Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice

Martijn E.T. Dollé, Rita A. Busuttil, Ana Maria Garcia, Susan Wijnhoven, Ellen van Drunen, Laura J. Niedernhofer, Gijsbertus van der Horst, Jan H.J. Hoeijmakers, Harry van Steeg, Jan Vijg

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Genetic defects in nucleotide excision repair (NER) are associated with premature aging, including cancer, in both humans and mice. To investigate the possible role of increased somatic mutation accumulation in the accelerated appearance of symptoms of aging as a consequence of NER deficiency, we crossed four different mouse mutants, Xpa-/-, Ercc6(Csb)-/-, Ercc2(Xpd)m/m and Ercc1-/m, with mice harboring lacZ-reporter genes to assess mutant frequencies and spectra in different organs during aging. The results indicate an accelerated accumulation of mutations in both liver and kidney of Xpa defective mice, which correlated with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum had undergone a shift, in both organs, to G:C → T:A transversions, a signature mutation of oxidative DNA damage. Ercc1-/m mice, with their short lifespan of 6 months and severe symptoms of premature aging, especially in liver and kidney, displayed an even faster lacZ-mutant accumulation in liver. In this case, the excess mutations were mostly genome rearrangements. Csb-/- mice, with mild premature aging features and no reduction in lifespan, and Xpdm/m mice, exhibiting prominent premature aging features and about 20% reduction in lifespan, did not have elevated lacZ-mutant frequencies. It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation.

Original languageEnglish (US)
Pages (from-to)22-35
Number of pages14
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume596
Issue number1-2 SPEC. ISS.
DOIs
StatePublished - Apr 11 2006
Externally publishedYes

Keywords

  • Aging
  • DNA-repair
  • Mice
  • Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

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    Dollé, M. E. T., Busuttil, R. A., Garcia, A. M., Wijnhoven, S., van Drunen, E., Niedernhofer, L. J., van der Horst, G., Hoeijmakers, J. H. J., van Steeg, H., & Vijg, J. (2006). Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 596(1-2 SPEC. ISS.), 22-35. https://doi.org/10.1016/j.mrfmmm.2005.11.008