RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair
RAP80 suppresses the vulnerability of R-loops during DNA double-strand break repair
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RAP80 抑制 DNA 双链断裂修复过程中 R 环的脆弱性
DOI：
10.1016/j.celrep.2022.110335
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发表时间：
2022
期刊：
影响因子：
8.8
通讯作者：
Shibata Atsushi
中科院分区：
文献类型：
--
作者：
Yasuhara Takaaki;Kato Reona;Yamauchi Motohiro;Uchihara Yuki;Zou Lee;Miyagawa Kiyoshi;Shibata Atsushi
单链DNA（ssDNA）作为DNA上细胞过程的中间体出现，是基因组的潜在脆弱性，除非它得到适当的保护。最近的证据表明，由ssDNA和DNA-RNA杂交体组成的R环可以在转录活性区域内的DNA双链断裂（DSB）附近形成。然而，在DSB修复过程中如何克服R环中ssDNA的脆弱性仍不清楚。在这里，我们确定RAP 80作为一个因素抑制的R环，染色体易位，并在DSB修复过程中的缺失的ssDNA的脆弱性。在机制上，RAP 80阻止CtIP对R环中ssDNA的非计划性溶核加工。该机制通过依赖于BRCA 1、Polθ和LIG 1/3的转录相关末端连接促进有效的DSB修复。因此，RAP 80在DSB修复期间抑制R环的脆弱性，从而排除由有害的R环加工引起的基因组的关键组分中的基因组异常。
Single-stranded DNA (ssDNA) arising as an intermediate of cellular processes on DNA is a potential vulnerability of the genome unless it is appropriately protected. Recent evidence suggests that R-loops, consisting of ssDNA and DNA-RNA hybrids, can form in the proximity of DNA double-strand breaks (DSBs) within transcriptionally active regions. However, how the vulnerability of ssDNA in R-loops is overcome during DSB repair remains unclear. Here, we identify RAP80 as a factor suppressing the vulnerability of ssDNA in R-loops, chromosome translocations, and deletions during DSB repair. Mechanistically, RAP80 prevents unscheduled nucleolytic processing of ssDNA in R-loops by CtIP. This mechanism promotes efficient DSB repair via transcription-associated end joining dependent on BRCA1, Polθ, and LIG1/3. Thus, RAP80 suppresses the vulnerability of R-loops during DSB repair, thereby precluding genomic abnormalities in a critical component of the genome caused by deleterious R-loop processing.