p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression

Abstract

senescence is triggered by various cellular stresses that result in genomic lesions and DnA damage response activation. However, the role of chromatin and DnA replication in senescence induction remains elusive. Here we show that downregulation of p300 histone acetyltransferase activity induces senescence by a mechanism that is independent of the activation of p53, p21 CIP1 and p16 InK4A . This inhibition leads to a global H3, H4 hypoacetylation, initiating senescence-associated heterochromatic foci formation during s phase, together with a global decrease in replication fork velocity, and alteration of DnA replication timing. This replicative stress occurs without DnA damage and checkpoint activation, but results in a robust G2/m cell cycle arrest, within only one cell cycle. These results provide new insights into the control of s-phase progression by p300, and identify an unexpected chromatindependent alternative mechanism for senescence induction, which could possibly be exploited to treat cancer by senescence induction without generating further DnA damage.

YAP/TEAD–Mediated Transcription Controls Cellular Senescence

“…Currently, most of the cellular senescence regulation molecules identified have been shown to play roles in p16-or p53-dependent manners (17). Recently, it has been reported that the downregulation of p300/CBP-mediated chromatin-dependent alteration of S-phase progression defect induces cellular senescence independent of the activation of p53/p16 (18). Here, we identify a novel function of YAP in the regulation of cellular senescence.…”

Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status

“…7 Generally, senescent cells are considered to be permanently arrested in the G1 phase of the cell cycle, however few other studies are supportive of a role of G2 arrest as well. 8,9 Senescent cells at least under in vitro conditions can be identified by enlarged and flattened morphology. Senescence-associated b-galactosidase staining was the first biomarker reported for the identification of senescent cells.…”

La sénescence cellulaire

“…seraient impliquées dans la répression des gènes qui contrôlent le cycle cellulaire tandis que le rôle de SAHF serait plutôt de maintenir l'arrêt et/ou de supprimer la réponse au stress génotoxique. En accord avec cette hypothèse, il a été montré que l'inhibition de la p300 histone-acétyltransférase (p300 HAT) peut bloquer le cycle cellulaire en phase G2 en induisant la formation de SAHF et la sénescence, et ce en l'absence des voies p53/p21 et pRb/p16 [23]. La progression dans la phase S du cycle et la formation des SAHF sont, dans ce cas, essentielles pour l'arrêt en sénescence.…”

“…Néanmoins, des développe-ments récents incitent à revoir cette attitude dans certains cas. D'une part, les inhibiteurs des p300 HAT pourraient être utilisés en thérapeutique pour induire la sénescence de cellules cancéreuses déficientes pour p53 et/ou pRb/p16 [23]. D'autre part, le ciblage spécifique du suppresseur de tumeur PTEN pourrait induire la sénescence dans des tumeurs précoces ou des tumeurs où la fonction antiproliférative de p53 est préservée ou rétablie.…”