Titre :

Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Auteur(s) :

Mendez-Bermudez, Aaron [Auteur]
Lototska, Liudmyla [Auteur]
Pousse, Melanie [Auteur]
Tessier, Florent [Auteur]
Croce, Oliver [Auteur]
Latrick, Chrysa M [Auteur]
Cherdyntseva, Veronica [Auteur]
Nassour, Joe [Auteur]
Xiaohua, Jiang [Auteur]
Lu, Yiming [Auteur]
Abbadie, Corinne [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Gagos, Sarantis [Auteur]
Ye, Jing [Auteur]
Gilson, Eric [Auteur]

Titre de la revue :

Nucleic Acids Research

Pagination :

7493-7510

Éditeur :

Oxford University Press

Date de publication :

2022-07-22

ISSN :

0305-1048

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Abstract Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how ...
Lire la suite >Abstract Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and constitutive 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 TP53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres triggers 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 with 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 TP53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leads to selective pericentromeric dismantling through the downregulation of TRF2.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie

Collections :

• Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277

Source :

Harvested from HAL