JavaScript is disabled in your browser. Please enable JavaScript to view this website.

CHEK1

GeneName

CHEK1

Summary

CHEK1, also known as Chk1 or checkpoint kinase 1, is a 54 kDa serine/threonine protein kinase that plays a crucial role in the DNA damage response and cell cycle regulation. It is primarily localised in the nucleus and cytoplasm, with additional presence at the centrosome and chromatin. CHEK1 is activated in response to DNA damage, particularly during the G2/M transition of the mitotic cell cycle, and is involved in processes such as DNA repair, chromatin remodelling, and apoptosis. Its kinase activity includes ATP binding and phosphorylation of target proteins, which are essential for maintaining genomic stability and preventing the propagation of damaged DNA.

Importance

CHEK1 is relevant to: - Cancer research due to its role in the DNA damage response and cell cycle regulation, making it a potential target for cancer therapies. - Understanding the mechanisms of replicative senescence and its implications in ageing and cancer biology. - Investigating the regulation of the G2/M checkpoint, which is critical for preventing mitotic errors and maintaining genomic integrity. - Exploring therapeutic strategies that exploit CHEK1 inhibition in combination with DNA-damaging agents in cancer treatment.

Top Products

For researchers investigating CHEK1, we highly recommend the top-selling recombinant antibody, Anti-Chk1 antibody [EP691Y] (ab40866). This antibody has been validated for use in a variety of applications, including Western blotting (WB), immunohistochemistry (IHC), immunocytochemistry (ICC), and flow cytometry (FC), making it a versatile tool for your research needs. With 43 citations, it is well-regarded in the scientific community, reflecting its reliability and effectiveness in detecting CHEK1. This recombinant antibody ensures batch-to-batch consistency, providing confidence in your experimental results. The Anti-Chk1 antibody ELISA Kit (ab47574), supported by 29 citations, is an excellent option for researchers looking to accurately measure CHEK1 levels in their samples.

Abcam Product Citation Summary

The CHEK1 target has been studied extensively in human HT29 cells, particularly in the context of Chk1 inhibitors and activation. The use of immunofluorescence and western blotting techniques highlights the importance of CHEK1 in cancer research, especially regarding therapeutic interventions.

Abcam Product Citation Table

Product Code
Species
Application
Study Context
PMID
ab40866
Human
WB, IF
Chk1 inhibitors
29617433
ab40866
Human
WB, IF
Chk1 activation
29617433
ab40866
Human
IF
Effects of V158411 treatment
29617433

Domain

The autoinhibitory region (AIR) inhibits the activity of the kinase domain.

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 (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856, PubMed:32357935). May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856). This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856). Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:11535615, PubMed:12399544, PubMed:12446774, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15650047, PubMed:15665856). Binds to and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:12676583, PubMed:12676925, PubMed:12759351, PubMed:14559997, PubMed:14681206, PubMed:19734889, PubMed:9278511). 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 (PubMed:9278511). Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A (PubMed:12676583, PubMed:12676925, PubMed:12759351, PubMed:14681206, PubMed:19734889, PubMed:9278511). 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 (PubMed:19734889, PubMed:20090422, PubMed:9278511). Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression (PubMed:9278511). Also phosphorylates NEK6 (PubMed:18728393). 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 (PubMed:15665856). 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 (PubMed:10673501, PubMed:15659650, PubMed:16511572). Also promotes repair of DNA cross-links through phosphorylation of FANCE (PubMed:17296736). Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A (PubMed:12660173, PubMed:12955071). This may enhance chromatin assembly both in the presence or absence of DNA damage (PubMed:12660173, PubMed:12955071). May also play a role in replication fork maintenance through regulation of PCNA (PubMed:18451105). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones (By similarity). Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (By similarity). May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest (PubMed:17380128). Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (PubMed:31316063). Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (PubMed:33108758).

Isoform 2

Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.

Involvement in disease

Oocyte/zygote/embryo maturation arrest 21

OZEMA21

An autosomal dominant, female infertility disorder characterized by zygote development arrest due to failure of pronuclei fusion.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication (PubMed:10859164, PubMed:11390642, PubMed:12446774, PubMed:12588868, PubMed:12676583, PubMed:12676925, PubMed:12676962, PubMed:14681223, PubMed:14988723, PubMed:15650047, PubMed:15707391, PubMed:15870257, PubMed:25083873, PubMed:31316063). Phosphorylated by ATM in response to ionizing irradiation (PubMed:12588868, PubMed:12676583). ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity (PubMed:11390642, PubMed:12446774, PubMed:12588868, PubMed:12660173, PubMed:12676583, PubMed:12676962, PubMed:14657349, PubMed:15665856, PubMed:15707391, PubMed:15870257, PubMed:25083873). 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 (PubMed:19716789). Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention (PubMed:12676962). Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest (PubMed:15870257). 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 (By similarity).

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. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (PubMed:32357935).

Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity.

Sequence Similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.

Tissue Specificity

Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.

Cellular localization

Alternative names

CHK1, CHEK1, Serine/threonine-protein kinase Chk1, CHK1 checkpoint homolog, Cell cycle checkpoint kinase, Checkpoint kinase-1

swissprot:O14757 omim:603078 entrezGene:1111

Other research areas