F. d'Adda di Fagagna, P.M. Reaper, L. Clay-Farrace, T. von Zglinicki, G. Saretzki, S.P. Jackson

Telomere-initiated cellular senescence is triggered when telomeres, the ends of linear chromosomes, cannot fulfil their normal protective functions. Although changes in several cellular markers have been shown to be associated with senescence, the mechanisms that control it are largely unknown. In order to gain a better molecular understanding of this phenomenon, we studied the molecular markers associated with senescence in primary human MRC5 and BJ fibroblasts. Since their life span can be extended by the expression of telomerase, senescence is telomere-initiated in these cells. Our analysis reveals that senescent human fibroblasts display molecular markers of DNA damage checkpoint activation characteristic of cells bearing DNA double-strand breaks. These markers include the accumulation of nuclear foci of several activated DNA repair and DNA damage checkpoint factors. We also show that many of these DNA damage response proteins, but intriguingly not all, associate with uncapped telomeres. Finally, we reveal that interfering with the actions of DNA damage checkpoint kinases can restore the DNA replicative ability of senescent cells. These data demonstrate that the DNA damage checkpoint apparatus is activated in senescent cells, it plays a causative role in senescence and that senescent cells can be induced to re-enter the cell cycle by interfering with the DNA damage checkpoint functions of the cell.

Keywords (Optional): 
DNA damage
human fibroblasts