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CHEK2 (CHK2 checkpoint homolog (S. pombe))

Identity

Other namesCHK2
CDS1
Rad53
HGNC (Hugo) CHEK2
LocusID (NCBI) 11200
Location 22q12.1
Location_base_pair Starts at 29083731 and ends at 29137822 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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.
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors ProstateOverviewID5041

External links

Nomenclature
HGNC (Hugo)CHEK2   16627
Cards
AtlasCHEK2ID312
Entrez_Gene (NCBI)CHEK2  11200  checkpoint kinase 2
GeneCards (Weizmann)CHEK2
Ensembl (Hinxton)ENSG00000183765 [Gene_View]  chr22:29083731-29137822 [Contig_View]  CHEK2 [Vega]
ICGC DataPortalENSG00000183765
cBioPortalCHEK2
AceView (NCBI)CHEK2
Genatlas (Paris)CHEK2
WikiGenes11200
SOURCE (Princeton)NM_001005735 NM_001257387 NM_007194 NM_145862
Genomic and cartography
GoldenPath (UCSC)CHEK2  -  22q12.1   chr22:29083731-29137822 -  22q12.1   [Description]    (hg19-Feb_2009)
EnsemblCHEK2 - 22q12.1 [CytoView]
Mapping of homologs : NCBICHEK2 [Mapview]
OMIM114480   176807   259500   604373   609265   
Gene and transcription
Genbank (Entrez)AB040105 AF086904 AF096279 AF174135 AF217975
RefSeq transcript (Entrez)NM_001005735 NM_001257387 NM_007194 NM_145862
RefSeq genomic (Entrez)AC_000154 NC_000022 NC_018933 NG_008150 NT_011520 NW_001838745 NW_004929430
Consensus coding sequences : CCDS (NCBI)CHEK2
Cluster EST : UnigeneHs.505297 [ NCBI ]
CGAP (NCI)Hs.505297
Alternative Splicing : Fast-db (Paris)GSHG0020283
Alternative Splicing GalleryENSG00000183765
Gene ExpressionCHEK2 [ NCBI-GEO ]     CHEK2 [ SEEK ]   CHEK2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO96017 (Uniprot)
NextProtO96017  [Medical]
With graphics : InterProO96017
Splice isoforms : SwissVarO96017 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)FHA_DOMAIN (PS50006)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)FHA_dom [organisation]   Kinase-like_dom [organisation]   Prot_kinase_dom [organisation]   Ser/Thr_dual-sp_kinase_dom [organisation]   Ser/Thr_kinase_AS [organisation]   SMAD_FHA_domain [organisation]  
Related proteins : CluSTrO96017
Domain families : Pfam (Sanger)FHA (PF00498)    Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00498    pfam00069   
Domain families : Smart (EMBL)FHA (SM00240)  S_TKc (SM00220)  
DMDM Disease mutations11200
Blocks (Seattle)O96017
PDB (SRS)1GXC    2CN5    2CN8    2W0J    2W7X    2WTC    2WTD    2WTI    2WTJ    2XBJ    2XK9    2XM8    2XM9    2YCF    2YCQ    2YCR    2YCS    2YIQ    2YIR    2YIT    3I6U    3I6W    3VA4    4A9R    4A9S    4A9T    4A9U    4BDA    4BDB    4BDC    4BDD    4BDE    4BDF    4BDG    4BDH    4BDI    4BDJ    4BDK   
PDB (PDBSum)1GXC    2CN5    2CN8    2W0J    2W7X    2WTC    2WTD    2WTI    2WTJ    2XBJ    2XK9    2XM8    2XM9    2YCF    2YCQ    2YCR    2YCS    2YIQ    2YIR    2YIT    3I6U    3I6W    3VA4    4A9R    4A9S    4A9T    4A9U    4BDA    4BDB    4BDC    4BDD    4BDE    4BDF    4BDG    4BDH    4BDI    4BDJ    4BDK   
PDB (IMB)1GXC    2CN5    2CN8    2W0J    2W7X    2WTC    2WTD    2WTI    2WTJ    2XBJ    2XK9    2XM8    2XM9    2YCF    2YCQ    2YCR    2YCS    2YIQ    2YIR    2YIT    3I6U    3I6W    3VA4    4A9R    4A9S    4A9T    4A9U    4BDA    4BDB    4BDC    4BDD    4BDE    4BDF    4BDG    4BDH    4BDI    4BDJ    4BDK   
PDB (RSDB)1GXC    2CN5    2CN8    2W0J    2W7X    2WTC    2WTD    2WTI    2WTJ    2XBJ    2XK9    2XM8    2XM9    2YCF    2YCQ    2YCR    2YCS    2YIQ    2YIR    2YIT    3I6U    3I6W    3VA4    4A9R    4A9S    4A9T    4A9U    4BDA    4BDB    4BDC    4BDD    4BDE    4BDF    4BDG    4BDH    4BDI    4BDJ    4BDK   
Human Protein AtlasENSG00000183765 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO96017
HPRD05084
IPIIPI00014072   IPI00607851   IPI00423157   IPI00030746   IPI00607753   IPI00607709   IPI00607739   IPI00423149   IPI00607680   IPI00607619   IPI00423156   IPI00423146   IPI00953558   IPI00878704   IPI00982188   IPI00871524   IPI00877689   IPI00878496   IPI00877980   IPI00878892   IPI00878345   IPI00879227   IPI00879419   
Protein Interaction databases
DIP (DOE-UCLA)O96017
IntAct (EBI)O96017
FunCoupENSG00000183765
BioGRIDCHEK2
InParanoidO96017
Interologous Interaction database O96017
IntegromeDBCHEK2
STRING (EMBL)CHEK2
Ontologies - Pathways
Ontology : AmiGODNA damage checkpoint  G2/M transition of mitotic cell cycle  chromosome, telomeric region  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleoplasm  double-strand break repair  transcription, DNA-templated  regulation of transcription, DNA-dependent  protein phosphorylation  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  DNA damage induced protein phosphorylation  intrinsic apoptotic signaling pathway in response to DNA damage  intrinsic apoptotic signaling pathway in response to DNA damage  response to gamma radiation  PML body  protein kinase binding  ubiquitin protein ligase binding  regulation of protein catabolic process  signal transduction in response to DNA damage  identical protein binding  protein homodimerization activity  cellular protein catabolic process  positive regulation of transcription, DNA-dependent  protein autophosphorylation  metal ion binding  protein stabilization  cell division  signal transduction involved in intra-S DNA damage checkpoint  spindle assembly involved in mitosis  replicative senescence  
Ontology : EGO-EBIDNA damage checkpoint  G2/M transition of mitotic cell cycle  chromosome, telomeric region  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleoplasm  double-strand break repair  transcription, DNA-templated  regulation of transcription, DNA-dependent  protein phosphorylation  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  DNA damage induced protein phosphorylation  intrinsic apoptotic signaling pathway in response to DNA damage  intrinsic apoptotic signaling pathway in response to DNA damage  response to gamma radiation  PML body  protein kinase binding  ubiquitin protein ligase binding  regulation of protein catabolic process  signal transduction in response to DNA damage  identical protein binding  protein homodimerization activity  cellular protein catabolic process  positive regulation of transcription, DNA-dependent  protein autophosphorylation  metal ion binding  protein stabilization  cell division  signal transduction involved in intra-S DNA damage checkpoint  spindle assembly involved in mitosis  replicative senescence  
Pathways : BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    Cell Cycle: G2/M Checkpoint [Genes]    ATM Signaling Pathway [Genes]    Regulation of cell cycle progression by Plk3 [Genes]   
Pathways : KEGGCell cycle    p53 signaling pathway    HTLV-I infection   
Protein Interaction DatabaseCHEK2
Wikipedia pathwaysCHEK2
Gene fusion - rearrangments
Rearrangement : TICdbPPP2R2A [8p21.2]  -  CHEK2 [7p22.1]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CHEK2
snp3D : Map Gene to Disease11200
SNP (GeneSNP Utah)CHEK2
SNP : HGBaseCHEK2
Genetic variants : HAPMAPCHEK2
Exome VariantCHEK2
1000_GenomesCHEK2 
ICGC programENSG00000183765 
Cancer Gene: CensusCHEK2 
Somatic Mutations in Cancer : COSMICCHEK2 
CONAN: Copy Number AnalysisCHEK2 
Mutations and Diseases : HGMDCHEK2
Genomic VariantsCHEK2  CHEK2 [DGVbeta]
dbVarCHEK2
ClinVarCHEK2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM114480    176807    259500    604373    609265   
MedgenCHEK2
GENETestsCHEK2
Disease Genetic AssociationCHEK2
Huge Navigator CHEK2 [HugePedia]  CHEK2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCHEK2
Homology/Alignments : Family Browser (UCSC)CHEK2
Phylogenetic Trees/Animal Genes : TreeFamCHEK2
Chemical/Protein Interactions : CTD11200
Chemical/Pharm GKB GenePA404
Clinical trialCHEK2
Cancer Resource (Charite)ENSG00000183765
Other databases
Probes
Litterature
PubMed414 Pubmed reference(s) in Entrez
CoreMineCHEK2
iHOPCHEK2

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
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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. 2004;8(3):191-192.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CHEK2ID312.html

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indexed on : Fri Jul 11 17:02:05 CEST 2014

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