CHEK2 (CHK2 checkpoint homolog (S. pombe))

2004-05-01   Nancy Uhrhammer  

Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France

Identity

HGNC
LOCATION
22q12.1
LOCUSID
ALIAS
CDS1,CHK2,HuCds1,LFS2,PP1425,RAD53,hCds1
FUSION GENES

DNA/RNA

Description

17 exons spanning 57 kb

Transcription

Two isoforms are expressed, isoform a (2547nt) includes all 17 exons, while isoform b (2460 nt) does not include exon 12, deleting 87nt (29 codons) from the mRNA. The translation start site is in exon 4.

Proteins

Description

61 kDa. Isoform a: 543 amino acids; isoform b: 514 amino acids. Contains FHA and ser/thr kinase domains. Molecular studies of Chk2 typically do not distinguish between the different isoforms.

Expression

All tissues tested.

Localisation

nuclear

Function

Chk2 plays a role in the DNA damage signal cascade, especially in response to double-strand breaks. After detection of DNA damage, Chk2 is phosphorylated on Thr-68 by ATM and ATR. Thus activated, Chk2 targets p53 for phosphorylation on Ser20, releasing p53 from its inhibitor MDM2 and allowing transcriptional activation of genes responsible for cell cycle arrest, such as p21waf1/cip1, as well as initiation of apoptosis. In S phase, Chk2 phosphorylates Cdc25A on Ser123, targeting it for degradation and making it unavailable for the activation of cdk2, thus inhibiting the advance of S phase. In G2 phase, Chk2 phosphorylates Ser216 of Cdc25C, blocking entry into mitosis.

Chk2 is also involved in the regulation of BRCA1. Under normal conditions the two proteins are associated; after irradiation Chk2 phosphorylates Ser988 of BRCA1. This step is required for their dissociation, and the liberated BRCA1 participates directly in DNA repair and cell cycle arrest.

Finally, Chk2 can provoke apoptosis independently of p53, for example via phosphorylation of PML.

Homology

26 % identical to the Rad53 S. cereviscea homolog. The FHA and kinase domains are particularly conserved.

Mutations

Germinal

The northern european founder mutation "1100delC" is the most common found in breast cancer families. Other small deletions, stops, and missense mutations in the FHA or kinase domains such as Arg145Trp and Ile157Thr are rare in cancer families but not found in controls. The 1100delC mutation appears to increase the penetrance of mutations in certain other breast cancer genes, notably BRCA2. It should be noted that the publications describing "1100delC" have used the A of the initiation codon as nucleotide 1. This mutation thus corresponds to position 1861 in the complete, isoform a mRNA.

Somatic

Missense mutations in the FHA and kinase domains as well as frameshifts and nonsense mutations have been found at low frequencies in osteosarcoma and more rarely in carcinomas of the ovary, lung, and vulva. Reduced or missing protein expression has been observed in some cases of non-Hodgkins lymphoma, although neither mutation nor silencing of the gene by methylation was detected.

Implicated in

Entity name
Li-Fraumeni, Li-Fraumeni-like syndrome, somatic osteosarcoma and familial aggregations of breast cancer and colon cancer.
Note
The importance of Chk2 mutations in hereditary cancer risk is controversial, as some studies have failed to show an excess of mutations in selected populations, such as male breast cancer and patients with multiple colorectal adenomas developing colon cancer. In addition, some studies of breast cancer families suggest that only the relatively frequent 1100delC mutation is significant.
Prognosis
No known association with the clinical parameters of solid tumors. There is a possible association with more agressive non-Hodgkins lymphomas.

Article Bibliography

Pubmed IDLast YearTitleAuthors
106306411999DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis.Dasika GK et al
145681682003Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma.Lipton L et al
98366401998Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.Matsuoka S et al
117469832002Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors.Miller CW et al
126107802003Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.Schutte M et al
146487172004CHEK2 1100delC is not a risk factor for male breast cancer population.Syrjäkoski K et al
114792052001p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.Vahteristo P et al

Other Information

Locus ID:

NCBI: 11200
MIM: 604373
HGNC: 16627
Ensembl: ENSG00000183765

Variants:

dbSNP: 11200
ClinVar: 11200
TCGA: ENSG00000183765
COSMIC: CHEK2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000183765ENST00000348295O96017
ENSG00000183765ENST00000382565C9JFD7
ENSG00000183765ENST00000382580O96017
ENSG00000183765ENST00000398017B7ZBF8
ENSG00000183765ENST00000402731O96017
ENSG00000183765ENST00000403642O96017
ENSG00000183765ENST00000404276O96017
ENSG00000183765ENST00000405598O96017
ENSG00000183765ENST00000416671C9JFD7
ENSG00000183765ENST00000417588O96017
ENSG00000183765ENST00000425190B7ZBF2
ENSG00000183765ENST00000433028F8WCV2
ENSG00000183765ENST00000433728O96017
ENSG00000183765ENST00000434810H0Y820
ENSG00000183765ENST00000439200B7ZBF7
ENSG00000183765ENST00000439346H7C0V7
ENSG00000183765ENST00000447421B7ZBF6
ENSG00000183765ENST00000448511O96017
ENSG00000183765ENST00000454252H7BZ30
ENSG00000183765ENST00000456369H0Y4V6
ENSG00000183765ENST00000464581A0A087X102
ENSG00000183765ENST00000649563O96017
ENSG00000183765ENST00000650233A0A3B3ITA7
ENSG00000183765ENST00000650281O96017

Expression (GTEx)

0
5
10
15

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
DNA damage-induced cell cycle checkpointsKEGGhsa_M00691
DNA damage-induced cell cycle checkpointsKEGGM00691
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G1/S DNA Damage CheckpointsREACTOMER-HSA-69615
p53-Dependent G1/S DNA damage checkpointREACTOMER-HSA-69580
p53-Dependent G1 DNA Damage ResponseREACTOMER-HSA-69563
Stabilization of p53REACTOMER-HSA-69541
p53-Independent G1/S DNA damage checkpointREACTOMER-HSA-69613
p53-Independent DNA Damage ResponseREACTOMER-HSA-69610
Ubiquitin Mediated Degradation of Phosphorylated Cdc25AREACTOMER-HSA-69601
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
DNA RepairREACTOMER-HSA-73894
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Regulation of TP53 Activity through MethylationREACTOMER-HSA-6804760

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA61ATMGenePathwayassociated
PA74ATRGenePathwayassociated
PA95CCNB1GenePathwayassociated

References

Pubmed IDYearTitleCitations
377259242024Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants.1
379458982024Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.0
380398872024The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families.1
380474732024In silico and structure-based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein kinase.0
380616842024Profiling of the genetic features of patients with breast, ovarian, colorectal and extracolonic cancers: Association to CHEK2 and PALB2 germline mutations.0
380911532024Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants.3
382798232024CHEK2 Founder Variants and Thyroid Cancer Risk.0
383327302024Comprehensive splicing analysis of the alternatively spliced CHEK2 exons 8 and 10 reveals three enhancer/silencer-rich regions and 38 spliceogenic variants.0
383628522024The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.0
383676722024CHEK2 germline variants identified in familial nonmedullary thyroid cancer lead to impaired protein structure and function.0
383788422024Germline CHEK2 mutations in patients with myeloid neoplasms.0
385545512024A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.1
388551882024LINC00982-encoded protein PRDM16-DT regulates CHEK2 splicing to suppress colorectal cancer metastasis and chemoresistance.0
377259242024Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants.1
379458982024Checkpoint kinase 2 controls insulin secretion and glucose homeostasis.0

Citation

Nancy Uhrhammer

CHEK2 (CHK2 checkpoint homolog (S. pombe))

Atlas Genet Cytogenet Oncol Haematol. 2004-05-01

Online version: http://atlasgeneticsoncology.org/gene/312/meetings/css/js/lib/all.min.js