Transcriptional Regulation at DNA Double-Strand Break Sites:
A Spotlight on Lysine Crotonylation

Double‐strand breaks (DSBs) at the vicinity of transcriptionally active genes trigger rapid and transient transcriptional silencing. Previously, we showed that CDYL1 is recruited to DNA double-strand breaks (DSBs) to promote homologous recombination (HR) repair and foster transcriptional silencing. Yet, how CDYL1 elicits DSB-induced silencing is not fully understood. Recently, we identified a CDYL1-dependent local decrease in the transcriptionally active marks lysine crotonylation (PanKcr) and crotonylated histone residue H3K9cr at AsiSI-induced DSBs, which correlates with transcriptional silencing. Mechanistically, we revealed that CDYL1 crotonyl-CoA hydratase activity counteracts PanKcr and H3K9cr at AsiSI sites and triggers the eviction of the transcriptional elongation factor ENL to foster transcriptional silencing. Furthermore, genetic inhibition of CDYL1 hydratase activity blocks the reduction in H3K9cr and alleviates DSB-induced silencing, while HR efficiency unexpectedly remains intact. Therefore, our results functionally uncouple the repair and silencing activity of CDYL1 at DSBs. In a broader context, we addressed a long-standing question concerning the crosstalk between HR and DSB-induced transcriptional silencing, suggesting that they are functionally uncoupled and may occur independently.