Shaw Annabelle, Ajit Kamal, Chataignier Manon, Gullerova Monika
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, United Kingdom.
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf517.
To protect genome integrity from pervasive threats of damage and prevent diseases like cancer, cells employ an integrated network of signalling pathways called the DNA damage response. These pathways involve both protein and RNA components, which can act within the damaged cell or be transferred intercellularly to influence population-wide responses to damage. Here, we show that radioprotection can be conferred by damage-derived exosomes and is dependent on YBX1-packaged Y3-derived ysRNA. In recipient cells, ysRNAs are methylated on cytosine and bound by m5C reader, YBX1. YBX1/ysRNA localise at double strand break (DSB) sites to promote efficient DNA repair and cell survival through complex formation with PARP1. YBX1 modulates PARP1 auto-modification by facilitating ysRNA ADP-ribosylation, promoting increased PARP1 residency at DSBs. Our data highlight an unprecedented role for these under-studied species of small non-coding RNAs, identifying them as a novel substrate for PARP1 mediated ADP-ribosylation with a function in DNA repair.
为保护基因组完整性免受广泛的损伤威胁并预防癌症等疾病，细胞采用了一个名为DNA损伤反应的信号通路整合网络。这些通路涉及蛋白质和RNA成分，它们可在受损细胞内发挥作用，或在细胞间传递以影响群体对损伤的反应。在这里，我们表明损伤来源的外泌体可赋予辐射防护作用，且依赖于YBX1包装的Y3衍生的ysRNA。在受体细胞中，ysRNAs在胞嘧啶上发生甲基化，并被m5C阅读器YBX1结合。YBX1/ysRNA定位于双链断裂（DSB）位点，通过与PARP1形成复合物来促进有效的DNA修复和细胞存活。YBX1通过促进ysRNA的ADP核糖基化来调节PARP1的自身修饰，从而促进PARP1在DSBs处的驻留增加。我们的数据突出了这些研究不足的小非编码RNA物种的前所未有的作用，将它们鉴定为PARP1介导的ADP核糖基化的新底物，具有DNA修复功能。
