A DNA damage checkpoint response in telomere-initiated senescence

Fabrizio d'Adda di Fagagna (), Philip M. Reaper, Lorena Clay-Farrace, Heike Fiegler, Philippa Carr, Thomas von Zglinicki, Gabriele Saretzki, Nigel P. Carter and Stephen P. Jackson ()
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Fabrizio d'Adda di Fagagna: University of Cambridge
Philip M. Reaper: University of Cambridge
Lorena Clay-Farrace: University of Cambridge
Heike Fiegler: The Wellcome Trust Sanger Institute
Philippa Carr: The Wellcome Trust Sanger Institute
Thomas von Zglinicki: University of Newcastle upon Tyne
Gabriele Saretzki: University of Newcastle upon Tyne
Nigel P. Carter: The Wellcome Trust Sanger Institute
Stephen P. Jackson: University of Cambridge

Nature, 2003, vol. 426, issue 6963, 194-198

Abstract: Abstract Most human somatic cells can undergo only a limited number of population doublings in vitro1. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres—the ends of linear chromosomes—cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.

Date: 2003
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DOI: 10.1038/nature02118

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