title: Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis.
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 Mlh1(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 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, Mlh1(G67R/G67R) mice were sterile because of the inability of the mutant Mlh1(G67R) protein to interact with meiotic chromosomes at pachynema, demonstrating that the ATPase activity of Mlh1 is essential for fertility in mammals.
authors.affiliation: Department of Cell Biology and Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Avdievich
authors.forename: Cora
authors.initials: C
authors.lastname: Reiss
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Maier
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Harry
authors.initials: H
authors.lastname: Hou
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hubertus
authors.initials: H
authors.lastname: Riedmiller
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Paula E
authors.initials: PE
authors.lastname: Cohen
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002875:Chromosomes / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D053843:DNA Mismatch Repair; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1; D002945:Cisplatin; D005998:Glycine