Journal
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
Volume 596, Issue 1-2, Pages 22-35Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.mrfmmm.2005.11.008
Keywords
DNA-repair; aging; mutation; mice
Funding
- NCI NIH HHS [K22 CA111525] Funding Source: Medline
- NIA NIH HHS [AG20438, AG17242] Funding Source: Medline
- NIEHS NIH HHS [UO1 ES11044] Funding Source: Medline
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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 harbofing 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 Xpd(m/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. (c) 2005 Elsevier B.V. All rights reserved.
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