Role of Parp-1 in suppressing spontaneous deletion mutation in the liver and brain of mice at adolescence and advanced age

Atsushi Shibata, Daisuke Maeda, Hideki Ogino, Masahiro Tsutsumi, Takehiko Nohmi, Hitoshi Nakagama, Takashi Sugimura, Hirobumi Teraoka, Mitsuko Masutani

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase-1 knockout (Parp-1-/-) mice show increased frequency of spontaneous liver tumors compared to wild-type mice after aging. To understand the impact of Parp-1 deficiency on mutations during aging, in this study, we analyzed spontaneous mutations in Parp-1-/- aged mice. Parp-1-/- mice showed tendencies of higher mutation frequencies of the red/gam genes at 18 months of age, compared to Parp-1+/+ mice, in the liver and brain. Complex-type deletions, accompanying small insertion were observed only in Parp-1-/- mice in the liver and brain. Further analysis in the liver showed that the frequency of single base deletion mutations at non-repeat or short repeat sequences was 5.8-fold higher in Parp-1-/- than in Parp-1+/+ mice (p < 0.05). A 3.2-fold higher tendency of the deletion frequency of two bases or more was observed in Parp-1-/- mice compared to Parp-1+/+ mice (p = 0.084). These results support the model that Parp-1 is involved in suppressing imprecise repair of endogenous DNA damage leading to deletion mutation during aging. The mutation frequencies of the gpt gene in the brain were found to be 3-fold lower in Parp-1-/- than in Parp-1+/+ mice at 4 months of age (p < 0.01), implying that Parp-1 may be positively involved in imprecise DNA repair in the brain. On the other hand, the frequencies of gpt mutation showed an increase at 18 months of age in the Parp-1-/- (p < 0.05) but not in Parp-1+/+ brains, suggesting that Parp-1 deficiency causes an increase of point mutations in the brain by aging.

Original languageEnglish
Pages (from-to)20-27
Number of pages8
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume664
Issue number1-2
DOIs
Publication statusPublished - 2009 May 12
Externally publishedYes

Keywords

  • Aging
  • Deletion
  • Mutation
  • Parp-1
  • gpt delta

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

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