DYRK1B network mediates transcriptional silencing on damaged chromatin

Abstract

DNA double-strand breaks (DSBs) are the most lethal type of DNA damage and trigger transient transcriptional silencing on the local chromatin. Although ATM, the master DNA damage response (DDR) kinase, plays an essential role in orchestrating DSB-induced transcriptional repression, the molecular determinants that regulate transcriptional silencing and DNA repair remain obscure.

In this study, I performed a chemical screen to identify protein kinases that participate in DSB-induced transcriptional repression. High-content screen led to our isolation of DYRK1B as a novel mediator of DSB-induced transcriptional silencing. Accordingly, I found that DYRK1B was rapidly and transiently recruited to laser microirradiated sites in a PARP-dependent manner. Moreover, DYRK1B deficiency or chemical inhibition of DYRK1B catalytic activity compromised transcription silencing on DSB-flanking chromatin and attenuated DNA repair. Intriguingly, I found that global transcription inhibition alleviated DYRK1B deficiency-associated DNA repair defects and genome instability, indicating DYRK1B might preferentially promote DNA repair on actively transcribed chromatin. Notably, I also uncovered that the metabolic syndrome-derived DYRK1B mutants did not complement loss of DYRK1B in promoting DSB-induced transcription silencing and in DNA repair.

In order to investigate the underlying mechanism of DYRK1B-mediated DDR, we performed phospho-proteomic profiling of DYRK1B substrates, and identified histone methyltransferase EHMT2 as a downstream target of DYRK1B. Importantly, I showed that DYRK1B promoted EHMT2 phosphorylation and its subsequent recruitment to damaged chromatin. Moreover, I found that EHMT2, in resemblance to DYRK1B and in a manner that requires its methyltransferase activity, promoted DSB-induced transcription silencing.

Taken together, the findings unveiled DYRK1B as a novel DDR factor, and that via EHMT2, promotes DSB repair on actively transcribed chromatin. The findings also shed light on the molecular regulation of transcription during DSB metabolism.