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CHEK2 (CHK2 checkpoint homolog (S. pombe))

Identity

Other namesCHK2
CDS1
Rad53
Hugo CHEK2
Location 22q12.1

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.

Protein

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 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.
  

External links

Nomenclature
HugoCHEK2
GDBCHEK2
Entrez_GeneCHEK2  11200  CHK2 checkpoint homolog (S. pombe)
Cards
AtlasCHEK2ID312
GeneCardsCHEK2
EnsemblCHEK2 [Search_View]   ENSG00000183765 [Gene_View]
GenatlasCHEK2
GeneLynxCHEK2
eGenomeCHEK2
euGene11200
Genomic and cartography
GoldenPathCHEK2  -  22q12.1   chr22:27413731-27467822 -  22q12.1   [Description]    (hg18-Mar_2006)
EnsemblCHEK2 - 22q12.1 [CytoView]
NCBIMapview
OMIMDisease map [OMIM]
HomoloGeneCHEK2
Gene and transcription
GenbankAB040105 [ ENTREZ ]
GenbankAF086904 [ ENTREZ ]
GenbankAF096279 [ ENTREZ ]
GenbankAF174135 [ ENTREZ ]
GenbankAF217975 [ ENTREZ ]
RefSeqNM_001005735 [ SRS ]    NM_001005735 [ ENTREZ ]
RefSeqNM_007194 [ SRS ]    NM_007194 [ ENTREZ ]
RefSeqNM_145862 [ SRS ]    NM_145862 [ ENTREZ ]
RefSeqAC_000065 [ SRS ]    AC_000065 [ ENTREZ ]
RefSeqAC_000154 [ SRS ]    AC_000154 [ ENTREZ ]
RefSeqNC_000022 [ SRS ]    NC_000022 [ ENTREZ ]
RefSeqNG_008150 [ SRS ]    NG_008150 [ ENTREZ ]
RefSeqNT_011520 [ SRS ]    NT_011520 [ ENTREZ ]
RefSeqNW_001838745 [ SRS ]    NW_001838745 [ ENTREZ ]
RefSeqNW_927628 [ SRS ]    NW_927628 [ ENTREZ ]
AceViewCHEK2 AceView - NCBI
UnigeneHs.505297 [ SRS ]    Hs.505297 [ NCBI ]     HS505297 [ spliceNest ]
Fast-db3445 (alternative variants)
Protein : pattern, domain, 3D structure
SwissProtO96017 [ SRS]    O96017 [ EXPASY ]     O96017 [ INTERPRO ]
PrositePS50006 FHA_DOMAIN [ SRS ]    PS50006 FHA_DOMAIN [ Expasy ]
PrositePS00107 PROTEIN_KINASE_ATP [ SRS ]    PS00107 PROTEIN_KINASE_ATP [ Expasy ]
PrositePS50011 PROTEIN_KINASE_DOM [ SRS ]    PS50011 PROTEIN_KINASE_DOM [ Expasy ]
PrositePS00108 PROTEIN_KINASE_ST [ SRS ]    PS00108 PROTEIN_KINASE_ST [ Expasy ]
InterproIPR000253 FHA [ SRS ]    IPR000253 FHA [ EBI ]
InterproIPR000719 Prot_kinase_core [ SRS ]    IPR000719 Prot_kinase_core [ EBI ]
InterproIPR017441 Protein_kinase_ATP_bd_CS [ SRS ]    IPR017441 Protein_kinase_ATP_bd_CS [ EBI ]
InterproIPR008271 Ser_thr_pkin_AS [ SRS ]    IPR008271 Ser_thr_pkin_AS [ EBI ]
InterproIPR002290 Ser_thr_pkinase [ SRS ]    IPR002290 Ser_thr_pkinase [ EBI ]
CluSTrO96017
PfamPF00498 FHA [ SRS ]    PF00498 FHA [ Sanger ]    pfam00498 [ NCBI-CDD ]
SmartSM00240 FHA [EMBL]
SmartSM00220 S_TKc [EMBL]
ProdomPD000001 Prot_kinase[INRA-Toulouse]
ProdomO96017 CHK2_HUMAN [ Domain structure ]   O96017 CHK2_HUMAN  [ sequences sharing at least 1 domain ]
BlocksO96017
PDBCHEK2 [ SRS ]    CHEK2 [ PdbSum ],   CHEK2 [ IMB ]   CHEK2 [ RSDB ]
HPRD05084
Protein Interaction databases
DIPO96017
IntActO96017
Polymorphism : SNP, mutations, diseases
OMIM114480;176807;259500;604373;609265    [ map ]   
GENECLINICS114480;176807;259500;604373;609265
SNPCHEK2 [dbSNP-NCBI]  
SNPNM_001005735 [SNP-NCI]  
SNPNM_007194 [SNP-NCI]  
SNPNM_145862 [SNP-NCI]  
SNPCHEK2 [GeneSNPs - Utah]  CHEK2] [HGBASE - SRS]
HAPMAPCHEK2 [HAPMAP]  
COSMICCHEK2 [Somatic mutation (COSMIC-CGP-Sanger)]  
TICdbCHEK2 [Translocation breakpoints In Cancer]  
HGMDCHEK2
General knowledge
Family BrowserCHEK2 [UCSC Family Browser]
SOURCENM_001005735
SOURCENM_007194
SOURCENM_145862
SMDHs.505297
SAGEHs.505297
Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.1 [ Enzyme-SRS ]   2.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   2.7.11.1 [ WIT ]
GODNA damage checkpoint [Amigo]  DNA damage checkpoint
GOnucleotide binding [Amigo]  nucleotide binding
GOmagnesium ion binding [Amigo]  magnesium ion binding
GOprotein serine/threonine kinase activity [Amigo]  protein serine/threonine kinase activity
GOprotein serine/threonine kinase activity [Amigo]  protein serine/threonine kinase activity
GOprotein binding [Amigo]  protein binding
GOATP binding [Amigo]  ATP binding
GOnucleus [Amigo]  nucleus
GOprotein amino acid phosphorylation [Amigo]  protein amino acid phosphorylation
GOcell cycle [Amigo]  cell cycle
GODNA damage response, signal transduction resulting in induction of apoptosis [Amigo]  DNA damage response, signal transduction resulting in induction of apoptosis
GOPML body [Amigo]  PML body
GOtransferase activity [Amigo]  transferase activity
BIOCARTAATM Signaling Pathway    [Genes]
BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility    [Genes]
BIOCARTACell Cycle: G2/M Checkpoint    [Genes]
BIOCARTARegulation of cell cycle progression by Plk3    [Genes]
KEGGCell cycle
PubGeneCHEK2
TreeFamCHEK2
CTD11200 [Comparative ToxicoGenomics Database]
Other databases
Probes
ProbeCHEK2 Related clones (RZPD - Berlin)
PubMed
PubMed229 Pubmed reference(s) in LocusLink

Bibliography

Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
Matsuoka S, Huang M, Elledge SJ
Science (New York, N.Y.). 1998 ; 282 (5395) : 1893-1897.
PMID 9836640
 
DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis.
Dasika GK, Lin SC, Zhao S, Sung P, Tomkinson A, Lee EY
Oncogene. 1999 ; 18 (55) : 7883-7899.
PMID 10630641
 
p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.
Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomˆ§ki K, Nevanlinna H
Cancer research. 2001 ; 61 (15) : 5718-5722.
PMID 11479205
 
Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors.
Miller CW, Ikezoe T, Krug U, Hofmann WK, Tavor S, Vegesna V, Tsukasaki K, Takeuchi S, Koeffler HP
Genes, chromosomes & cancer. 2002 ; 33 (1) : 17-21.
PMID 11746983
 
Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma.
Lipton L, Fleischmann C, Sieber OM, Thomas HJ, Hodgson SV, Tomlinson IP, Houlston RS
Cancer letters. 2003 ; 200 (2) : 149-152.
PMID 14568168
 
Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.
Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, Evans DG, Eccles D, Meijers C, Lohman F, Klijn J, van den Ouweland A, Futreal PA, Nathanson KL, Weber BL, Easton DF, Stratton MR, Breast Cancer Linkage Consortium, Rahman N
American journal of human genetics. 2003 ; 72 (4) : 1023-1028.
PMID 12610780
 
CHEK2 1100delC is not a risk factor for male breast cancer population.
Syrjˆ§koski K, Kuukasjˆ§rvi T, Auvinen A, Kallioniemi OP
International journal of cancer. Journal international du cancer. 2004 ; 108 (3) : 475-476.
PMID 14648717
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written05-2004Nancy Uhrhammer

Citation

This paper should be referenced as such :
Uhrhammer N . CHEK2 (CHK2 checkpoint homolog (S. pombe)). Atlas Genet Cytogenet Oncol Haematol. May 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/CHEK2ID312.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jul 14 17:43:05 2008


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