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

26 Citations (Scopus)

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

Fingerprint

DNA Mismatch Repair
Meiosis
Mutation
Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
Missense Mutation
Pachytene Stage
DNA Repair-Deficiency Disorders
Mutant Proteins
Intestinal Mucosa
Cisplatin
DNA Damage
Fertility
Adenosine Triphosphatases
Mammals
Colorectal Neoplasms
Chromosomes
Adenosine Triphosphate
Epithelial Cells
Genome

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis. / Avdievich, Elena; Reiss, Cora; Scherer, Stefan J.; Zhang, Yongwei; Maier, Sandra M.; Jin, Bo; Hou, Harry; Rosenwald, Andreas; Riedmiller, Hubertus; Kucherlapati, Raju; Cohen, Paula E.; Edelmann, Winfried; Kneitz, Burkhard.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 11, 18.03.2008, p. 4247-4252.

Research output: Contribution to journalArticle

Avdievich, E, Reiss, C, Scherer, SJ, Zhang, Y, Maier, SM, Jin, B, Hou, H, Rosenwald, A, Riedmiller, H, Kucherlapati, R, Cohen, PE, 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, vol. 105, no. 11, pp. 4247-4252. https://doi.org/10.1073/pnas.0800276105
Avdievich, Elena ; Reiss, Cora ; Scherer, Stefan J. ; Zhang, Yongwei ; Maier, Sandra M. ; Jin, Bo ; Hou, Harry ; Rosenwald, Andreas ; Riedmiller, Hubertus ; Kucherlapati, Raju ; Cohen, Paula E. ; Edelmann, Winfried ; Kneitz, Burkhard. / Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 11. pp. 4247-4252.
@article{a2c733ad607c4e9ea598f19e89a9465e,
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 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.",
keywords = "DNA damage response, HNPCC, Meiosis, Mlh1, MMR",
author = "Elena Avdievich and Cora Reiss and Scherer, {Stefan J.} and Yongwei Zhang and Maier, {Sandra M.} and Bo Jin and Harry Hou and Andreas Rosenwald and Hubertus Riedmiller and Raju Kucherlapati and Cohen, {Paula E.} and Winfried Edelmann and Burkhard Kneitz",
year = "2008",
month = "3",
day = "18",
doi = "10.1073/pnas.0800276105",
language = "English (US)",
volume = "105",
pages = "4247--4252",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "11",

}

TY - JOUR

T1 - Distinct effects of the recurrent Mlh1G67R mutation on MMR functions, cancer, and meiosis

AU - Avdievich, Elena

AU - Reiss, Cora

AU - Scherer, Stefan J.

AU - Zhang, Yongwei

AU - Maier, Sandra M.

AU - Jin, Bo

AU - Hou, Harry

AU - Rosenwald, Andreas

AU - Riedmiller, Hubertus

AU - Kucherlapati, Raju

AU - Cohen, Paula E.

AU - Edelmann, Winfried

AU - Kneitz, Burkhard

PY - 2008/3/18

Y1 - 2008/3/18

N2 - 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.

AB - 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.

KW - DNA damage response

KW - HNPCC

KW - Meiosis

KW - Mlh1

KW - MMR

UR - http://www.scopus.com/inward/record.url?scp=41949093631&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41949093631&partnerID=8YFLogxK

U2 - 10.1073/pnas.0800276105

DO - 10.1073/pnas.0800276105

M3 - Article

C2 - 18337503

AN - SCOPUS:41949093631

VL - 105

SP - 4247

EP - 4252

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 11

ER -