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

Content Provider	PubMed Central
Author	Elena, Avdievich Reiss, Cora Scherer, Stefan J. Zhang, Yongwei Maier, Sandra M. Jin, Bo Hou, Harry Rosenwald, Andreas Riedmiller, Hubertus Raju, Kucherlapati Cohen, Paula E. Edelmann, Winfried Burkhard, Kneitz
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 Mlh1G67R/G67R mice. Similar to Mlh1 −/− mice, Mlh1G67R/G67R mutant mice displayed a strong cancer predisposition phenotype. However, in contrast to Mlh1 −/− mice, Mlh1G67R/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.
Related Links	http://dx.doi.org/10.1073/pnas.0800276105
Ending Page	4252
Page Count	6
Starting Page	4247
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	11
Volume Number	105
Language	English
Publisher	National Academy of Sciences
Publisher Date	2008-03-18
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Assembly of RecA-like recombinases: Distinct roles for mediator proteins in mitosis and meiosis

Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I

Effects of the Mitotic Cell-Cycle Mutation cdc4 on Yeast Meiosis

Diversity of the clinical presentation of the MMR gene biallelic mutations

Evidence for Distinct Functions of MRE11 in Arabidopsis Meiosis

Dystrophin and utrophin have distinct effects on the structural dynamics of actin

Localization and roles of Ski8p protein in Sordaria meiosis and delineation of three mechanistically distinct steps of meiotic homolog juxtaposition

Distinct functions for the catalytic and hemopexin domains of a Drosophila matrix metalloproteinase

Distinct functions of S. pombe Rec12 (Spo11) protein and Rec12-dependent crossover recombination (chiasmata) in meiosis I; and a requirement for Rec12 in meiosis II

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

Similar Documents

Assembly of RecA-like recombinases: Distinct roles for mediator proteins in mitosis and meiosis

Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I

Effects of the Mitotic Cell-Cycle Mutation cdc4 on Yeast Meiosis

Diversity of the clinical presentation of the MMR gene biallelic mutations

Evidence for Distinct Functions of MRE11 in Arabidopsis Meiosis

Dystrophin and utrophin have distinct effects on the structural dynamics of actin

Localization and roles of Ski8p protein in Sordaria meiosis and delineation of three mechanistically distinct steps of meiotic homolog juxtaposition

Distinct functions for the catalytic and hemopexin domains of a Drosophila matrix metalloproteinase

Distinct functions of S. pombe Rec12 (Spo11) protein and Rec12-dependent crossover recombination (chiasmata) in meiosis I; and a requirement for Rec12 in meiosis II

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