Biophysics Department, Faculty of Science, Cairo University, 12613 Giza, Egypt; Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
Cell Rep. 2022 Mar 22;38(12):110536. doi: 10.1016/j.celrep.2022.110536.
BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.
BMI-1 是发育过程中转录沉默的重要调节因子。最近，BMI-1 在 DNA 损伤反应中的作用引起了广泛关注，但 BMI-1 参与该过程的确切机制尚不清楚。在这里，我们确立了 BMI-1 在同源重组（HR）修复 DNA 双链断裂中的作用，它促进 DNA 末端切除。在机制上，BMI-1 通过促进 CtIP 的募集来介导 DNA 末端切除，从而允许 RPA 和 RAD51 在 DNA 损伤部位积累。有趣的是，转录抑制剂的处理挽救了 BMI-1 耗尽细胞的 DNA 末端切除缺陷，这表明 BMI-1 依赖的转录沉默介导 DNA 末端切除。此外，我们发现 H2A 在 K119 上的泛素化（H2AK119ub）促进末端切除。总之，我们的结果确定了 BMI-1 介导的转录沉默和促进 H2AK119ub 沉积是 DNA 末端切除和 HR 进展的必要调节因子。
