15918: Polycomb-Associated Non-Coding RNAs. MA611600 - JP 2018138019-A/183526: Polycomb-Associated Non-Coding RNAs. MA611597 - JP 2018138019-A/183523: Polycomb-Associated Non-Coding RNAs. MA611596 - JP 2018138019-A/183522: Polycomb-Associated Non-Coding RNAs. MA611595 - JP 2018138019-A/183521: Polycomb-Associated Non-Coding RNAs.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04110 - Cell cycle hsa04115 - p53 signaling pathway
BioCarta from NCI Cancer Genome Anatomy Project h_cdc25Pathway - cdc25 and chk1 Regulatory Pathway in response to DNA damage h_rbPathway - RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage h_atrbrcaPathway - Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility h_g2Pathway - Cell Cycle: G2/M Checkpoint h_plk3Pathway - Regulation of cell cycle progression by Plk3 h_atmPathway - ATM Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein O14757 (Reactome details) participates in the following event(s):
R-HSA-69889 Phosphorylation and activation of Chk1 by ATM R-HSA-176116 Recruitment and activation of Chk1 R-HSA-5684882 CHEK1 is recruited to resected DNA DSBs R-HSA-5684887 Activation of CHEK1 at resected DNA DSBs R-HSA-69604 Phosphorylation of Cdc25A at Ser-123 by Chk1 R-HSA-75028 Phosphorylation of Wee1 kinase by Chk1 R-HSA-75010 Phosphorylation of Cdc25C at Ser 216 by Chk1 R-HSA-5685230 CHEK1 phosphorylates RAD51 R-HSA-5685242 CHEK1 phosphorylates BRCA2 R-HSA-6799246 CHEK1 phosphorylates TP53 R-HSA-9007539 CHEK1 phosphorylates E2F6 R-HSA-205328 Interaction of other tyrosine kinases with p-KIT R-HSA-69601 Ubiquitin Mediated Degradation of Phosphorylated Cdc25A R-HSA-69473 G2/M DNA damage checkpoint R-HSA-176187 Activation of ATR in response to replication stress R-HSA-5693607 Processing of DNA double-strand break ends R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-69610 p53-Independent DNA Damage Response R-HSA-69481 G2/M Checkpoints R-HSA-5693567 HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA) R-HSA-75035 Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex R-HSA-5693616 Presynaptic phase of homologous DNA pairing and strand exchange R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation R-HSA-8953750 Transcriptional Regulation by E2F6 R-HSA-1433557 Signaling by SCF-KIT R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-69613 p53-Independent G1/S DNA damage checkpoint R-HSA-69620 Cell Cycle Checkpoints R-HSA-5693538 Homology Directed Repair R-HSA-5693579 Homologous DNA Pairing and Strand Exchange R-HSA-5633007 Regulation of TP53 Activity R-HSA-212436 Generic Transcription Pathway R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-69615 G1/S DNA Damage Checkpoints R-HSA-1640170 Cell Cycle R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-5685942 HDR through Homologous Recombination (HRR) R-HSA-73857 RNA Polymerase II Transcription R-HSA-162582 Signal Transduction R-HSA-73894 DNA Repair R-HSA-74160 Gene expression (Transcription)
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
