کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2147697 1548422 2006 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
پیش نمایش صفحه اول مقاله
Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice
چکیده انگلیسی

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis - Volume 596, Issues 1–2, 11 April 2006, Pages 22–35
نویسندگان
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