CHEK2

CHK2 checkpoint homolog (S. pombe)
PDB rendering based on 1gxc.
Available structures PDB 1GXC, 2CN5, 2CN8, 2W0J, 2W7X, 2WTC, 2WTD, 2WTI, 2WTJ, 3I6U, 3I6W
Identifiers
Symbols	CHEK2; CDS1; CHK2; HuCds1; LFS2; PP1425; RAD53
External IDs	OMIM: 604373 MGI: 1355321 HomoloGene: 38289 GeneCards: CHEK2 Gene
EC number	2.7.11.1
Gene Ontology Molecular function • nucleotide binding • protein serine/threonine kinase activity • protein binding • ATP binding • kinase activity • metal ion binding Cellular component • chromosome, telomeric region • nucleus • nucleoplasm • PML body Biological process • cell cycle checkpoint • DNA damage checkpoint • response to DNA damage stimulus • cell cycle • DNA damage response, signal transduction resulting in induction of apoptosis • phosphorylation • signal transduction in response to DNA damage • replicative senescence Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	11200	50883
Ensembl	ENSG00000183765	ENSMUSG00000029521
UniProt	O96017	Q543W6
RefSeq (mRNA)	NM_001005735.1	NM_016681.3
RefSeq (protein)	NP_001005735.1	NP_057890.1
Location (UCSC)	Chr 22: 29.08 – 29.14 Mb	Chr 5: 111.27 – 111.3 Mb
PubMed search	[1]	[2]

CHEK2 is the official symbol for the human gene CHK2 checkpoint homolog. It is located on the long (q) arm of chromosome 22.^[1][2][3]

Function

The protein encoded by this gene, CHK2 a protein kinase that is activated in response to DNA damage and is involved in cell cycle arrest.^[1]

In response to DNA damage and replication blocks, cell cycle progression is halted through the control of cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1.^[4] In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage.^[5][6]

Related conditions

A mutation in CHEK2 gene results in decreased DNA-repair, or inability of the cell to undergo apoptosis when it ought to have done so. Thus, a mutation leads to an increased susceptibility to cancer. The following conditions are examples of such cancers.

Breast cancer

A deletion-mutation at position 1100 of the CHEK2 gene is associated with an increased risk of breast cancer, particularly in the European population. In women of Northern and Eastern European descent CHEK2*1100delC carrier status confers a 2-3 fold risk of breast cancer. In this ethnic group, women with a familial history of breast cancer have a 4.8 fold risk of breast cancer equal to a lifetime risk of breast cancer of 37%.^[7]

Li-Fraumeni syndrome

The CHEK2*1100delC mutation was originally associated with the Li-Fraumeni syndrome,^[8] however the relative high prevalence of the mutation in the general population (0.5%) has made this association unlikely.^[9]

Interactions

CHEK2 has been shown to interact with PLK1,^[10] MDC1,^[11] MSH2,^[12][13] GINS2,^[14] PLK3,^[15] MUS81^[16] and BRCA1.^[5][17]

References

1. ^ ^{a b} Matsuoka S, Huang M, Elledge SJ (December 1998). "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase". Science 282 (5395): 1893–7. doi:10.1126/science.282.5395.1893. PMID 9836640. 
2. ^ Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH (January 1999). "A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase". Curr. Biol. 9 (1): 1–10. doi:10.1016/S0960-9822(99)80041-4. PMID 9889122. 
3. ^ Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD, Zhou BB (July 1999). "Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway". Oncogene 18 (28): 4047–54. doi:10.1038/sj.onc.1202925. PMID 10435585. 
4. ^ Chehab NH, Malikzay A, Appel M, Halazonetis TD (February 2000). "Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53". Genes Dev. 14 (3): 278–88. doi:10.1101/gad.14.3.278. PMC 316357. PMID 10673500. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316357. 
5. ^ ^{a b} Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (March 2000). "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response". Nature 404 (6774): 201–4. doi:10.1038/35004614. PMID 10724175. 
6. ^ "Entrez Gene: CHEK2 CHK2 checkpoint homolog (S. pombe)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11200. 
7. ^ Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. (May 2002). "Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations". Nat. Genet. 31 (1): 55–9. doi:10.1038/ng879. PMID 11967536. 
8. ^ Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA (December 1999). "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome". Science 286 (5449): 2528–31. doi:10.1126/science.286.5449.2528. PMID 10617473. 
9. ^ Evans DG, Birch JM, Narod SA (January 2008). "Is CHEK2 a cause of the Li-Fraumeni syndrome?". J. Med. Genet. 45 (1): 63–4. doi:10.1136/jmg.2007.054700. PMID 18178638. 
10. ^ Tsvetkov, Lyuben; Xu Xingzhi, Li Jia, Stern David F (Mar. 2003). "Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody". J. Biol. Chem. (United States) 278 (10): 8468–75. doi:10.1074/jbc.M211202200. ISSN 0021-9258. PMID 12493754. 
11. ^ Lou, Zhenkun; Minter-Dykhouse Katherine, Wu Xianglin, Chen Junjie (Feb. 2003). "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways". Nature (England) 421 (6926): 957–61. doi:10.1038/nature01447. ISSN 0028-0836. PMID 12607004. 
12. ^ Adamson, Aaron W; Beardsley Dillon I, Kim Wan-Ju, Gao Yajuan, Baskaran R, Brown Kevin D (Mar. 2005). "Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2". Mol. Biol. Cell (United States) 16 (3): 1513–26. doi:10.1091/mbc.E04-02-0089. ISSN 1059-1524. PMC 551512. PMID 15647386. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=551512. 
13. ^ Brown, Kevin D; Rathi Abhilasha, Kamath Ravindra, Beardsley Dillon I, Zhan Qimin, Mannino Jennifer L, Baskaran R (Jan. 2003). "The mismatch repair system is required for S-phase checkpoint activation". Nat. Genet. (United States) 33 (1): 80–4. doi:10.1038/ng1052. ISSN 1061-4036. PMID 12447371. 
14. ^ Matsuoka, Shuhei; Ballif Bryan A, Smogorzewska Agata, McDonald E Robert, Hurov Kristen E, Luo Ji, Bakalarski Corey E, Zhao Zhenming, Solimini Nicole, Lerenthal Yaniv, Shiloh Yosef, Gygi Steven P, Elledge Stephen J (May. 2007). "ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage". Science (United States) 316 (5828): 1160–6. doi:10.1126/science.1140321. PMID 17525332. 
15. ^ Bahassi, El Mustapha; Conn Christopher W, Myer David L, Hennigan Robert F, McGowan Clare H, Sanchez Yolanda, Stambrook Peter J (Sep. 2002). "Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways". Oncogene (England) 21 (43): 6633–40. doi:10.1038/sj.onc.1205850. ISSN 0950-9232. PMID 12242661. 
16. ^ Chen, X B; Melchionna R, Denis C M, Gaillard P H, Blasina A, Van de Weyer I, Boddy M N, Russell P, Vialard J, McGowan C H (Nov. 2001). "Human Mus81-associated endonuclease cleaves Holliday junctions in vitro". Mol. Cell (United States) 8 (5): 1117–27. doi:10.1016/S1097-2765(01)00375-6. ISSN 1097-2765. PMID 11741546. 
17. ^ Chabalier-Taste, Corinne; Racca Carine, Dozier Christine, Larminat Florence (Dec. 2008). "BRCA1 is regulated by Chk2 in response to spindle damage". Biochim. Biophys. Acta (Netherlands) 1783 (12): 2223–33. doi:10.1016/j.bbamcr.2008.08.006. ISSN 0006-3002. PMID 18804494. 

Further reading

• Caspari T (2000). "How to activate p53.". Curr. Biol. 10 (8): R315–7. doi:10.1016/S0960-9822(00)00439-5. PMID 10801407. 
• McGowan CH (2002). "Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor.". Bioessays 24 (6): 502–11. doi:10.1002/bies.10101. PMID 12111733. 
• Honrado E, Osorio A, Palacios J, Benitez J (2006). "Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations.". Oncogene 25 (43): 5837–45. doi:10.1038/sj.onc.1209875. PMID 16998498. 
• Nevanlinna H, Bartek J (2006). "The CHEK2 gene and inherited breast cancer susceptibility.". Oncogene 25 (43): 5912–9. doi:10.1038/sj.onc.1209877. PMID 16998506. 
• Peng CY, Graves PR, Thoma RS, et al. (1997). "Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.". Science 277 (5331): 1501–5. doi:10.1126/science.277.5331.1501. PMID 9278512. 
• Lykidis A, Jackson PD, Rock CO, Jackowski S (1998). "The role of CDP-diacylglycerol synthetase and phosphatidylinositol synthase activity levels in the regulation of cellular phosphatidylinositol content.". J. Biol. Chem. 272 (52): 33402–9. doi:10.1074/jbc.272.52.33402. PMID 9407135. 
• Lindsay HD, Griffiths DJ, Edwards RJ, et al. (1998). "S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe.". Genes Dev. 12 (3): 382–95. doi:10.1101/gad.12.3.382. PMC 316487. PMID 9450932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316487. 
• Matsuoka S, Huang M, Elledge SJ (1998). "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.". Science 282 (5395): 1893–7. doi:10.1126/science.282.5395.1893. PMID 9836640. 
• Martinho RG, Lindsay HD, Flaggs G, et al. (1999). "Analysis of Rad3 and Chk1 protein kinases defines different checkpoint responses.". EMBO J. 17 (24): 7239–49. doi:10.1093/emboj/17.24.7239. PMC 1171070. PMID 9857181. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1171070. 
• Blasina A, de Weyer IV, Laus MC, et al. (1999). "A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase.". Curr. Biol. 9 (1): 1–10. doi:10.1016/S0960-9822(99)80041-4. PMID 9889122. 
• Brown AL, Lee CH, Schwarz JK, et al. (1999). "A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage.". Proc. Natl. Acad. Sci. U.S.A. 96 (7): 3745–50. doi:10.1073/pnas.96.7.3745. PMC 22365. PMID 10097108. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=22365. 
• Chaturvedi P, Eng WK, Zhu Y, et al. (1999). "Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.". Oncogene 18 (28): 4047–54. doi:10.1038/sj.onc.1202925. PMID 10435585. 
• Ouyang B, Li W, Pan H, et al. (1999). "The physical association and phosphorylation of Cdc25C protein phosphatase by Prk.". Oncogene 18 (44): 6029–36. doi:10.1038/sj.onc.1202983. PMID 10557092. 
• Dunham I, Shimizu N, Roe BA, et al. (1999). "The DNA sequence of human chromosome 22.". Nature 402 (6761): 489–95. doi:10.1038/990031. PMID 10591208. 
• Bell DW, Varley JM, Szydlo TE, et al. (2000). "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.". Science 286 (5449): 2528–31. doi:10.1126/science.286.5449.2528. PMID 10617473. 
• Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000). "Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.". Genes Dev. 14 (3): 278–88. doi:10.1101/gad.14.3.278. PMC 316357. PMID 10673500. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=316357. 
• Hirao A, Kong YY, Matsuoka S, et al. (2000). "DNA damage-induced activation of p53 by the checkpoint kinase Chk2.". Science 287 (5459): 1824–7. doi:10.1126/science.287.5459.1824. PMID 10710310. 
• Lee JS, Collins KM, Brown AL, et al. (2000). "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.". Nature 404 (6774): 201–4. doi:10.1038/35004614. PMID 10724175. 
• Zhou BB, Chaturvedi P, Spring K, et al. (2000). "Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity.". J. Biol. Chem. 275 (14): 10342–8. doi:10.1074/jbc.275.14.10342. PMID 10744722. 

External links

• Educational resources
• Gene Reviews
• Gene Tests
• MeSH CHEK2+protein,+human

This article incorporates text from the United States National Library of Medicine, which is in the public domain.