The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

CHEK2  -  checkpoint kinase 2

Homo sapiens

Synonyms: CDS1, CHK2, CHK2 checkpoint homolog, Cds1 homolog, Checkpoint kinase 2, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of CHEK2


High impact information on CHEK2

  • In this cell line, both USP28 and Chk2 are required for DNA-damage-induced apoptosis, and they accomplish this in part through regulation of the p53 induction of proapoptotic genes like PUMA [7].
  • Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage [7].
  • These findings indicate that the mismatch repair complex formed at the sites of DNA damage facilitates the phosphorylation of CHK2 by ATM, and that defects in this mechanism form the molecular basis for the RDS observed in cells deficient in mismatch repair [8].
  • Here we show that experimental blockade of either the Nbs1-Mre11 function or the Chk2-triggered events leads to a partial RDS phenotype in human cells [9].
  • MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage [10].

Chemical compound and disease context of CHEK2

  • We identified three serine residues (S19, S33, and S35) on Chk2 that became phosphorylated in vivo rapidly and exclusively in response to ionizing radiation (IR)-induced DNA double-strand breaks in an ATM- and Nbs1-dependent but ataxia telangiectasia- and Rad3-related-independent manner [11].
  • Examination of Chk2 protein revealed a decreased expression of Chk2 protein in cisplatin-resistant ovarian cancer cell lines, suggesting that degradation or decreased expression of Chk2 is partially responsible for chemo-resistance [12].
  • Distinct Chk2 activation pathways are triggered by genistein and DNA-damaging agents in human melanoma cells [13].
  • The CHK2 gene, whose product is a checkpoint kinase that plays a central role in DNA damage response and acts upstream of TP53, has been found to be mutated in a subset of Li-Fraumeni syndrome without mutations of TP53 and in some other sporadic human tumors, earmarking this serine/threonine kinase as a candidate tumor suppressor gene [14].
  • We found that Ccr4 cooperated with the Dun1 branch of the replication checkpoint, such that ccr4Delta dun1Delta strains exhibited irreversible hypersensitivity to HU and persistent activation of Rad53 [15].

Biological context of CHEK2


Anatomical context of CHEK2

  • The truncated protein encoded by CHEK2 carrying the 1368insA was stable yet mislocalized to the cytoplasm in tumour sections and when ectopically expressed in cultured cells [18].
  • We have here studied CHEK2 protein expression by immunohistochemistry on a tissue microarray of 611 unselected breast tumors and also evaluated the tumor characteristics among 1,297 unselected breast cancer patients defined for the c.1100delC germ line mutation status (2.5% carrier frequency) [19].
  • No significant correlation was seen between CHEK2 status and hormone receptor status, histology, lymph node status, or overall survival [19].
  • In earlier work, we found that an activity present in rabbit reticulocyte lysates phosphorylates and activates Chk2 [20].
  • We now find that hypophosphorylated Chk2 can be phosphorylated at Thr68 by various subcellular fractions of HEK293 cells [20].

Associations of CHEK2 with chemical compounds


Physical interactions of CHEK2

  • Activated CHK2 stabilizes TP53, and acts on other cell cycle and stress regulators [24].
  • Endogenous Chk2 coimmunoprecipitates Ku70 and Ku80 [20].
  • Finally, both Chk1 and Chk2 interact with the MMR protein MSH2, and this interaction is enhanced after MNNG exposure, supporting the notion that the MMR system functions as a molecular scaffold at the sites of DNA damage that facilitates activation of these kinases [25].
  • Plk3 physically interacts with Chk2 and the interaction is enhanced upon DNA damage [26].
  • Although phospho-dependent binding is important for Chk2 activity, previously uncharacterized phospho-independent FHA domain interactions appear to be the primary target of oncogenic lesions [27].

Enzymatic interactions of CHEK2


Regulatory relationships of CHEK2


Other interactions of CHEK2


Analytical, diagnostic and therapeutic context of CHEK2


  1. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Meijers-Heijboer, H., van den Ouweland, A., Klijn, J., Wasielewski, M., de Snoo, A., Oldenburg, R., Hollestelle, A., Houben, M., Crepin, E., van Veghel-Plandsoen, M., Elstrodt, F., van Duijn, C., Bartels, C., Meijers, C., Schutte, M., McGuffog, L., Thompson, D., Easton, D., Sodha, N., Seal, S., Barfoot, R., Mangion, J., Chang-Claude, J., Eccles, D., Eeles, R., Evans, D.G., Houlston, R., Murday, V., Narod, S., Peretz, T., Peto, J., Phelan, C., Zhang, H.X., Szabo, C., Devilee, P., Goldgar, D., Futreal, P.A., Nathanson, K.L., Weber, B., Rahman, N., Stratton, M.R. Nat. Genet. (2002) [Pubmed]
  2. Mutations in CHEK2 associated with prostate cancer risk. Dong, X., Wang, L., Taniguchi, K., Wang, X., Cunningham, J.M., McDonnell, S.K., Qian, C., Marks, A.F., Slager, S.L., Peterson, B.J., Smith, D.I., Cheville, J.C., Blute, M.L., Jacobsen, S.J., Schaid, D.J., Tindall, D.J., Thibodeau, S.N., Liu, W. Am. J. Hum. Genet. (2003) [Pubmed]
  3. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Vahteristo, P., Bartkova, J., Eerola, H., Syrjäkoski, K., Ojala, S., Kilpivaara, O., Tamminen, A., Kononen, J., Aittomäki, K., Heikkilä, P., Holli, K., Blomqvist, C., Bartek, J., Kallioniemi, O.P., Nevanlinna, H. Am. J. Hum. Genet. (2002) [Pubmed]
  4. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Meijers-Heijboer, H., Wijnen, J., Vasen, H., Wasielewski, M., Wagner, A., Hollestelle, A., Elstrodt, F., van den Bos, R., de Snoo, A., Fat, G.T., Brekelmans, C., Jagmohan, S., Franken, P., Verkuijlen, P., van den Ouweland, A., Chapman, P., Tops, C., Möslein, G., Burn, J., Lynch, H., Klijn, J., Fodde, R., Schutte, M. Am. J. Hum. Genet. (2003) [Pubmed]
  5. Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukemia. Rudd, M.F., Sellick, G.S., Webb, E.L., Catovsky, D., Houlston, R.S. Blood (2006) [Pubmed]
  6. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer. Wasielewski, M., Vasen, H., Wijnen, J., Hooning, M., Dooijes, D., Tops, C., Klijn, J.G., Meijers-Heijboer, H., Schutte, M. Clin. Cancer Res. (2008) [Pubmed]
  7. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Zhang, D., Zaugg, K., Mak, T.W., Elledge, S.J. Cell (2006) [Pubmed]
  8. The mismatch repair system is required for S-phase checkpoint activation. Brown, K.D., Rathi, A., Kamath, R., Beardsley, D.I., Zhan, Q., Mannino, J.L., Baskaran, R. Nat. Genet. (2003) [Pubmed]
  9. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Falck, J., Petrini, J.H., Williams, B.R., Lukas, J., Bartek, J. Nat. Genet. (2002) [Pubmed]
  10. MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Lou, Z., Minter-Dykhouse, K., Wu, X., Chen, J. Nature (2003) [Pubmed]
  11. DNA damage-induced cell cycle regulation and function of novel chk2 phosphoresidues. Buscemi, G., Carlessi, L., Zannini, L., Lisanti, S., Fontanella, E., Canevari, S., Delia, D. Mol. Cell. Biol. (2006) [Pubmed]
  12. Inducible degradation of checkpoint kinase 2 links to cisplatin-induced resistance in ovarian cancer cells. Zhang, P., Gao, W., Li, H., Reed, E., Chen, F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  13. Distinct Chk2 activation pathways are triggered by genistein and DNA-damaging agents in human melanoma cells. Darbon, J.M., Penary, M., Escalas, N., Casagrande, F., Goubin-Gramatica, F., Baudouin, C., Ducommun, B. J. Biol. Chem. (2000) [Pubmed]
  14. Aberrations of the CHK2 gene are rare in pediatric solid tumors. Chen, Y.Y., Takita, J., Tanaka, K., Ida, K., Koh, K., Igarashi, T., Hanada, R., Kikuchi, A., Tanaka, Y., Toyoda, Y., Hayashi, Y. Int. J. Mol. Med. (2005) [Pubmed]
  15. Ccr4 contributes to tolerance of replication stress through control of CRT1 mRNA poly(A) tail length. Woolstencroft, R.N., Beilharz, T.H., Cook, M.A., Preiss, T., Durocher, D., Tyers, M. J. Cell. Sci. (2006) [Pubmed]
  16. CHEK2 is a multiorgan cancer susceptibility gene. Cybulski, C., Górski, B., Huzarski, T., Masojć, B., Mierzejewski, M., Debniak, T., Teodorczyk, U., Byrski, T., Gronwald, J., Matyjasik, J., Zlowocka, E., Lenner, M., Grabowska, E., Nej, K., Castaneda, J., Medrek, K., Szymańska, A., Szymańska, J., Kurzawski, G., Suchy, J., Oszurek, O., Witek, A., Narod, S.A., Lubiński, J. Am. J. Hum. Genet. (2004) [Pubmed]
  17. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Shaag, A., Walsh, T., Renbaum, P., Kirchhoff, T., Nafa, K., Shiovitz, S., Mandell, J.B., Welcsh, P., Lee, M.K., Ellis, N., Offit, K., Levy-Lahad, E., King, M.C. Hum. Mol. Genet. (2005) [Pubmed]
  18. Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Staalesen, V., Falck, J., Geisler, S., Bartkova, J., Børresen-Dale, A.L., Lukas, J., Lillehaug, J.R., Bartek, J., Lønning, P.E. Oncogene (2004) [Pubmed]
  19. Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Kilpivaara, O., Bartkova, J., Eerola, H., Syrjäkoski, K., Vahteristo, P., Lukas, J., Blomqvist, C., Holli, K., Heikkilä, P., Sauter, G., Kallioniemi, O.P., Bartek, J., Nevanlinna, H. Int. J. Cancer (2005) [Pubmed]
  20. Regulation of CHK2 by DNA-dependent protein kinase. Li, J., Stern, D.F. J. Biol. Chem. (2005) [Pubmed]
  21. Homozygosity for a CHEK2*1100delC mutation identified in familial colorectal cancer does not lead to a severe clinical phenotype. van Puijenbroek, M., van Asperen, C.J., van Mil, A., Devilee, P., van Wezel, T., Morreau, H. J. Pathol. (2005) [Pubmed]
  22. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Lee, J.S., Collins, K.M., Brown, A.L., Lee, C.H., Chung, J.H. Nature (2000) [Pubmed]
  23. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K., Elledge, S.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  24. Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Miller, C.W., Ikezoe, T., Krug, U., Hofmann, W.K., Tavor, S., Vegesna, V., Tsukasaki, K., Takeuchi, S., Koeffler, H.P. Genes Chromosomes Cancer (2002) [Pubmed]
  25. Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2. Adamson, A.W., Beardsley, D.I., Kim, W.J., Gao, Y., Baskaran, R., Brown, K.D. Mol. Biol. Cell (2005) [Pubmed]
  26. Genotoxic stress-induced activation of Plk3 is partly mediated by Chk2. Xie, S., Wu, H., Wang, Q., Kunicki, J., Thomas, R.O., Hollingsworth, R.E., Cogswell, J., Dai, W. Cell Cycle (2002) [Pubmed]
  27. Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2. Li, J., Williams, B.L., Haire, L.F., Goldberg, M., Wilker, E., Durocher, D., Yaffe, M.B., Jackson, S.P., Smerdon, S.J. Mol. Cell (2002) [Pubmed]
  28. Role of human Cds1 (Chk2) kinase in DNA damage checkpoint and its regulation by p53. Tominaga, K., Morisaki, H., Kaneko, Y., Fujimoto, A., Tanaka, T., Ohtsubo, M., Hirai, M., Okayama, H., Ikeda, K., Nakanishi, M. J. Biol. Chem. (1999) [Pubmed]
  29. TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. Wei, J.H., Chou, Y.F., Ou, Y.H., Yeh, Y.H., Tyan, S.W., Sun, T.P., Shen, C.Y., Shieh, S.Y. J. Biol. Chem. (2005) [Pubmed]
  30. HDM2 negatively affects the Chk2-mediated phosphorylation of p53. Bjørling-Poulsen, M., Meek, D., Issinger, O.G. FEBS Lett. (2005) [Pubmed]
  31. Chk2 activates E2F-1 in response to DNA damage. Stevens, C., Smith, L., La Thangue, N.B. Nat. Cell Biol. (2003) [Pubmed]
  32. The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation. Lee, C.H., Chung, J.H. J. Biol. Chem. (2001) [Pubmed]
  33. PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Yang, S., Kuo, C., Bisi, J.E., Kim, M.K. Nat. Cell Biol. (2002) [Pubmed]
  34. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Ingvarsson, S., Sigbjornsdottir, B.I., Huiping, C., Hafsteinsdottir, S.H., Ragnarsson, G., Barkardottir, R.B., Arason, A., Egilsson, V., Bergthorsson, J.T. Breast Cancer Res. (2002) [Pubmed]
  35. Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains. Ng, C.P., Lee, H.C., Ho, C.W., Arooz, T., Siu, W.Y., Lau, A., Poon, R.Y. J. Biol. Chem. (2004) [Pubmed]
  36. The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe. Castedo, M., Perfettini, J.L., Roumier, T., Yakushijin, K., Horne, D., Medema, R., Kroemer, G. Oncogene (2004) [Pubmed]
  37. The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oliva-Trastoy, M., Berthonaud, V., Chevalier, A., Ducrot, C., Marsolier-Kergoat, M.C., Mann, C., Leteurtre, F. Oncogene (2007) [Pubmed]
  38. Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation. Turner, J., Koumenis, C., Kute, T.E., Planalp, R.P., Brechbiel, M.W., Beardsley, D., Cody, B., Brown, K.D., Torti, F.M., Torti, S.V. Blood (2005) [Pubmed]
  39. Chk2 activation dependence on Nbs1 after DNA damage. Buscemi, G., Savio, C., Zannini, L., Miccichè, F., Masnada, D., Nakanishi, M., Tauchi, H., Komatsu, K., Mizutani, S., Khanna, K., Chen, P., Concannon, P., Chessa, L., Delia, D. Mol. Cell. Biol. (2001) [Pubmed]
  40. Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors. Honrado, E., Osorio, A., Palacios, J., Milne, R.L., Sánchez, L., Díez, O., Cazorla, A., Syrjakoski, K., Huntsman, D., Heikkilä, P., Lerma, E., Kallioniemi, A., Rivas, C., Foulkes, W.D., Nevanlinna, H., Benítez, J. J. Clin. Oncol. (2005) [Pubmed]
  41. Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals. Jekimovs, C.R., Chen, X., Arnold, J., Gatei, M., Richard, D.J., Spurdle, A.B., Khanna, K.K., Chenevix-Trench, G. Br. J. Cancer (2005) [Pubmed]
  42. Colorectal cancer and the CHEK2 1100delC mutation. de Jong, M.M., Nolte, I.M., Te Meerman, G.J., van der Graaf, W.T., Mulder, M.J., van der Steege, G., Bruinenberg, M., Schaapveld, M., Niessen, R.C., Berends, M.J., Sijmons, R.H., Hofstra, R.M., de Vries, E.G., Kleibeuker, J.H. Genes Chromosomes Cancer (2005) [Pubmed]
  43. Chromosomal radiosensitivity of breast cancer with a CHEK2 mutation. Baeyens, A., Claes, K., Willems, P., De Ruyck, K., Thierens, H., Vral, A. Cancer Genet. Cytogenet. (2005) [Pubmed]
  44. Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. de Bock, G.H., Schutte, M., Krol-Warmerdam, E.M., Seynaeve, C., Blom, J., Brekelmans, C.T., Meijers-Heijboer, H., van Asperen, C.J., Cornelisse, C.J., Devilee, P., Tollenaar, R.A., Klijn, J.G. J. Med. Genet. (2004) [Pubmed]
WikiGenes - Universities