A cell culture comparative biology approach to study mechanisms of genome stability and their relevance for species longevity: a newer interpretation of 53BP1 nuclear foci

The DNA-damage response (DDR) initiates cellular processes that can lead to a difficult choice: DNA repair, senescence or apoptosis. Differences in DDR efficiency may contribute to species-specific differences in lifespan and partially explain the exceptional longevity of some mammal species. To better understand the differences in genomic stability between species we have examined, in fibroblast cultures from several mammals, the appearance of micronuclei and the recruitment of 53BP1 in nuclear structures termed foci, after a genotoxic insult represented by the treatment with Etoposide and Neocarcinostatin. Quantification of 53BP1 foci formation together with micronuclei appearance up to three days after damage showed that cells from long lived species appear to be better equipped in the control of DNA damage repair system and the control of progression into the cell cycle. This capacity may be the consequence of a better capacity to detect DNA damage. We propose a newer interpretation of nuclear foci: they do not simply represent the presence of DNA damage but rather the cell awarness of it. We suggest that a key element for a long lived species is the capacity to detect damage and to take the necessary time to make an accurate choice between repair, senescence or apoptosis.