Telomere-initiated cellular senescence is a DNA damage checkpoint-mediated response
F. d'Adda di Fagagna, P.M. Reaper, L. Clay-Farrace, T. von Zglinicki, G. Saretzki and S.P. Jackson
The Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, UK.
Present address: IFOM - FIRC Institute of Molecular Biology, via Adamello 16, 20139 Milan, Italy
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.
Key words:
Telomeres, senescence, DNA damage, checkpoints, human fibroblasts
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