In order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage- and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation. Indeed, we described how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events, but increases the sensitivity to DNA damaging agents if the expression is maintained long-term.

中文翻译：

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CtIP 介导的选择性 mRNA 剪接微调 DNA 损伤反应


为了在 DNA 损伤剂的暴露下生存，细胞激活了协调细胞代谢、细胞周期进程和 DNA 修复的复杂反应。在许多其他事件中，最近的证据描述了用基因毒性剂处理的细胞中 mRNA 剪接的整体变化。在这里，我们进一步探讨了这种 DNA 损伤依赖性选择性剪接。事实上，我们发现剪接因子 SF3B2 和修复蛋白 CtIP 都有助于在经过或未经过 DNA 损伤剂处理的细胞中的整体剪接模式。此外，我们关注解旋酶 PIF1 的特定 DNA 损伤和 CtIP 依赖​​性选择性剪接事件，并探讨其与暴露于电离辐射后细胞存活的相关性。事实上，我们描述了 PIF1 的核活性形式如何被称为 vPIF1 的剪接变体取代，其方式需要同时存在 DNA 损伤和 CtIP。有趣的是，vPIF1 的及时表达对于暴露于 DNA 损伤剂时获得最佳生存是必需的，但该亚型的早期表达会延迟 DNA 损伤反应的早期事件。相反，全长 PIF1 的表达促进了这些早期事件，但如果长期维持表达，则会增加对 DNA 损伤剂的敏感性。