Cellular senescence is a state of stable and irreversible cell cycle arrest with active metabolism, that normal cells undergo after a finite number of divisions (Hayflick limit). Senescence can be triggered by intrinsic and/or extrinsic stimuli including telomere shortening at the end of a cell's lifespan (telomere-initiated senescence) and in response to oxidative, genotoxic or oncogenic stresses (stress-induced premature senescence). Several effector mechanisms have been proposed to explain senescence programmes in diploid cells, including the induction of DNA damage responses, a senescence-associated secretory phenotype and epigenetic changes. Senescent cells display senescence-associated-β-galactosidase activity and undergo chromatin remodeling resulting in heterochromatinisation. Senescence is established by the pRb and p53 tumour suppressor networks. Senescence has been detected in in vitro cellular settings and in premalignant, but not malignant lesions in mice and humans expressing mutant oncogenes. Despite oncogene-induced senescence, which is believed to be a cancer initiating barrier and other tumour suppressive mechanisms, benign cancers may still develop into malignancies by bypassing senescence. Here, we summarise the functional genetic screens that have identified genes, uncovered pathways and characterised mechanisms involved in senescence evasion. These include cell cycle regulators and tumour suppressor pathways, DNA damage response pathways, epigenetic regulators, SASP components and noncoding RNAs.
Keywords: Cell cycle regulators and tumour suppressors; Chromatin modifiers; Noncoding RNAs; Oncogenic signalling; Transcription factors and SASP.
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