Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse

Peng Chieh Chen, Sandra Dudley, Wayne Hagen, Diana Dizon, Leslie Paxton, Denise Reichow, Song Ro Yoon, Kan Yang, Norman Arnheim, Robert (Mike) Liskay, Steven M. Lipkin

Research output: Contribution to journalArticle

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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 nonpolyposis colon cancer.

Original languageEnglish (US)
Pages (from-to)8662-8670
Number of pages9
JournalCancer Research
Volume65
Issue number19
DOIs
StatePublished - Oct 1 2005

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DNA Mismatch Repair
Neoplasms
Microsatellite Instability
DNA Damage
Phenotype
Hereditary Nonpolyposis Colorectal Neoplasms
Mutation
Saccharomycetales
Germ-Line Mutation
Germ Cells
Colonic Neoplasms
MutL Proteins
Escherichia coli

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chen, P. C., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., ... Lipkin, S. M. (2005). Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Research, 65(19), 8662-8670. https://doi.org/10.1158/0008-5472.CAN-05-0742

Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. / Chen, Peng Chieh; Dudley, Sandra; Hagen, Wayne; Dizon, Diana; Paxton, Leslie; Reichow, Denise; Yoon, Song Ro; Yang, Kan; Arnheim, Norman; Liskay, Robert (Mike); Lipkin, Steven M.

In: Cancer Research, Vol. 65, No. 19, 01.10.2005, p. 8662-8670.

Research output: Contribution to journalArticle

Chen, PC, Dudley, S, Hagen, W, Dizon, D, Paxton, L, Reichow, D, Yoon, SR, Yang, K, Arnheim, N, Liskay, RM & Lipkin, SM 2005, 'Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse', Cancer Research, vol. 65, no. 19, pp. 8662-8670. https://doi.org/10.1158/0008-5472.CAN-05-0742
Chen, Peng Chieh ; Dudley, Sandra ; Hagen, Wayne ; Dizon, Diana ; Paxton, Leslie ; Reichow, Denise ; Yoon, Song Ro ; Yang, Kan ; Arnheim, Norman ; Liskay, Robert (Mike) ; Lipkin, Steven M. / Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. In: Cancer Research. 2005 ; Vol. 65, No. 19. pp. 8662-8670.
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AU - Paxton, Leslie

AU - Reichow, Denise

AU - Yoon, Song Ro

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AU - Arnheim, Norman

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