NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair
NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair
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DOI：
10.15252/embr.201643191
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发表时间：
2017-05-01
期刊：
影响因子：
7.7
通讯作者：
Ayoub, Nabieh
中科院分区：
文献类型：
--
作者：
Awwad, Samah W.;Abu-Zhayia, Enas R.;Ayoub, Nabieh
双链断裂（DSB）触发快速和短暂的转录暂停，以防止损伤位点的修复和转录机制之间的碰撞。对DNA损伤后确保转录阻断的机制知之甚少。在这里，我们揭示了一个新的负延伸因子NELF在阻断转录活性附近的DSB的作用。我们发现，NELF-E和NELF-A被迅速招募到DSB网站。此外，NELF-E募集及其抑制活性都是关闭DSB转录所必需的。值得注意的是，使用I-SceI内切核酸酶和CRISPR-Cas9系统，我们观察到NELF-E以PARP 1依赖性方式优先招募到转录活性基因上游诱导的DSB，而不是无活性基因。此外，RNA聚合酶II的存在是NELF-E优先募集到DNA断裂位点的先决条件。此外，我们证明NELF-E是完整修复DSB所必需的。总之，我们的数据确定NELF复合物作为DNA损伤反应中的新组分。
Double-strand breaks (DSBs) trigger rapid and transient transcription pause to prevent collisions between repair and transcription machineries at damage sites. Little is known about the mechanisms that ensure transcriptional block after DNA damage. Here, we reveal a novel role of the negative elongation factor NELF in blocking transcription activity nearby DSBs. We show that NELF-E and NELF-A are rapidly recruited to DSB sites. Furthermore, NELF-E recruitment and its repressive activity are both required for switching off transcription at DSBs. Remarkably, using I-SceI endonuclease and CRISPR-Cas9 systems, we observe that NELF-E is preferentially recruited, in a PARP1-dependent manner, to DSBs induced upstream of transcriptionally active rather than inactive genes. Moreover, the presence of RNA polymerase II is a prerequisite for the preferential recruitment of NELF-E to DNA break sites. Additionally, we demonstrate that NELF-E is required for intact repair of DSBs. Altogether, our data identify the NELF complex as a new component in the DNA damage response.