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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 29; pp. 17019 - 17030
• Main Authors: Dong, Chao, West, Kirk L., Tan, Xin Yi, Li, Junshi, Ishibashi, Toyotaka, Yu, Cheng-han, Sy, Shirley M. H., Leung, Justin W. C., Huen, Michael S. Y.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21-07-2020
• Subjects: Biological Sciences; Cell Line, Tumor; Chromatin; Chromatin - genetics; Chromatin - metabolism; Damage; Deactivation; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA repair; DNA Repair - genetics; Double-strand break repair; Dyrk Kinases; Gene Silencing; Genomic instability; Histocompatibility Antigens - genetics; Histocompatibility Antigens - metabolism; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Inactivation; Kinases; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Repair; Shutdowns; Transcription, Genetic - genetics; DYRK1B; transcription; DNA double-strand breaks; DNA repair; DNA damage
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2002193117

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.