SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.
SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.
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DOI：
10.1016/j.molcel.2013.06.018
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发表时间：
2013-08-22
期刊：
影响因子：
16
通讯作者：
Mostoslavsky, Raul
中科院分区：
文献类型：
--
作者：
Toiber, Debra;Erdel, Fabian;Bouazoune, Karim;Silberman, Dafne M.;Zhong, Lei;Mulligan, Peter;Sebastian, Carlos;Cosentino, Claudia;Martinez-Pastor, Barbara;Giacosa, Sofia;D'Urso, Agustina;Naeaer, Anders M.;Kingston, Robert;Rippe, Karsten;Mostoslavsky, Raul
DNA损伤与多种人类疾病有关，如癌症、神经变性和衰老。关于染色质可及性在DNA修复中的作用知之甚少。在这里，我们发现组蛋白去乙酰化酶SIRT 6是最早招募到双链断裂（DSB）位点的因子之一。SIRT 6将ISWI-染色质重塑剂SNF 2 H招募到DSB，并使组蛋白H3 K56局部脱乙酰化。缺乏SIRT 6和SNF 2 H会损害染色质重塑，增加对基因毒性损伤的敏感性，并招募下游因子，如53 BP 1，BRCA 1和RPA。值得注意的是，SIRT 6缺陷小鼠在特定组织中表现出较低水平的染色质相关SNF 2 H，这是一种伴随DNA损伤增加的表型。我们证明，SIRT 6是至关重要的招聘的染色质重塑作为DNA损伤反应的早期步骤，表明正确的展开染色质起着限速作用。我们提出了一种新的组蛋白修饰剂和染色质重塑之间的串扰，调节协调反应，以防止DNA损伤。
DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration and senescence. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the histone deacetylase SIRT6 is one of the earliest factors recruited to sites of Double-Strand Breaks (DSBs). SIRT6 recruits the ISWI-chromatin remodeler SNF2H to DSBs, and deacetylates focally histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors, such as 53BP1, BRCA1 and RPA. Remarkably, SIRT6 deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by increased DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a novel crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.
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DOI：
10.1038/nrg3345
发表时间：
2013-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Costelloe, Thomas;Louge, Raphael;Tomimatsu, Nozomi;Mukherjee, Bipasha;Martini, Emmanuelle;Khadaroo, Basheer;Dubois, Kenny;Wiegant, Wouter W.;Thierry, Agnes;Burma, Sandeep;van Attikum, Haico;Llorente, Bertrand
通讯作者：
Llorente, Bertrand
DOI：
10.1016/j.bbrc.2010.10.066
发表时间：
2010-11-26
影响因子：
3.1
作者：
Kashiwaba, Shu-ichiro;Kitahashi, Kazuyuki;Murakami, Yasufumi
通讯作者：
Murakami, Yasufumi
DOI：
10.1073/pnas.1003438107
发表时间：
2010-11-16
影响因子：
11.1
作者：
Erdel, Fabian;Schubert, Thomas;Rippe, Karsten
通讯作者：
Rippe, Karsten
影响因子：
4.8
作者：
Liszt, G;Ford, E;Guarente, L
通讯作者：
Guarente, L