Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
Mol Cell. 2022 May 19;82(10):1940-1955.e7. doi: 10.1016/j.molcel.2022.03.031. Epub 2022 Apr 20.
Previously, we showed that CDYL1 is recruited to DNA double-strand breaks (DSBs) to promote homologous recombination (HR) repair and foster transcriptional silencing. However, how CDYL1 elicits DSB-induced silencing is not fully understood. Here, we identify a CDYL1-dependent local decrease in the transcriptionally active marks histone lysine crotonylation (Kcr) and crotonylated lysine 9 of H3 (H3K9cr) at AsiSI-induced DSBs, which correlates with transcriptional silencing. Mechanistically, we reveal that CDYL1 crotonyl-CoA hydratase activity counteracts Kcr and H3K9cr at DSB sites, which triggers the eviction of the transcription elongation factor ENL and fosters transcriptional silencing. Furthermore, genetic inhibition of CDYL1 hydratase activity blocks the reduction in H3K9cr and alleviates DSB-induced silencing, whereas HR efficiency unexpectedly remains intact. Therefore, our results functionally uncouple the repair and silencing activity of CDYL1 at DSBs. In a broader context, we address a long-standing question concerning the functional relationship between HR repair and DSB-induced silencing, suggesting that they may occur independently.
先前，我们表明 CDYL1 被募集到 DNA 双链断裂（DSBs）处以促进同源重组（HR）修复并促进转录沉默。然而，CDYL1 如何引发 DSB 诱导的沉默尚不完全清楚。在这里，我们发现 CDYL1 依赖性的 AsiSI 诱导的 DSB 处转录活性标记组蛋白赖氨酸巴豆酰化（Kcr）和 H3 巴豆酰化赖氨酸 9（H3K9cr）的局部减少与转录沉默相关。从机制上讲，我们揭示了 CDYL1 巴豆酰 CoA 水合酶活性在 DSB 位点拮抗 Kcr 和 H3K9cr，从而触发转录延伸因子 ENL 的驱逐并促进转录沉默。此外，CDYL1 水合酶活性的遗传抑制会阻止 H3K9cr 的减少并减轻 DSB 诱导的沉默，而 HR 效率出人意料地保持完整。因此，我们的结果从功能上解耦了 DSB 处 CDYL1 的修复和沉默活性。在更广泛的背景下，我们解决了关于 HR 修复和 DSB 诱导的沉默之间功能关系的一个长期存在的问题，表明它们可能独立发生。
