DNA damage-induced cellular senescence is regulated by 53BP1 accumulation in the nuclear foci and phase separation.
DNA damage-induced cellular senescence is regulated by 53BP1 accumulation in the nuclear foci and phase separation.
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DOI：
10.1111/cpr.13398
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发表时间：
2023-06
影响因子：
8.5
通讯作者：
中科院分区：
文献类型：
--
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细胞衰老与多种年龄相关疾病有关，并可由各种压力引发，包括DNA损伤。多种遗传毒性应激物，如抗癌药物，会导致DNA双链断裂（DSB），从而引发肿瘤抑制蛋白p53在细胞核中的积累。细胞应激稳定并激活p53信号通路，其调节各种细胞过程，如凋亡、DNA修复和衰老。虽然p53信号传导是一种众所周知的肿瘤抑制途径，但仍不清楚它在细胞衰老过程中如何调节。在这里，我们表明，p53结合蛋白1（53 BP 1）在核灶中的积累是通过p53激活DNA损伤诱导细胞衰老所必需的。在人永生化成纤维细胞中，shRNA介导的53 BP 1缺失不仅降低了p53靶基因的表达，还降低了阿霉素处理诱导的细胞衰老。此外，我们证实DSB触发53 BP 1在核灶中的过度积累，这在细胞衰老的调节中起着关键作用。为了防止53 BP 1在核灶中的积累，我们使用了相分离抑制剂和针对RNF 168的siRNA，RNF 168在DSB基因座处积累并与53 BP 1形成复合物。这通过激活p53信号通路阻断了53 BP 1核灶的形成和DNA损伤诱导的细胞衰老。最后，委员会认为， 我们证明了DNA损伤后核灶中53 BP 1积累的增加激活了p53，并通过液-液相分离机制控制细胞衰老。53 BP 1核灶在DSB诱导的细胞衰老中的作用由DSB激活的ATM使CHK 2和H2 A/H2 AX磷酸化。ATM和CHK 2通过CDC 25诱导S期细胞周期停滞。DSB位点周围的磷酸化H2 A/H2 AX随后被RNF-8-RNF 168泛素化。然后，53 BP 1在DSB位点积累，并且通过相分离形成53 BP 1核灶。53 BP 1核灶通过p53激活参与DSB诱导的细胞衰老。53 BP 1核灶也可能与其他核因子，如PML核灶相互作用，以调节细胞衰老。
Cellular senescence is linked to a wide range of age‐related diseases and can be triggered by a variety of stresses, including DNA damage. A variety of genotoxic stressors, such as anti‐cancer drugs, cause DNA double‐strand breaks (DSBs), which trigger the accumulation of the tumour suppressor protein p53 in the nucleus. Cellular stresses stabilize and activate the p53 signalling pathway, which regulates various cellular processes, such as apoptosis, DNA repair, and senescence. Although p53 signalling is a well‐known tumour suppressor pathway, it remains unclear how it is regulated during cellular senescence. Here, we show that p53‐binding protein 1 (53BP1) accumulation in the nuclear foci is required for DNA damage‐induced cellular senescence via p53 activation. In human immortalized fibroblast, shRNA‐mediated 53BP1 depletion decreased not only the expression of p53‐target genes but also the cellular senescence induced by adriamycin treatment. Furthermore, we confirmed that DSBs trigger the hyperaccumulation of 53BP1 in the nuclear foci, which plays a key role in the regulation of cellular senescence. To prevent the accumulation of 53BP1 in the nuclear foci, we used phase separation inhibitors, and siRNA against RNF168, which accumulates at DSB loci and forms complexes with 53BP1. This blocks the formation of 53BP1 nuclear foci and DNA damage‐induced cellular senescence by activating the p53 signaling pathway. In conclusion, we demonstrated that increased accumulation of 53BP1 in the nuclear foci following DNA damage activates p53 and governs cellular senescence via a liquid–liquid phase separation mechanism. Role of 53BP1 nuclear foci in DSB‐induced cellular senescence. ATM activated by DSBs phosphorylates CHK2 and H2A/H2AX. ATM and CHK2 induce S‐phase cell cycle arrest via CDC25. Phosphorylated H2A/H2AX around the DSB sites are subsequently ubiquitinated by RNF‐8‐RNF168. Then, 53BP1 is accumulated at the DSB sites, and 53BP1 nuclear foci is formed by phase separation. 53BP1 nuclear foci participates DSB‐induced cellular senescence via p53 activation. 53BP1 nuclear foci may also interact with other nuclear factors, such as PML nuclear foci, to regulate cellular senescence.
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影响因子：
21.3
作者：
Nowsheen S;Aziz K;Aziz A;Deng M;Qin B;Luo K;Jeganathan KB;Zhang H;Liu T;Yu J;Deng Y;Yuan J;Ding W;van Deursen JM;Lou Z
通讯作者：
Lou Z
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
8
作者：
Carbone, R;Pearson, M;Pelicci, PG
通讯作者：
Pelicci, PG
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5.6
作者：
Bobkova, Elizaveta;Depes, Daniel;Falk, Martin
通讯作者：
Falk, Martin