title: 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 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wei
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.forename: Edmund
authors.initials: E
authors.lastname: Wong
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kane
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Mazur
authors.forename: Tchaiko
authors.initials: T
authors.lastname: Parris
authors.forename: Nadine K
authors.initials: NK
authors.lastname: Kolas
authors.forename: Robert
authors.initials: R
authors.lastname: Russell
authors.forename: Harry
authors.initials: H
authors.lastname: Hou
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
authors.forename: Guohze
authors.initials: G
authors.lastname: Yang
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
authors.forename: Paula E
authors.initials: PE
authors.lastname: Cohen
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
mesh_terms: D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D001755:Blastocyst; D002460:Cell Line; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D007246:Infertility / Q000209:etiology / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000502:physiology; D008677:Metaphase / Q000502:physiology; D051379:Mice / Q000196:embryology; D018895:Microsatellite Repeats; D009369:Neoplasms / Q000235:genetics*
chemical_list: D005090:Exodeoxyribonucleases; C028450:exodeoxyribonuclease I