Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Cell Rep. 2022 Feb 1;38(5):110335. doi: 10.1016/j.celrep.2022.110335.
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.
单链 DNA（ssDNA）作为 DNA 上细胞过程的中间产物，如果不加以适当保护，可能会对基因组造成潜在的危害。最近的证据表明，由 ssDNA 和 DNA-RNA 杂交体组成的 R 环可以在转录活跃区域的 DNA 双链断裂（DSB）附近形成。然而，在 DSB 修复过程中，R 环中 ssDNA 的脆弱性如何被克服仍不清楚。在这里，我们发现 RAP80 是一种抑制因子，可抑制 DSB 修复过程中 R 环、染色体易位和缺失中 ssDNA 的脆弱性。在机制上，RAP80 通过 CtIP 防止 R 环中 ssDNA 的非调度核酶处理。该机制通过依赖于 BRCA1、Polθ 和 LIG1/3 的转录相关末端连接促进有效的 DSB 修复。因此，RAP80 抑制了 DSB 修复过程中 R 环的脆弱性，从而防止了由有害 R 环处理引起的基因组中关键成分的基因组异常。
