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 nonpolyposis colon cancer. (Cancer Res 2005; 65(19): 8662-70)

<div>Abstract<p>Germ line DNA mismatch repair mutations in <i>MLH1</i> and <i>MSH2</i> underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of <i>Escherichia coli</i> 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 <i>Mlh3</i> contributes to mechanisms of tumor suppression in the mouse. <i>Mlh3</i> deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, <i>Mlh3;Pms2</i> double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from <i>Mlh1</i>-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between <i>MLH3</i> and <i>PMS2</i> orthologues for mutation avoidance and show a role for <i>Mlh3</i> 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 <i>Mlh1</i>- versus <i>Mlh3</i>- or <i>Pms2</i>-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 <i>MLH1</i> are common in hereditary non-polyposis colon cancer.</p></div>

Supplementary Table 1 from Contributions by MutL Homologues <i>Mlh3</i> and <i>Pms2</i> to DNA Mismatch Repair and Tumor Suppression in the Mouse

<div>Abstract<p>Germ line DNA mismatch repair mutations in <i>MLH1</i> and <i>MSH2</i> underlie the vast majority of hereditary non-polyposis colon cancer. Four mammalian homologues of <i>Escherichia coli</i> 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 <i>Mlh3</i> contributes to mechanisms of tumor suppression in the mouse. <i>Mlh3</i> deficiency alone causes microsatellite instability, impaired DNA-damage response, and increased gastrointestinal tumor susceptibility. Furthermore, <i>Mlh3;Pms2</i> double-deficient mice have tumor susceptibility, shorter life span, microsatellite instability, and DNA-damage response phenotypes that are indistinguishable from <i>Mlh1</i>-deficient mice. Our data support previous results from budding yeast that show partial functional redundancy between <i>MLH3</i> and <i>PMS2</i> orthologues for mutation avoidance and show a role for <i>Mlh3</i> 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 <i>Mlh1</i>- versus <i>Mlh3</i>- or <i>Pms2</i>-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 <i>MLH1</i> are common in hereditary non-polyposis colon cancer.</p></div>

Supplementary Figure 1 from Contributions by MutL Homologues <i>Mlh3</i> and <i>Pms2</i> to DNA Mismatch Repair and Tumor Suppression in the Mouse