Inactivation of Exonuclease 1 in Mice Results in DNA Mismatch Repair Defects, Increased Cancer Susceptibility, and Male and Female Sterility

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2003 Mar 12

PMID 12629043

Citations 149

Authors

Kaichun Wei

Alan B Clark

Edmund Wong

Michael F Kane

Dan J Mazur

Tchaiko Parris

Nadine K Kolas

Robert Russell

Harry Hou Jr

Burkhard Kneitz

Guohze Yang

Thomas A Kunkel

Richard D Kolodner

Paula E Cohen

Winfried Edelmann

Affiliations

Soon will be listed here.

Abstract

Exonuclease 1 (Exo1) is a 5'-3' exonuclease that interacts with MutS and MutL homologs and has been implicated in the excision step of DNA mismatch repair. To investigate the role of Exo1 in mammalian mismatch repair and assess its importance for tumorigenesis and meiosis, we generated an Exo1 mutant mouse line. Analysis of Exo1(-/-) cells for mismatch repair activity in vitro showed that Exo1 is required for the repair of base:base and single-base insertion/deletion mismatches in both 5' and 3' nick-directed repair. The repair defect in Exo1(-/-) cells also caused elevated microsatellite instability at a mononucleotide repeat marker and a significant increase in mutation rate at the Hprt locus. Exo1(-/-) animals displayed reduced survival and increased susceptibility to the development of lymphomas. In addition, Exo1(-/-) male and female mice were sterile because of a meiotic defect. Meiosis in Exo1(-/-) animals proceeded through prophase I; however, the chromosomes exhibited dynamic loss of chiasmata during metaphase I, resulting in meiotic failure and apoptosis. Our results show that mammalian Exo1 functions in mutation avoidance and is essential for male and female meiosis.

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