SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence.
SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence.
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DOI：
10.1038/nsmb.3202
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发表时间：
2016-05
影响因子：
16.8
通讯作者：
Chua KF
中科院分区：
文献类型：
--
作者：
Tasselli L;Xi Y;Zheng W;Tennen RI;Odrowaz Z;Simeoni F;Li W;Chua KF
哺乳动物着丝粒处的着丝粒周异染色质沉默对于有丝分裂保真度和基因组稳定性是必不可少的。在衰老细胞、衰老组织和哺乳动物肿瘤中观察到有缺陷的臂间沉默，但这些缺陷的潜在机制和功能后果尚不清楚。在这里，我们揭示了人类SIRT6酶在臂间转录沉默中的关键作用，并表明这种功能可以防止有丝分裂缺陷，基因组不稳定性和细胞衰老。在臂间异染色质中，SIRT6促进新底物组蛋白H3赖氨酸K18（H3K18）的脱乙酰化，并且细胞中SIRT6的失活导致H3K18过度乙酰化和臂间转录物的异常积累。引人注目的是，这些转录本的RNAi耗尽挽救了SIRT6缺陷细胞的有丝分裂和衰老表型。总之，我们的发现揭示了SIRT6和H3K18Ac在异染色质调节的新功能，并证明了去调节的臂间转录在衰老和癌症相关的细胞功能障碍中的致病作用。
Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and show that this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction.
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影响因子：
13.8
作者：
Kugel, Site;Mostoslavsky, Raul
通讯作者：
Mostoslavsky, Raul
影响因子：
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作者：
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通讯作者：
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通讯作者：
Sutherland, Heidi G.
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作者：
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通讯作者：
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