Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence.
Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence.
复制标题
衰老过程中 TP53 激活引起的选择性着丝粒周围异染色质拆除。
DOI：
10.1093/nar/gkac603
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发表时间：
2022-07-22
影响因子：
14.9
通讯作者：
Gilson, Eric
中科院分区：
文献类型：
--
作者：
Mendez-Bermudez, Aaron;Lototska, Liudmyla;Pousse, Melanie;Tessier, Florent;Croce, Oliver;Latrick, Chrysa M.;Cherdyntseva, Veronica;Nassour, Joe;Xiaohua, Jiang;Lu, Yiming;Abbadie, Corinne;Gagos, Sarantis;Ye, Jing;Gilson, Eric
细胞衰老触发各种类型的异染色质重塑，有助于衰老。然而，导致这些表观遗传改变的与年龄相关的机制仍然难以捉摸。在这里，我们询问了两个关键的衰老标志，端粒缩短和组成性异染色质损失，在衰老过程中是如何机械地联系在一起的。我们发现，在衰老开始时，中心点周围异染色质被特异性地拆除，包括染色质去浓缩、DNA断裂的积累、非法重组和DNA的丢失。这一过程是由端粒缩短或由端粒保护蛋白TRF2的tp53依赖性下调开始的一系列事件引起的遗传毒性胁迫引起的。中心粒周围TRF2的缺失触发DNA断裂，激活ATM，进而通过释放KAP1和Lamin B1、重组和在cGAS相关的细胞质中发现的卫星DNA切除导致异染色质去浓缩。当细胞摆脱衰老生长停滞时，TP53-TRF2轴激活干扰素反应和染色体重排的形成。总的来说，这些结果揭示了TP53作为中心体周围拆解者的作用，并定义了TP53依赖的衰老诱导剂如何通过下调TRF2分层导致选择性中心体周围拆解的基本原理。
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.
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影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
影响因子：
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作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
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影响因子：
21.3
作者：
Fujita, Kaori;Horikawa, Izumi;Mondal, Abdul M.;Jenkins, Lisa M. Miller;Appella, Ettore;Vojtesek, Borivoj;Bourdon, Jean-Christophe;Lane, David P.;Harris, Curtis C.
通讯作者：
Harris, Curtis C.