Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Abstract Cellular senescence triggers various types of heterochromatin remodelling that contribute to aging. However the age-ralated mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and consititutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from p53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres trigger DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing Kap1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated to cGAS. This TP53-TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of p53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leadns to selective pericentromeric dismantling through the downregulation of TRF2.