Selective pericentromeric heterochromatin ...
Document type :
Article dans une revue scientifique: Article original
DOI :
Title :
Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence
Author(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]
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]
Journal title :
Nucleic Acids Research
Pages :
7493-7510
Publisher :
Oxford University Press
Publication date :
2022-07-22
ISSN :
0305-1048
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
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