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

Kaichun Wei, Alan B. Clark, Edmund Wong, Michael F. Kane, Dan J. Mazur, Tchaiko Parris, Nadine K. Kolas, Robert Russell, Harry Hou, Burkhard Kneitz, Guohze Yang, Thomas A. Kunkel, Richard D. Kolodner, Paula E. Cohen, Winfried Edelmann

Research output: Contribution to journalArticle

229 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)603-614
Number of pages12
JournalGenes and Development
Volume17
Issue number5
DOIs
StatePublished - Mar 1 2003

Fingerprint

Female Infertility
DNA Mismatch Repair
Male Infertility
Neoplasms
Meiosis
Meiotic Prophase I
exodeoxyribonuclease I
Exonucleases
Microsatellite Instability
Mutation Rate
Metaphase
Lymphoma
Carcinogenesis
Chromosomes
Apoptosis
Mutation

Keywords

  • Exonuclease 1
  • Infertility
  • Lymphoma, meiosis
  • MMR

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Inactivation of exonuclease I in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. / Wei, Kaichun; Clark, Alan B.; Wong, Edmund; Kane, Michael F.; Mazur, Dan J.; Parris, Tchaiko; Kolas, Nadine K.; Russell, Robert; Hou, Harry; Kneitz, Burkhard; Yang, Guohze; Kunkel, Thomas A.; Kolodner, Richard D.; Cohen, Paula E.; Edelmann, Winfried.

In: Genes and Development, Vol. 17, No. 5, 01.03.2003, p. 603-614.

Research output: Contribution to journalArticle

Wei, K, Clark, AB, Wong, E, Kane, MF, Mazur, DJ, Parris, T, Kolas, NK, Russell, R, Hou, H, Kneitz, B, Yang, G, Kunkel, TA, Kolodner, RD, Cohen, PE & Edelmann, W 2003, 'Inactivation of exonuclease I in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility', Genes and Development, vol. 17, no. 5, pp. 603-614. https://doi.org/10.1101/gad.1060603
Wei, Kaichun ; Clark, Alan B. ; Wong, Edmund ; Kane, Michael F. ; Mazur, Dan J. ; Parris, Tchaiko ; Kolas, Nadine K. ; Russell, Robert ; Hou, Harry ; Kneitz, Burkhard ; Yang, Guohze ; Kunkel, Thomas A. ; Kolodner, Richard D. ; Cohen, Paula E. ; Edelmann, Winfried. / Inactivation of exonuclease I in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. In: Genes and Development. 2003 ; Vol. 17, No. 5. pp. 603-614.
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