Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols

Masashi Takao, Shin Ichiro Kanno, Tatsuya Shiromoto, Rei Hasegawa, Hiroshi Ide, Shogo Ikeda, Altraf H. Sarker, Shuji Seki, James Z. Xing, X. Chris Le, Michael Weinfeld, Kumiko Kobayashi, Jun ichi Miyazaki, Manja Muijtjens, Jan H.J. Hoeijmakers, Gijsbertus Van der Horst, Akira Yasui

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127 Citations (Scopus)

Abstract

Endonuclease III, encoded by nth in Escherichia coli, removes thymine glycols (Tg), a toxic oxidative DNA lesion. To determine the biological significance of this repair in mammals, we established a mouse model with mutated mNth1, a homolog of nth, by gene targeting. The homozygous mNth1 mutant mice showed no detectable phenotypical abnormality. Embryonic cells with or without wild-type mNth1 showed no difference in sensitivity to menadione or hydrogen peroxide. Tg produced in the mutant mouse liver DNA by x-ray irradiation disappeared with time, though more slowly than in the wild-type mouse. In extracts from mutant mouse liver, we found, instead of mNTH1 activity, at least two novel DNA glycosylase activities against Tg. One activity is significantly higher in the mutant than in wild-type mouse in mitochondria, while the other is another nuclear glycosylase for Tg. These results underscore the importance of base excision repair of Tg both in the nuclei and mitochondria in mammals.

Original languageEnglish
Pages (from-to)3486-3493
Number of pages8
JournalEMBO Journal
Volume21
Issue number13
DOIs
Publication statusPublished - 2002 Jul 1

Keywords

  • Base excision repair
  • DNA glycosylase
  • Endonuclease III
  • Mitochondria
  • Thymine glycol

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Takao, M., Kanno, S. I., Shiromoto, T., Hasegawa, R., Ide, H., Ikeda, S., Sarker, A. H., Seki, S., Xing, J. Z., Le, X. C., Weinfeld, M., Kobayashi, K., Miyazaki, J. I., Muijtjens, M., Hoeijmakers, J. H. J., Van der Horst, G., & Yasui, A. (2002). Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols. EMBO Journal, 21(13), 3486-3493. https://doi.org/10.1093/emboj/cdf350