The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model

Bahassi, El Mustapha; Penner, C. Gail; Robbins, Susan B.; Tichy, Elisia D.; Feliciano, Estrella; Yin, Moying; Liang, Li; Deng, Li; Tischfield, Jay A.; Stambrook, Peter J.

doi:10.1016/j.mrfmmm.2006.11.025

Cited by 21 publications

(32 citation statements)

References 43 publications

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“…Chk1 and Chk2 play parallel roles in hBRCA2-CT-Rad51 complex formation In order to determine whether Chk1 and Chk2 have separate or redundant roles in the formation of the hBRCA2-Rad51 complex and the localization of Rad51 to sites of DNA damage in response to replication arrest, we took advantage of MEFs derived from mice lacking Chk2 kinase activity (Bahassi et al, 2007). The Chk2 allele in these mice is designated Chk2*1100delC and has a single cytosine deletion at position 1100.…”

Section: Resultsmentioning

confidence: 99%

The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

et al. 2008

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Section: Resultsmentioning

confidence: 99%

The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

et al. 2008

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“…MEFs derived from mice that are homozygous for Chk2*1100delC display characteristics of genomic instability (22). The cells spontaneously accumulate in the G 2 /M and S phases, indicating that one or more DNA damage checkpoints are constitutively active.…”

Section: Spontaneous Tumors Are More Prevalent In Mice Harboring Thementioning

confidence: 99%

“…The CHEK2*1100delC-encoded protein is truncated with a nonsense amino-terminal tail and lacks kinase activity (3). Because CHEK2*1100delC mRNA is degraded by nonsense-mediated mRNA decay (NMD) (22), the truncated protein is not detectable by Western blots (23). However, in the Chk2*1100delC mouse model, NMD appears variable between tissues (22).…”

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confidence: 99%

“…Because CHEK2*1100delC mRNA is degraded by nonsense-mediated mRNA decay (NMD) (22), the truncated protein is not detectable by Western blots (23). However, in the Chk2*1100delC mouse model, NMD appears variable between tissues (22). Thus, impaired CHEK2 function may lead to genomic instability and cancer by compromising the regulation of Cdc25A stability.…”

mentioning

confidence: 99%

“…We have described previously the generation of a knockin mouse in which the wild-type CHEK2 (Chk2 in mouse) allele has been replaced with the Chk2*1100delC variant (22). Mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2*1100delC have an altered cell cycle profile and show signs of genomic instability, as indicated by constitutive activation of ataxia telangiectasia mutated (ATM)-mediated signaling pathways, suggestive of persistent DNA damage.…”

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confidence: 99%

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Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Bahassi

Robbins²,

Yin³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The CHEK2 kinase (Chk2 in mouse) is a member of a DNA damage response pathway that regulates cell cycle arrest at cell cycle checkpoints and facilitates the repair of dsDNA breaks by a recombination-mediated mechanism. There are numerous variants of the CHEK2 gene, at least one of which, CHEK2*1100delC (SNP), associates with breast cancer. A mouse model in which the wild-type Chk2 has been replaced by a Chk2*1100delC allele was tested for elevated risk of spontaneous cancer and increased sensitivity to challenge by a carcinogenic compound. Mice homozygous for Chk2*1100delC produced more tumors than wild-type mice, whereas heterozygous mice were not statistically different. When fractionated by gender, however, homozygous and heterozygous mice developed spontaneous tumors more rapidly and to a far greater extent than wild-type mice, indicative of a marked gender bias in mice harboring the variant allele. Consistent with our previous data showing elevated genomic instability in mouse embryonic fibroblasts (MEFs) derived from mice homozygous for Chk2*1100delC, the level of Cdc25A was elevated in heterozygous and homozygous MEFs and tumors. When challenged with the carcinogen 7,12-dimethylbenz[a]anthracene, all mice, regardless of genotype, had a reduced lifespan. Latency for mammary tumorigenesis was reduced significantly in mice homozygous for Chk2*1100delC but unexpectedly increased for the development of lymphomas. An implication from this study is that individuals who harbor the variant CHEK2*1100delC allele not only are at an elevated risk for the development of cancer but also that this risk can be further increased as a result of environmental exposure.cancer predisposition ͉ Cdc25A ͉ polymorphism

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Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

Bell

Kim

Godwin

et al. 2007

Intl Journal of Cancer

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The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a populationbased case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically-and geographically-selected populations. ' 2007 Wiley-Liss, Inc.Key words: CHEK2; susceptibility; breast; cancer; mutation The highly penetrant breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to 80% of familial breast cancer, 1,2 but to only 10% of cases without a strong family history. [3][4][5]

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The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model

Cited by 21 publications

References 43 publications

The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage

Mice with the CHEK2 *1100delC SNP are predisposed to cancer with a strong gender bias

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

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