Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.
Sir William Dunn School of Pathology, University of Oxford, South Parks Road OX1 3RE, UK.
Mol Cell. 2024 Oct 3;84(19):3610-3626. doi: 10.1016/j.molcel.2024.09.003.
Complex pathways involving the DNA damage response (DDR) contend with cell-intrinsic and -extrinsic sources of DNA damage. DDR mis-regulation results in genome instability that can contribute to aging and diseases including cancer and neurodegeneration. Recent studies have highlighted key roles for several RNA species in the DDR, including short RNAs and RNA/DNA hybrids (R-loops) at DNA break sites, all contributing to efficient DNA repair. RNAs can undergo more than 170 distinct chemical modifications. These RNA modifications have emerged as key orchestrators of the DDR. Here, we highlight the function of enzyme- and non-enzyme-induced RNA modifications in the DDR, with particular emphasis on mA, mC, and RNA editing. We also discuss stress-induced RNA damage, including RNA alkylation/oxidation, RNA-protein crosslinks, and UV-induced RNA damage. Uncovering molecular mechanisms that underpin the contribution of RNA modifications to DDR and genome stability will have direct application to disease and approaches for therapeutic intervention.
涉及 DNA 损伤反应 (DDR) 的复杂途径与细胞内在和外在的 DNA 损伤源相抗衡。DDR 调节失常会导致基因组不稳定，从而导致衰老和疾病，包括癌症和神经退行性疾病。最近的研究强调了几种 RNA 物种在 DDR 中的关键作用，包括 DNA 断裂部位的短 RNA 和 RNA/DNA 杂交体 (R 环)，它们都有助于有效的 DNA 修复。RNA 可以经历 170 多种不同的化学修饰。这些 RNA 修饰已成为 DDR 的关键协调因子。在这里，我们重点介绍酶和非酶诱导的 RNA 修饰在 DDR 中的功能，特别强调 mA、mC 和 RNA 编辑。我们还讨论了应激诱导的 RNA 损伤，包括 RNA 烷基化/氧化、RNA-蛋白质交联和 UV 诱导的 RNA 损伤。揭示 RNA 修饰对 DDR 和基因组稳定性贡献的分子机制将直接应用于疾病和治疗干预方法。
