Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility

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 anExo1mutant mouse line. Analysis ofExo1−/−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 inExo1−/−cells also caused elevated microsatellite instability at a mononucleotide repeat marker and a significant increase in mutation rate at theHprtlocus.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 inExo1−/−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.