Autophagy-Independent Senescence and Genome Instability Driven by Targeted Telomere Dysfunction
Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Autophagy is a highly conserved stress response pathway that degrades cytoplasmic components and, in recent work, has been shown to regulate both senescence and genome instability in various contexts.
In this study, we apply models of acute telomere dysfunction to determine whether autophagy modulates the resulting genome instability and senescence responses. While telomere dysfunction rapidly induces autophagic flux in human fibroblast cell lines, inhibition of the autophagy pathway does not have a significant impact on the transition to senescence, in contrast to what has previously been reported for oncogene-induced senescence. Our results suggest that this difference may be explained by disparities in the development of the senescence-associated secretory phenotype as a result of different levels of DNA damage. We also show that chromosome fusions induced by telomere dysfunction are comparable in autophagy-proficient and autophagy-deficient cells. Altogether, our results highlight the complexity of the senescence-autophagy interface and indicate that autophagy induction is unlikely to play a significant role in telomere dysfunction-driven senescence and chromosome fusions.
Chapter 1 provides an overview of the autophagy and senescence pathways as well as the research available to date linking autophagy to senescence and genome instability with a focus on the major open questions. In Chapter 2, I will present data identifying the autophagy-independent nature of senescence triggered by targeted telomere dysfunction. In Chapter 3, I will present data defining the autophagy-independent nature of genome instability that results from telomere dysfunction. Finally, Chapter 4 is a discussion of the implications of this work for the fields of telomere dysfunction, senescence, and autophagy in a basic biology and clinical context.