A DNA damage checkpoint response in telomere-initiated senescence

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