CHEK1: Checkpoint Kinase 1 - DNA Damage Response Regulator
A key serine/threonine kinase in cell cycle checkpoint control and genomic stability
Gene Information Card
| Symbol | CHEK1 |
|---|---|
| Full Name | Checkpoint Kinase 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 11q24.2 |
| NCBI Gene ID | 1111 ncbi.nlm.nih.gov/gene/1111 |
| Ensembl ID | ENSG00000149554 |
| UniProt ID | O14757 |
| OMIM ID | 603078 |
| HGNC ID | 1925 |
| Aliases | CHK1, CHEK1, CHK1 checkpoint homolog |
Description
CHEK1 (Checkpoint Kinase 1) encodes a serine/threonine kinase that is a central mediator of the DNA damage response. It is activated by phosphorylation by ATR in response to replication stress or DNA damage, leading to cell cycle arrest at the G2/M checkpoint, stabilization of replication forks, and activation of DNA repair pathways. CHEK1 is essential for maintaining genomic integrity and is frequently dysregulated in cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast cancer | CHEK1 overexpression or amplification promotes resistance to DNA-damaging chemotherapy by enhancing checkpoint activation and DNA repair. | PMID: 23555292; COSMIC |
| Colorectal cancer | Loss of CHEK1 function leads to genomic instability and increased mutation rate, contributing to tumorigenesis. | PMID: 18316792; ClinVar |
| Lung cancer | CHEK1 mutations and altered expression are associated with poor prognosis and resistance to platinum-based therapies. | PMID: 25691885; COSMIC |
| Ovarian cancer | CHEK1 inhibition sensitizes ovarian cancer cells to PARP inhibitors and DNA-damaging agents. | PMID: 28490518; ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 12.5 | High |
| Bone marrow | 8.2 | Medium |
| Lymph node | 6.7 | Medium |
| Brain | 3.1 | Low |
| Liver | 2.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.3 | Cervical cancer cell line; high CHEK1 expression |
| MCF7 | 10.1 | Breast cancer cell line; moderate expression |
| A549 | 8.9 | Lung cancer cell line; moderate expression |
| HCT116 | 7.4 | Colorectal cancer cell line; moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1100delC | Frameshift deletion | <1% | Loss of function; associated with breast cancer risk |
| p.Ser317Phe | Missense | <0.5% | Reduced kinase activity; impaired checkpoint function |
| p.Arg145Trp | Missense | <0.1% | Dominant negative effect; disrupts ATR-mediated activation |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., c.1100delC) lead to truncated, non-functional protein, impairing DNA damage checkpoint activation and increasing genomic instability.
Gain of Function (GOF)
Amplification or overexpression of wild-type CHEK1 in tumors confers resistance to DNA-damaging therapies by enhancing checkpoint arrest and DNA repair.
Dominant Negative (DN)
Missense mutations in the kinase domain (e.g., p.Arg145Trp) produce a protein that interferes with wild-type CHEK1 function, reducing checkpoint activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Cell Cycle Checkpoints (Reactome: R-HSA-69620)
• ATM/ATR signaling (Reactome: R-HSA-5693571)
• DNA Damage Response (KEGG: hsa03460)
• p53-Independent G2/M DNA Damage Checkpoint (WikiPathways: WP3874)
Protein Summary
CHEK1 is a 476-amino acid serine/threonine kinase with an N-terminal kinase domain and a C-terminal regulatory domain. It is activated by ATR-mediated phosphorylation at Ser317 and Ser345 in response to replication stress or DNA damage. Active CHEK1 phosphorylates downstream targets such as CDC25A, CDC25C, and WEE1 to enforce cell cycle arrest, and also regulates replication fork stability and DNA repair. CHEK1 is overexpressed in many cancers and is a target for cancer therapy, with inhibitors in clinical development.
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