Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse.
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.
Chen
Peng-Chieh
PC
Department of Medicine and Biological Chemistry, University of California, Irvine, California, USA.
Dudley
Sandra
S
Hagen
Wayne
W
Dizon
Diana
D
Paxton
Leslie
L
Reichow
Denise
D
Yoon
Song-Ro
SR
Yang
Kan
K
Arnheim
Norman
N
Liskay
R Michael
RM
Lipkin
Steven M
SM
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501485:Mlh1 protein, mouse; C492407:Mlh3 protein, mouse; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes