Abstract 2924: The role of autophagy in telomere damage-induced replicative senescence.

Abstract

Abstract Recent studies have implicated autophagy in multiple aspects of cancer biology, including oncogene-induced senescence (OIS) and genome instability. Autophagy is thought to control the transition to OIS through its ability to regulate the Senescence Associated Secretory Phenotype (SASP), which is necessary and sufficient for OIS. In addition, autophagy can suppress genome instability by limiting p62 accumulation in an apoptosis-deficient setting. In this study, we explored the role of autophagy in replicative senescence, an important barrier to tumorigenesis that is driven by telomere dysfunction and that is very distinct from OIS. We modeled replicative senescence by expressing mutant telomerase in human diploid fibroblasts, which rapidly induces telomere dysfunction and senescence. We observed strong induction of autophagic flux in response to telomere dysfunction prior to and during senescence. To determine the role of autophagy in the cellular response to telomere damage, we examined multiple components of the dysfunctional telomere response: transition and maintenance of senescence, SASP, DNA damage response, genome instability, and heterochromatin foci. In cells depleted of key autophagy mediators (ATGs), we did not observe a clear defect in the transition to senescence, as was previously seen with OIS. However, we did observe an outgrowth population of non-senescent cells among the senescent autophagy-deficient population, suggesting a possible defect in the maintenance of senescence. We also found that telomere dysfunction induced secretion of IL6 in an autophagy-dependent manner. Lastly, we observed an increase in polyploid cells in Atg7-deficient checkpoint-proficient cells, suggesting a role for autophagy in maintaining genome stability during the dysfunctional telomere response. Our results suggest that autophagy controls several aspects of the cellular response to telomere dysfunction in normal human cells. Citation Format: Florie Charles, Jayanta Debnath, Bradley Stohr. The role of autophagy in telomere damage-induced replicative senescence. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2013-2924