CHEK2 (CHK2 checkpoint homolog (S. pombe))

Identity

Other names	CHK2
	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
Hugo	CHEK2
GDB	CHEK2
Entrez_Gene	CHEK2  11200  CHK2 checkpoint homolog (S. pombe)
	Cards
Atlas	CHEK2ID312
GeneCards	CHEK2
Ensembl	CHEK2 [Search_View]   ENSG00000183765 [Gene_View]
Genatlas	CHEK2
GeneLynx	CHEK2
eGenome	CHEK2
euGene	11200
	Genomic and cartography
GoldenPath	CHEK2  -  22q12.1   chr22:27413731-27467822 -  22q11|22q12.1   [Description]    (hg18-Mar_2006)
Ensembl	CHEK2 - 22q11|22q12.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	CHEK2
	Gene and transcription
Genbank	AB040105 [ ENTREZ ]
Genbank	AF086904 [ ENTREZ ]
Genbank	AF096279 [ ENTREZ ]
Genbank	AF174135 [ ENTREZ ]
Genbank	AF217975 [ ENTREZ ]
RefSeq	NM_001005735 [ SRS ]    NM_001005735 [ ENTREZ ]
RefSeq	NM_007194 [ SRS ]    NM_007194 [ ENTREZ ]
RefSeq	NM_145862 [ SRS ]    NM_145862 [ ENTREZ ]
RefSeq	AC_000065 [ SRS ]    AC_000065 [ ENTREZ ]
RefSeq	NC_000022 [ SRS ]    NC_000022 [ ENTREZ ]
RefSeq	NT_011520 [ SRS ]    NT_011520 [ ENTREZ ]
RefSeq	NW_927628 [ SRS ]    NW_927628 [ ENTREZ ]
AceView	CHEK2 AceView - NCBI
Unigene	Hs.632780 [ SRS ]    Hs.632780 [ NCBI ]     HS632780 [ spliceNest ]
Fast-db	3445 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	O96017 [ SRS]    O96017 [ EXPASY ]     O96017 [ INTERPRO ]
Prosite	PS50006 FHA_DOMAIN [ SRS ]    PS50006 FHA_DOMAIN [ Expasy ]
Prosite	PS00107 PROTEIN_KINASE_ATP [ SRS ]    PS00107 PROTEIN_KINASE_ATP [ Expasy ]
Prosite	PS50011 PROTEIN_KINASE_DOM [ SRS ]    PS50011 PROTEIN_KINASE_DOM [ Expasy ]
Prosite	PS00108 PROTEIN_KINASE_ST [ SRS ]    PS00108 PROTEIN_KINASE_ST [ Expasy ]
Interpro	IPR000253 FHA [ SRS ]    IPR000253 FHA [ EBI ]
Interpro	IPR000719 Prot_kinase_core [ SRS ]    IPR000719 Prot_kinase_core [ EBI ]
Interpro	IPR008271 Ser_thr_pkin_AS [ SRS ]    IPR008271 Ser_thr_pkin_AS [ EBI ]
Interpro	IPR002290 Ser_thr_pkinase [ SRS ]    IPR002290 Ser_thr_pkinase [ EBI ]
CluSTr	O96017
Pfam	PF00498 FHA [ SRS ]    PF00498 FHA [ Sanger ]    pfam00498 [ NCBI-CDD ]
Pfam	PF00069 Pkinase [ SRS ]    PF00069 Pkinase [ Sanger ]    pfam00069 [ NCBI-CDD ]
Smart	SM00240 FHA [EMBL]
Smart	SM00220 S_TKc [EMBL]
Prodom	PD000001 Prot_kinase[INRA-Toulouse]
Prodom	O96017 CHK2_HUMAN [ Domain structure ]   O96017 CHK2_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	O96017
PDB	1GXC [ SRS ]    1GXC [ PdbSum ],   1GXC [ IMB ]   1GXC [ RSDB ]
PDB	2CN5 [ SRS ]    2CN5 [ PdbSum ],   2CN5 [ IMB ]   2CN5 [ RSDB ]
PDB	2CN8 [ SRS ]    2CN8 [ PdbSum ],   2CN8 [ IMB ]   2CN8 [ RSDB ]
HPRD	05084
	Protein Interaction databases
DIP	O96017
IntAct	O96017
	Polymorphism : SNP, mutations, diseases
OMIM	114480;176807;259500;604373;609265    [ map ]
GENECLINICS	114480;176807;259500;604373;609265
SNP	CHEK2 [dbSNP-NCBI]
SNP	NM_001005735 [SNP-NCI]
SNP	NM_007194 [SNP-NCI]
SNP	NM_145862 [SNP-NCI]
SNP	CHEK2 [GeneSNPs - Utah]  CHEK2] [HGBASE - SRS]
HAPMAP	CHEK2 [HAPMAP]
COSMIC	CHEK2 [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb	CHEK2 [Translocation breakpoints In Cancer]
HGMD	CHEK2
	General knowledge
Family Browser	CHEK2 [UCSC Family Browser]
SOURCE	NM_001005735
SOURCE	NM_007194
SOURCE	NM_145862
SMD	Hs.632780
SAGE	Hs.632780
Enzyme	2.7.11.1 [ Enzyme-SRS ]   2.7.11.1 [ Brenda-SRS ]   2.7.11.1 [ KEGG ]   2.7.11.1 [ WIT ]
GO	DNA damage checkpoint [Amigo]  DNA damage checkpoint
GO	nucleotide binding [Amigo]  nucleotide binding
GO	magnesium ion binding [Amigo]  magnesium ion binding
GO	protein serine/threonine kinase activity [Amigo]  protein serine/threonine kinase activity
GO	protein serine/threonine kinase activity [Amigo]  protein serine/threonine kinase activity
GO	protein binding [Amigo]  protein binding
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	protein amino acid phosphorylation [Amigo]  protein amino acid phosphorylation
GO	cell cycle [Amigo]  cell cycle
GO	DNA damage response, signal transduction resulting in induction of apoptosis [Amigo]  DNA damage response, signal transduction resulting in induction of apoptosis
GO	PML body [Amigo]  PML body
GO	transferase activity [Amigo]  transferase activity
BIOCARTA	ATM Signaling Pathway    [Genes]
BIOCARTA	Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility    [Genes]
BIOCARTA	Cell Cycle: G2/M Checkpoint    [Genes]
BIOCARTA	Regulation of cell cycle progression by Plk3    [Genes]
KEGG	Cell cycle
PubGene	CHEK2
TreeFam	CHEK2
CTD	11200 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CHEK2 Related clones (RZPD - Berlin)
	PubMed
PubMed	178 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 articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	05-2004	Nancy 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 : Wed Jul 2 08:22:43 2008