Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science, and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain; Department of Biochemistry and Molecular Biology. University of Barcelona, 08028 Barcelona, Spain.
Cell Rep. 2022 Oct 25;41(4):111526. doi: 10.1016/j.celrep.2022.111526.
Tudor-interacting repair regulator (TIRR) is an RNA-binding protein and a negative regulator of the DNA-repair factor p53-binding protein 1 (53BP1). In non-damage conditions, TIRR is bound to 53BP1. After DNA damage, TIRR and 53BP1 dissociate, and 53BP1 binds the chromatin at the double-strand break (DSB) to promote non-homologous end joining (NHEJ)-mediated repair. However, the exact mechanistic details of this dissociation after damage are unknown. Increasing evidence has implicated RNA as a crucial factor in the DNA damage response (DDR). Here, we show that RNA can separate TIRR/53BP1. Specifically, RNA with a hairpin secondary structure, transcribed at the DSB by RNA polymerase II (RNAPII), promotes TIRR/53BP1 complex separation. This hairpin RNA binds to the same residues on TIRR as 53BP1. Our results uncover a role of DNA-damage-derived RNA in modulating a protein-protein interaction and contribute to our understanding of DSB repair.
Tudor 相互作用修复调节因子（TIRR）是一种 RNA 结合蛋白，也是 DNA 修复因子 p53 结合蛋白 1（53BP1）的负调节剂。在非损伤条件下，TIRR 与 53BP1 结合。在 DNA 损伤后，TIRR 和 53BP1 解离，53BP1 结合双链断裂（DSB）处的染色质，以促进非同源末端连接（NHEJ）介导的修复。然而，损伤后这种解离的确切机制细节尚不清楚。越来越多的证据表明 RNA 是 DNA 损伤反应（DDR）的关键因素。在这里，我们表明 RNA 可以分离 TIRR/53BP1。具体而言，由 RNA 聚合酶 II（RNAPII）在 DSB 处转录的具有发夹二级结构的 RNA 促进 TIRR/53BP1 复合物分离。这种发夹 RNA 与 53BP1 结合在 TIRR 上的相同残基上。我们的结果揭示了 DNA 损伤衍生 RNA 在调节蛋白质-蛋白质相互作用中的作用，并有助于我们理解 DSB 修复。
