Contributions by MutL Homologues Mlh3 and Pms2 to DNA Mismatch Repair and Tumor Suppression in the Mouse

Peng-Chieh Chen,Diana Dizon,Steven M Lipkin,Denise Reichow,Song-Ro Yoon,Leslie Paxton,Wayne Hagen,Sandra Dudley,R Michael Liskay,Norman Arnheim,Kan Yang

doi:10.1158/0008-5472.can-05-0742

Abstract

Germ line DNA mismatch repair mutations in MLH1 and MSH2 underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of Escherichia coli MutL heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. Although MLH1/PMS2 is generally thought to have the major MutL activity, the precise contributions of each MutL heterodimer to mismatch repair functions are poorly understood. Here, we show that Mlh3 contributes to mechanisms of tumor suppression in the mouse. Mlh3 deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from Mlh1-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role for Mlh3 in gastrointestinal and extragastrointestinal tumor suppression. The data also suggest a mechanistic basis for the more severe mismatch repair-related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice. Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair-mediated tumor suppression, therefore, provide an explanation why, among MutL homologues, only germ line mutations in MLH1 are common in hereditary non-polyposis colon cancer.

Highlights

DNA mismatch repair contributes to tumor suppression by reducing mutations and promoting apoptosis in response to certain types of DNA damage [1,2,3,4,5]
Because yeast studies predicted some degree of functional overlap between mammalian MLH3 and PMS2 [15], which could account for different phenotypes of Mlh1À/À and Pms2À/À mice [14], we compared life span and cancer susceptibility in wild-type (Wt), Mlh3À/À, Pms2À/À, Mlh3À/À;Pms2À/À, and Mlh1À/À mice on the same 129 Sv/Ev strain background
Analyses of the knockout mouse models for all the MutL homologues show that Mlh1deficient mice develop gastrointestinal tumors, whereas Pms2- or Pms1-deficient animals do not [13]

Summary

Introduction

DNA mismatch repair contributes to tumor suppression by reducing mutations and promoting apoptosis in response to certain types of DNA damage [1,2,3,4,5]. Studies in yeast and mammals have shown that MutS proteins form MSH2/MSH6 and MSH2/MSH3 heterodimers, which have partially overlapping specificities for binding to DNA mismatches [4, 8, 9]. These same studies show that deficiency in MSH2 or double deficiencies in MSH3 and MSH6 results in a mismatch repair ‘‘null’’ phenotype, whereas a single deficiency in either MSH6 or MSH3 produces attenuated mismatch repair defects. This partial functional overlap between MSH3 and MSH6 likely explains the preponderance of MSH2 mutations in HNPCC compared with either MSH6 or MSH3 mutations [10,11,12]

Methods

Results

Conclusion