Journal
GENES & DEVELOPMENT
Volume 17, Issue 5, Pages 603-614Publisher
COLD SPRING HARBOR LAB PRESS
DOI: 10.1101/gad.1060603
Keywords
Exonuclease 1; MMR; lymphoma; meiosis; infertility
Categories
Funding
- NCI NIH HHS [CA13330, R01 CA076329, P30 CA013330, CA93484, R01 CA093484, CA 76329] Funding Source: Medline
- NIGMS NIH HHS [R01 GM050006, GM50006] Funding Source: Medline
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Exonuclease 1 (Exol) 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 if 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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