The multistep path to replicative senescence onset: zooming on triggering and inhibitory events at telomeric DNA

Abstract

Replicative senescence is an essential cellular process playing important physiological functions, but it is better known for its implications in aging, cancer, and other pathologies. One of the main triggers of replicative senescence is telomere shortening and/or its dysfunction and, therefore, a deep understanding of the molecular determinants is crucial. However, replicative senescence is a heterogeneous and hard to study process, especially in mammalian cells, and some important questions still need an answer. These questions concern i) the exact molecular causes triggering replicative senescence, ii) the role of DNA repair mechanisms and iii) the importance of R-loops at telomeres in regulating senescence onset, and iv) the mechanisms underlying the bypass of replicative senescence. In this review, we will report and discuss recent findings about these mechanisms both in mammalian cells and in the model organism Saccharomyces cerevisiae.

Unwrap RAP1’s Mystery at Kinetoplastid Telomeres

“…Critically short telomeres recruit insufficient amounts of telomere proteins, exposing the natural chromosome ends and frequently inducing DNA damage responses, including cell growth arrest [56]. Therefore, maintaining a stable telomere length is essential for telomere end protection, and mammalian and yeast cells with critically short telomeres enter replicative senescence [57][58][59][60]. However, conventional DNA polymerases are incapable of replicating linear DNA molecules completely due to their enzymatic properties (they require a template and a primer and only extend DNA at the 3 ′ ends), resulting in progressive telomere shortening in proliferating cells [4].…”