DYRK1B Promotes Transcription Silencing on the Damaged Chromatin to Facilitate DSB Repair

Abstract

DNA double-strand breaks (DSBs) induce transient pausing of transcription on flanking chromatin. Although this phenomenon is driven by ATM and poly (ADP-ribose) polymerase activities, the molecular determinants that couple transcriptional silencing and DNA repair remain unclear. Here, we have isolated the DYRK1B kinase as a new component of the mammalian DNA Damage Response (DDR). Consistent with a role in the DDR, we found that the DYRK1B kinase is rapidly and transiently recruited to laser-induced DNA damage tracks in a PARPdependent manner. Interestingly, DYRK1B is preferentially recruited to DSBs on transcriptionally-active chromatin, where it suppresses nascent transcription at the local chromatin. Moreover, genetic inactivation or chemical inhibition of DYRK1B attenuated DSBassociated H2A ubiquitylation, and led to sustained RNAPII activity at the DSB-flanking chromatin. Finally, DYRK1B-deficient cells exhibited DSB repair defects that can be alleviated by cell pre-treatment with transcription inhibitor, suggesting that DYRK1B promotes transcriptional silencing at damaged chromatin to facilitate DSB repair. Our findings add the DYRK1B kinase to the emerging DDR network, and implicate DYRK1B kinase in promoting the tempo-spatially coupling of DSB repair at transcriptionally active chromatin.