Department of Radiation and Medical Oncology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
J Cell Biol. 2021 Feb 1;220(2). doi: 10.1083/jcb.201911025.
DNA double-strand breaks (DSBs) are mainly repaired by c-NHEJ and HR pathways. The enhanced DSB mobility after DNA damage is critical for efficient DSB repair. Although microtubule dynamics have been shown to regulate DSB mobility, the reverse effect of DSBs to microtubule dynamics remains elusive. Here, we uncovered a novel DSB-induced microtubule dynamics stress response (DMSR), which promotes DSB mobility and facilitates c-NHEJ repair. DMSR is accompanied by interphase centrosome maturation, which occurs in a DNA-PK-AKT-dependent manner. Depletion of PCM proteins attenuates DMSR and the mobility of DSBs, resulting in delayed c-NHEJ. Remarkably, DMSR occurs only in G1 or G0 cells and lasts around 6 h. Both inhibition of DNA-PK and depletion of 53BP1 abolish DMSR. Taken together, our study reveals a positive DNA repair mechanism in G1 or G0 cells in which DSBs actively promote microtubule dynamics and facilitate the c-NHEJ process.
DNA 双链断裂 (DSB) 主要通过 c-NHEJ 和 HR 途径修复。DNA 损伤后 DSB 的迁移率增强对于有效修复 DSB 至关重要。虽然微管动力学已被证明可以调节 DSB 的迁移率，但 DSB 对微管动力学的反向影响仍不清楚。在这里，我们揭示了一种新的 DSB 诱导的微管动力学应激反应 (DMSR)，它促进 DSB 的迁移率并促进 c-NHEJ 修复。DMSR 伴随着有丝分裂中心体成熟，这是一种 DNA-PK-AKT 依赖性的方式。PCM 蛋白的耗竭会减弱 DMSR 和 DSB 的迁移率，导致 c-NHEJ 延迟。值得注意的是，DMSR 仅发生在 G1 或 G0 细胞中，持续约 6 小时。DNA-PK 的抑制和 53BP1 的耗竭都可以消除 DMSR。总之，我们的研究揭示了 G1 或 G0 细胞中一种积极的 DNA 修复机制，其中 DSB 主动促进微管动力学并促进 c-NHEJ 过程。
