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d'Adda di Fagagna, F, Reaper, PM, Clay-Farrace, L, Fiegler, H, Carr, P, Von Zglinicki, T, Saretzki, G, Carter, NP and Jackson, SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194-8
Most human somatic cells can undergo only a limited number of population doublings in vitro. 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.
Carrier Proteins/metabolism; Cell Aging; Cell Cycle; Cell Cycle Proteins/metabolism; Checkpoint Kinase 2; Chromatin/metabolism; DNA Damage; DNA Repair; DNA-Binding Proteins/metabolism; Fibroblasts/cytology; Fibroblasts/metabolism; Histones/metabolism; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins/metabolism; Phosphoproteins; Phosphorylation; Protein Binding; Protein Kinases/metabolism; Protein-Serine-Threonine Kinases; S Phase; Telomere/metabolism; Telomere/pathology; Trans-Activators/metabolism