Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer.
Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer.
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癌基因诱导的DNA损伤反应与衰老和癌症异染色质之间的相互作用。
DOI：
10.1038/ncb2170
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发表时间：
2011-03
影响因子：
21.3
通讯作者：
d'Adda di Fagagna F
中科院分区：
文献类型：
--
作者：
Di Micco R;Sulli G;Dobreva M;Liontos M;Botrugno OA;Gargiulo G;dal Zuffo R;Matti V;d'Ario G;Montani E;Mercurio C;Hahn WC;Gorgoulis V;Minucci S;d'Adda di Fagagna F
两种主要机制与细胞衰老的建立有因果关系：DNA损伤反应（DDR）途径的激活和衰老相关异染色质灶（SAHF）的形成。在这里，我们表明，在人成纤维细胞抗过早p16INK4a诱导，SAHF优先形成癌基因激活后，但没有检测到在复制细胞衰老或暴露于各种衰老诱导刺激。癌基因诱导的SAHF形成取决于DNA复制和ATR（毛细血管扩张性共济失调和Rad3相关）。ATM（共济失调毛细血管扩张突变）或p53的失活允许癌基因表达细胞增殖，这些细胞保留增加的异染色质诱导。在人类癌症中，异染色质标记物的水平高于正常组织，并且与肿瘤的增殖指数或阶段无关。在癌基因表达细胞中异染色质的药理学和遗传扰动增加DDR信号传导并导致细胞凋亡。在体内，组蛋白脱乙酰酶抑制剂（HDACi）引起异染色质松弛、DDR增加、细胞凋亡和肿瘤消退。这些结果表明，致癌应激诱导的异染色质抑制DDR，并表明在癌症治疗中使用染色质修饰药物可能会受益于染色质和肿瘤的DDR状态的研究。
Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16INK4a induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
5.3
作者：
Denchi, EL;Attwooll, C;Helin, K
通讯作者：
Helin, K
影响因子：
7.8
作者：
Bandyopadhyay D;Curry JL;Lin Q;Richards HW;Chen D;Hornsby PJ;Timchenko NA;Medrano EE
通讯作者：
Medrano EE