Functional Mapping of Lysine Crotonylation at DNA Double‐Strand Break sites

Abstract

Mounting evidence demonstrates that unprogrammed double-strand breaks (DSBs) at the vicinity of transcriptionally active genes trigger rapid and transient transcriptional silencing. Recently, we have identified three novel factors that ensure DSB-induced transcriptional silencing (reviewed in [1]). Among these factors is the chromodomain Y-like (CDYL1) transcription repressor which fosters DSB-induced transcriptional silencing and promotes homology-directed repair (HDR) of DSBs [2]. In addition, we have recently demonstrated that the levels of histone lysine crotonylation, primarily associated with active transcription, are locally reduced at DNA breakage sites. However, the physiological function of this decrease remains unknown [3]. In this meeting, I will present unpublished data comprising of high-resolution ChIP-seq mapping of lysine crotonylation surrounding DSB sites. We showed that CDYL1 is recruited to DSBs and catalyzes the local reduction in lysine crotonylation at DSBs to foster transcriptional silencing. Unexpectedly, while inhibiting the reduction in lysine crotonylation at DSB sites alleviates transcriptional silencing, the integrity of HDR of DSBs remains intact. Our results uncoupled therefore the repair and the silencing activity of CDYL1 at DSBs. In a broader context, our data addresses a long-standing question in the field concerning the functional relationship between HDR and DSB-induced transcriptional silencing and suggest that they may occur independently.