Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction

Abstract

Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell-cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/C(Cdh1) and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. p16 is only required for maintenance of senescence. Analysis of human nevi also suggested the role of mitosis skip in in vivo senescence. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.

Senescence from G2 arrest, revisited

“…The Nakanishi group showed that replicative senescence or exposure to various senescence-causing stimuli induces p53-dependent mitotic bypass (referred to as mitotic skipping), entailing irreversible cell cycle arrest in the 4N G1 state and accumulation of the senescent markers p16 and b-galactosidase. 93 Moreover, stable G2 arrest induced by ionizing radiation (IR) was associated with p53/p21-dependent premature APC/C Cdh1 activation and degradation of mitotic cyclins, consistent with previous observations. [74][75][76] However, unlike p53-mediated mitotic bypass, APC/C Cdh1 activation alone does not appear to be sufficient to induce senescence, that additionally requires repression of mitotic regulators by pRb family pocket proteins (Fig.…”

“…Active pRb inhibits the expression of genes that control G2/M progression, leading to irreversible G2 arrest of the cell cycle. It is proposed that p53 might induce senescence independently of p21 93 through mechanisms that are not fully clear. Like in G1 arrest, p16 stabilizes senescence in G2 presumably by targeting pRb kinases.…”

“…3). Conversely, transient Chk1/2 activation, induced by partial TRF2 depletion 83 or acute DNA damage (by IR), 93 in the absence of (efficient) p21 induction can transiently delay, but not prevent mitosis.…”

“…88 In the absence of sustained Chk1/2 activation, p53/p21-deficient cells exposed to genotoxic agents arrest only transiently in G2 and then progress into mitosis and eventually die. 59,93 Similarly, in aging p53/pRbdeficient cells, extensive telomere erosion induces crisis with massive cell death and tetraploidization through endoreplication or mitotic failure. 92 tag, the Medema group investigated the role of p21-dependent cyclin B1 nuclear retention in senescence induction in G2-arrested cells upon IR.…”

Binucleated HeLa cells are formed by cytokinesis failure in starvation and keep the potential of proliferation

“…It seems that binucleated cells can be divided into two types: reversible and irreversible. Johmura et al (2014) showed that normal human diploid fibroblasts exposed to various senescence-inducing stimuli Serum-free examination Medium improvement examination Fig. 5 Results of the serum-free and the medium improvement examinations.…”