Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nat Struct Mol Biol. 2023 Oct;30(10):1456-1467. doi: 10.1038/s41594-023-01074-9. Epub 2023 Sep 11.
The extent and efficacy of DNA end resection at DNA double-strand breaks (DSB) determine the repair pathway choice. Here we describe how the 53BP1-associated protein DYNLL1 works in tandem with the Shieldin complex to protect DNA ends. DYNLL1 is recruited to DSBs by 53BP1, where it limits end resection by binding and disrupting the MRE11 dimer. The Shieldin complex is recruited to a fraction of 53BP1-positive DSBs hours after DYNLL1, predominantly in G1 cells. Shieldin localization to DSBs depends on MRE11 activity and is regulated by the interaction of DYNLL1 with MRE11. BRCA1-deficient cells rendered resistant to PARP inhibitors by the loss of Shieldin proteins can be resensitized by the constitutive association of DYNLL1 with MRE11. These results define the temporal and functional dynamics of the 53BP1-centric DNA end resection factors in cells.
DNA 双链断裂 (DSB) 处 DNA 末端切除的程度和效率决定了修复途径的选择。在这里，我们描述了 53BP1 相关蛋白 DYNLL1 如何与 Shieldin 复合物协同作用来保护 DNA 末端。DYNLL1 通过与 53BP1 结合来募集到 DSB 处，在那里通过结合和破坏 MRE11 二聚体来限制末端切除。Shieldin 复合物在 DYNLL1 数小时后被募集到一小部分 53BP1 阳性 DSB 处，主要在 G1 细胞中。Shieldin 定位于 DSB 处依赖于 MRE11 的活性，并受到 DYNLL1 与 MRE11 相互作用的调节。BRCA1 缺陷细胞通过 Shieldin 蛋白的缺失对 PARP 抑制剂产生抗性，通过 DYNLL1 与 MRE11 的组成性结合可以重新敏感化。这些结果定义了细胞中以 53BP1 为中心的 DNA 末端切除因子的时间和功能动态。
