Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis
View/ Open
Author
Avdievich, Elena
Reiss, Cora
Scherer, Stefan J.
Zhang, Yongwei
Maier, Sandra M.
Jin, Bo
Hou, Harry, Jr.
Rosenwald, Andreas
Riedmiller, Hubertus
Kucherlapati, Raju
Cohen, Paula E.
Edelmann, Winfried
Kneitz, Burkhard
Published Version
https://doi.org/10.1073/pnas.0800276105Metadata
Show full item recordCitation
Avdievich, E., C. Reiss, S. J. Scherer, Y. Zhang, S. M. Maier, B. Jin, H. Hou, et al. 2008. “Distinct Effects of the Recurrent Mlh1G67R Mutation on MMR Functions, Cancer, and Meiosis.” Proceedings of the National Academy of Sciences 105 (11): 4247–52. doi:10.1073/pnas.0800276105.Abstract
Mutations in the human DNA mismatch repair (MMR) gene MLH1 are associated with hereditary nonpolyposis colorectal cancer (Lynch syndrome, HNPCC) and a significant proportion of sporadic colorectal cancer. The inactivation of MLH1 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of DNA damaging agents. To study the effect of MLH1 missense mutations on cancer susceptibility, we generated a mouse line carrying the recurrent MIh1(G67R) mutation that is located in one of the ATP-binding domains of Mlh1. Although the Mlh1(G67R) mutation resulted in DNA repair deficiency in homozygous mutant mice, it did not affect the MMR-mediated cellular response to DNA damage, including the apoptotic response of epithelial cells in the intestinal mucosa to cisplatin, which was defective in Mlh1(-/-) mice but remained normal in Mlh1(G67R/G67R) mice. Similar to Mlh1(-/-) mice, Mlh1(G67R/G67R) mutant mice displayed a strong cancer predisposition phenotype. However, in contrast to Mlh(-/-) mice, Mlh1(G67R/G67R) mutant mice developed significantly fewer intestinal tumors, indicating that Mlh1 missense mutations can affect MMR tumor suppressor functions in a tissue-specific manner. In addition, Mlh1(G67R/G67R) mice were sterile because of the inability of the mutant MIh1G67R protein to interact with meiotic chromosomes at pachynema, demonstrating that the ATPase activity of Mlh1 is essential for fertility in mammals.Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:41543011
Collections
- HMS Scholarly Articles [17852]
Contact administrator regarding this item (to report mistakes or request changes)