dnA TRAnSLESIOn SynThESIS SuPPRESSES AGInG And AGInG-ASSOCIATEd CAnCER

The attrition of stem cells and of proliferating compartments that characterizes aging correlates with the accumulation of endogenous DNA lesions during life. To explore the existence of a causal relation between replicative stress at unrepaired endogenous DNA lesions and aging we used mice deficient for the translesion replication gene Rev1 . Rev1 -/- mice displayed stem cell attrition and mild progeroid phenotypes that were exacerbated by simultaneous deficiency of the global-genome nucleotide excision repair (GG-NER) gene Xpc . Rev1 -/- Xpc -/- mice displayed chronic replicative stress, cellular senescence and apoptosis in proliferating compartments, and predisposition to aging-associated lymphomas. We demonstrate the involvement of Rev1 in replicative bypass of peroxidated lipid aldehyde-DNA adducts, a known aging marker and GG-NER substrate. Replicative stress did not induce compensatory somatotrophic suppression, unlike transcriptional stress. Combined, these data provide strong support for a causal role in aging of replicative stress at accumulating endogenous bulky DNA adducts.

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