Screen identifies DYRK1B network as mediator of transcription repression on damaged chromatin

Chao Dong, Kirk L. West, Xin Yi Tan, Junshi Li, Toyotaka Ishibashi, Cheng Han Yu, Shirley M.H. Sy, Justin W.C. Leung, Michael S.Y. Huen

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

DNA double-strand breaks (DSBs) trigger transient pausing of nearby transcription, an emerging ATM-dependent response that suppresses chromosomal instability. We screened a chemical library designed to target the human kinome for new activities that mediate gene silencing on DSB-flanking chromatin, and have uncovered the DYRK1B kinase as an early respondent to DNA damage. We showed that DYRK1B is swiftly and transiently recruited to laser-microirradiated sites, and that genetic inactivation of DYRK1B or its kinase activity attenuated DSB-induced gene silencing and led to compromised DNA repair. Notably, global transcription shutdown alleviated DNA repair defects associated with DYRK1B loss, suggesting that DYRK1B is strictly required for DSB repair on active chromatin. We also found that DYRK1B mediates transcription silencing in part via phosphorylating and enforcing DSB accumulation of the histone methyltransferase EHMT2. Together, our findings unveil the DYRK1B signaling network as a key branch of mammalian DNA damage response circuitries, and establish the DYRK1B-EHMT2 axis as an effector that coordinates DSB repair on transcribed chromatin.

Original languageEnglish (US)
Pages (from-to)17019-17030
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number29
DOIs
StatePublished - Jul 21 2020
Externally publishedYes

Keywords

  • DNA damage
  • DNA double-strand breaks
  • DNA repair
  • DYRK1B
  • Transcription

ASJC Scopus subject areas

  • General

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