School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R.
Department of Occupational and Environmental Health, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Nucleic Acids Res. 2024 Sep 23;52(17):10297-10310. doi: 10.1093/nar/gkae661.
Transient halting of transcription activity on the damaged chromatin facilitates DNA double-strand break (DSB) repair. However, the molecular mechanisms that facilitate transcription recovery following DSB repair remain largely undefined. Notably, failure to restore gene expression in a timely manner can compromise transcriptome signatures and may impose deleterious impacts on cell identity and cell fate. Here, we report PHF8 as the major demethylase that reverses transcriptionally repressive epigenetic modification laid down by the DYRK1B-EHMT2 pathway. We found that PHF8 concentrates at laser-induced DNA damage tracks in a DYRK1B-dependent manner and promotes timely resolution of local H3K9me2 to facilitate the resumption of transcription. Moreover, PHF8 also assists in the recovery of ribosomal DNA (rDNA) transcription following the repair of nucleolar DSBs. Taken together, our findings uncover PHF8 as a key mediator that coordinates transcription activities during the recovery phase of DSB responses.
转录活性在受损染色质上的瞬时暂停有助于 DNA 双链断裂 (DSB) 的修复。然而，在 DSB 修复后促进转录恢复的分子机制在很大程度上仍未得到明确。值得注意的是，如果不能及时恢复基因表达，可能会损害转录组特征，并可能对细胞身份和细胞命运产生有害影响。在这里，我们报告 PHF8 是主要的去甲基酶，可逆转由 DYRK1B-EHMT2 途径建立的转录抑制性表观遗传修饰。我们发现 PHF8 以 DYRK1B 依赖的方式集中在激光诱导的 DNA 损伤轨迹上，并促进局部 H3K9me2 的及时解决，以促进转录的恢复。此外，PHF8 还协助修复核仁 DSB 后核糖体 DNA (rDNA) 的转录恢复。总之，我们的研究结果揭示了 PHF8 作为一个关键的调节剂，在 DSB 反应的恢复阶段协调转录活性。
