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.

DNA 双链断裂 (DSB) 会触发附近转录的短暂暂停，这是一种新兴的 ATM 依赖性反应，可抑制染色体不稳定。我们筛选了一个化学文库，旨在针对人类激酶组进行介导 DSB 侧翼染色质基因沉默的新活性，并发现 DYRK1B 激酶是 DNA 损伤的早期反应物。我们发现 DYRK1B 被快速且短暂地募集到激光微照射位点，并且 DYRK1B 或其激酶活性的基因失活减弱了 DSB 诱导的基因沉默并导致 DNA 修复受损。值得注意的是，全局转录关闭减轻了与 DYRK1B 丢失相关的 DNA 修复缺陷，这表明 DYRK1B 是活性染色质 DSB 修复所严格需要的。我们还发现 DYRK1B 部分通过磷酸化和强制组蛋白甲基转移酶 EHMT2 的 DSB 积累来介导转录沉默。总之，我们的研究结果揭示了 DYRK1B 信号网络作为哺乳动物 DNA 损伤反应电路的关键分支，并将 DYRK1B-EHMT2 轴确立为协调转录染色质 DSB 修复的效应器。