Key Elements of Cellular Senescence Involve Transcriptional Repression of Mitotic and DNA Repair Genes Through the p53-p16/pRB-E2F-DREAM Complex

Abstract

Cellular senescence is a dynamic stress response process that contributes to aging. From initiation to maintanence, senescent cells continuously undergo complex molecular changes and develop an altered transcriptome. Understanding how the molecular architecture of these cells evolves to sustain their non-proliferative state will open new therapeutic avenues to allievate or delay consequences of aging. Seeking to understand these molecular changes, we studied the transcriptomic profiles of endothelial replication-induced senescence and senescence induced by the inflammatory cytokine, TNF-α. The downregulated gene signature of both replicative and TNF-α senescence were highly overlapped: decreasing expression of several genes associated to cell cycle regulation, DNA replication, recombination, repair, chromatin structure, cellular assembly, and organization. We identified multiple targets of p53/p16-pRB-E2F-DREAM that are essential for proliferation, mitotic progression, resolving DNA damage, maintaining chromatin integrity, and DNA synthesis were repressed in senescent cells. Here we provide important molecular link between DREAM repressor complex and senescence, and identify pleothra of p53/p16-pRB-E2F-DREAM targets that controls the stability of the senescenct arrest. We propose stable repression of large number of mitotic genes by p53/p16-pRB-E2F-DREAM pathway contributes to the extended mitotic arrest and permanence of the senescent state.