Heterochromatin localization of p19INK4D is associated with senescence triggered by genotoxics

SONZOGNI SV; CASTILLO DS; CÁNEPA ET

Mendoza

Congreso; XLVIII Reunión anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2012

Cellular senescence is a permanent cell cycle arrest triggered by exogenous or endogenous stress. The DNA Damage Response (DDR) and global induction of heterochromatin (SAHF, senescence-associated heterochromatic foci) have been involved in the irreversibility of senescence. SAHF are proposed to enforce cellular senescence by suppressing the transcription of genes involved in proliferation. Previous work showed that senescent stimuli upregulates p19INK4d (p19) at both its mRNA and protein levels. We observed a significant increase in the percentage of cells undergoing senescence when p19 is stably overexpressed compared to wild type or p19 deficient counterparts. In this work, we evaluated the mechanism involved in p19 induction and the potential role of p19 in replicative and genotoxic-induced senescence. Reporter gene assays using the p19 promoter suggest that its induction is mediated by E2F1 in genotoxic but not replicative senescence. A senescence stimulus caused p19 translocation to the nucleus where it binds to chromatin enriched in HP1, suggesting its preferential interaction with heterochromatin. Moreover, p19 overexpressing cells exhibit reduced MNase chromatin accessibility. In vivo correlation was observed since mice tissue display an age-dependent increase in p19. We propose that p19 is involved in senescence playing a role in global heterochromatin arrangement.