XRN2 Links Transcription Termination to DNA Damage and Replication Stress.
XRN2 Links Transcription Termination to DNA Damage and Replication Stress.
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DOI：
10.1371/journal.pgen.1006107
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发表时间：
2016-07
期刊：
影响因子：
4.5
通讯作者：
Boothman DA
中科院分区：
文献类型：
--
作者：
Morales JC;Richard P;Patidar PL;Motea EA;Dang TT;Manley JL;Boothman DA
XRN 2是涉及转录终止的5 '-3'核糖核酸外切酶。在这里，我们证明了XRN 2在DNA损伤反应中的意想不到的作用，包括R环结构的解析和DNA双链断裂（DSB）的预防。我们表明，XRN 2经历DNA损伤诱导的核重新定位，共定位与53 BP 1和R环，在转录和R环依赖的过程。XRN 2缺失导致R环增加、基因组不稳定性、复制应激、DSB和细胞对各种DNA损伤剂的超敏反应。我们证明，DSB出现XRN 2损失发生在转录暂停位点。XRN 2缺陷细胞在电离辐射后DSB修复中也表现出R环和转录依赖性延迟，这表明XRN 2在R环解析、抑制复制应激和维持基因组稳定性中具有新的作用。我们的研究强调了调节转录相关活动作为维持遗传稳定性的关键组成部分的重要性。基因组不稳定性是疾病状态，特别是癌症的主要原因之一。基因组不稳定的一个主要原因是DNA双链断裂（DSB）的形成，这是细胞可能遇到的最危险的DNA损伤类型之一。如果不及时修复，一个DSB不仅会导致细胞死亡。如果错误修复，一个DSB可能导致危险的染色体畸变，如易位，最终可能导致癌症。细胞每天都会遇到并修复自然发生的细胞过程中产生的DSB。许多研究表明，在某些情况下，在转录过程中形成的异常结构，特别是RNA：DNA杂合体（R环），可导致DSB形成和基因组不稳定性，特别是在DNA合成期间。因此，重要的是要了解细胞如何响应和修复转录介导的DNA损伤，特别是R环相关的DNA损伤。这篇论文不仅证明了XRN转录终止因子将转录和DNA损伤联系起来，而且还提供了对细胞如何防止转录相关DNA损伤的更好理解。
XRN2 is a 5’-3’ exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability. Genomic instability is one of the primary causes of disease states, in particular cancer. One major cause of genomic instability is the formation of DNA double strand breaks (DSBs), which are one of the most dangerous types of DNA lesions the cell can encounter. If not repaired in a timely manner, one DSB can lead not only to cell death. If misrepaired, one DSB can lead to a hazardous chromosomal aberration, such as a translocation, that can eventually lead to cancer. The cell encounters and repairs DSBs that arise from naturally occurring cellular processes on a daily basis. A number of studies have demonstrated that aberrant structures that form during transcription under certain circumstances, in particular RNA:DNA hybrids (R loops), can lead to DSB formation and genomic instability, especially during DNA synthesis. Thus, it is important to understand how the cell responds and repairs transcription-mediated DNA damage in general and R loop-related DNA damage in particular. This paper both demonstrates that the XRN transcription termination factor links transcription and DNA damage, but also provides a better understanding of how the cell prevents transcription-related DNA damage.