2. Academic Validation
  3. Screen identifies DYRK1B network as mediator of transcription repression on damaged chromatin

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

  • Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17019-17030. doi: 10.1073/pnas.2002193117.
Chao Dong 1,  Kirk L West 2,  Xin Yi Tan 1,  Junshi Li 1,  Toyotaka Ishibashi 3,  Cheng-Han Yu 1,  Shirley M H Sy 1,  Justin W C Leung 4,  Michael S Y Huen 5 6
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 2 Department of Radiation Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
  • 3 Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, NT, Hong Kong SAR, China.
  • 4 Department of Radiation Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205; [email protected] [email protected].
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; [email protected] [email protected].
  • 6 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
PMID: 32611815 DOI: 10.1073/pnas.2002193117
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.

Keywords

DNA damage; DNA double-strand breaks; DNA repair; DYRK1B; transcription.

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