Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis

Elena Avdievich, Cora Reiss, Stefan J. Scherer, Yongwei Zhang, Sandra M. Maier, Bo Jin, Harry Hou, Andreas Rosenwald, Hubertus Riedmiller, Raju Kucherlapati, Paula E. Cohen, Winfried Edelmann, Burkhard Kneitz

Research output: Contribution to journalArticle

27 Scopus citations

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 Mlh1G67R mutation that is located in one of the ATP-binding domains of Mlh1. Although the Mlh1G67R 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 Mlh1-/- 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, Mlh1G67R/G67R mice were sterile because of the inability of the mutant Mlh1G67R protein to interact with meiotic chromosomes at pachynema, demonstrating that the ATPase activity of Mlh1 is essential for fertility in mammals.

Original languageEnglish (US)
Pages (from-to)4247-4252
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number11
DOIs
StatePublished - Mar 18 2008

Keywords

  • DNA damage response
  • HNPCC
  • MMR
  • Meiosis
  • Mlh1

ASJC Scopus subject areas

  • General

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  • Cite this

    Avdievich, E., Reiss, C., Scherer, S. J., Zhang, Y., Maier, S. M., Jin, B., Hou, H., Rosenwald, A., Riedmiller, H., Kucherlapati, R., Cohen, P. E., Edelmann, W., & Kneitz, B. (2008). Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis. Proceedings of the National Academy of Sciences of the United States of America, 105(11), 4247-4252. https://doi.org/10.1073/pnas.0800276105