SET8 methyltransferase activity during the DNA double-strand break response is required for recruitment of 53BP1.
SET8 methyltransferase activity during the DNA double-strand break response is required for recruitment of 53BP1.
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DOI：
10.15252/embr.201439434
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发表时间：
2014-11
期刊：
影响因子：
7.7
通讯作者：
Batada NN
中科院分区：
文献类型：
--
作者：
Dulev S;Tkach J;Lin S;Batada NN
DNA双链断裂（DSB）激活称为DNA损伤反应（DDR）的信号传导途径，其通过蛋白质-蛋白质相互作用和翻译后修饰将信号传导蛋白（例如53 BP 1）募集到病变侧翼的染色质。SET 8甲基转移酶的消耗防止了53 BP 1在DSB处的积累;然而，这种表型已被归因于SET 8在整个基因组中产生H4 K20甲基化的作用，这是在DNA损伤之前53 BP 1与染色质结合所必需的。在这里，我们报告说，SET 8直接作用于DSB在DNA损伤反应（DDR）。SET 8在DSB处积累，并在DSB处具有酶活性。就在诱导DNA损伤之前耗尽SET 8消除了53 BP 1在DSB处的积累，表明SET 8在DDR期间起作用。SET 8在DSB的占据受组蛋白脱乙酰酶（HDAC）调节。最后，SET 8在功能上是通过非同源末端连接途径（NHEJ）有效修复DSB所必需的。我们的研究结果表明，SET 8的积极作用，在DDR在DSB的53 BP 1的积累是必需的。
DNA double-strand breaks (DSBs) activate a signaling pathway known as the DNA damage response (DDR) which via protein–protein interactions and post-translational modifications recruit signaling proteins, such as 53BP1, to chromatin flanking the lesion. Depletion of the SET8 methyltransferase prevents accumulation of 53BP1 at DSBs; however, this phenotype has been attributed to the role of SET8 in generating H4K20 methylation across the genome, which is required for 53BP1 binding to chromatin, prior to DNA damage. Here, we report that SET8 acts directly at DSBs during the DNA damage response (DDR). SET8 accumulates at DSBs and is enzymatically active at DSBs. Depletion of SET8 just prior to the induction of DNA damage abrogates 53BP1’s accumulation at DSBs, suggesting that SET8 acts during DDR. SET8’s occupancy at DSBs is regulated by histone deacetylases (HDACs). Finally, SET8 is functionally required for efficient repair of DSBs specifically via the non-homologous end-joining pathway (NHEJ). Our findings reveal that SET8’s active role during DDR at DSBs is required for 53BP1’s accumulation.
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