Department of Radiation Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Nucleic Acids Res. 2019 Jul 9;47(12):6236-6249. doi: 10.1093/nar/gkz263.
The tumor suppressor protein 53BP1 plays key roles in response to DNA double-strand breaks (DSBs) by serving as a master scaffold at the damaged chromatin. Current evidence indicates that 53BP1 assembles a cohort of DNA damage response (DDR) factors to distinctly execute its repertoire of DSB responses, including checkpoint activation and non-homologous end joining (NHEJ) repair. Here, we have uncovered LC8 (a.k.a. DYNLL1) as an important 53BP1 effector. We found that LC8 accumulates at laser-induced DNA damage tracks in a 53BP1-dependent manner and requires the canonical H2AX-MDC1-RNF8-RNF168 signal transduction cascade. Accordingly, genetic inactivation of LC8 or its interaction with 53BP1 resulted in checkpoint defects. Importantly, loss of LC8 alleviated the hypersensitivity of BRCA1-depleted cells to ionizing radiation and PARP inhibition, highlighting the 53BP1-LC8 module in counteracting BRCA1-dependent functions in the DDR. Together, these data establish LC8 as an important mediator of a subset of 53BP1-dependent DSB responses.
肿瘤抑制蛋白 53BP1 在应对 DNA 双链断裂（DSBs）方面发挥着关键作用，它作为损伤染色质上的主要支架。目前的证据表明，53BP1 组装了一组 DNA 损伤反应（DDR）因子，以独特地执行其 DSB 反应谱，包括检查点激活和非同源末端连接（NHEJ）修复。在这里，我们发现 LC8（又名 DYNLL1）是 53BP1 的一个重要效应因子。我们发现 LC8 以依赖于 53BP1 的方式在激光诱导的 DNA 损伤轨迹中积累，并需要经典的 H2AX-MDC1-RNF8-RNF168 信号转导级联。因此，LC8 的遗传失活或与 53BP1 的相互作用导致检查点缺陷。重要的是，LC8 的缺失减轻了 BRCA1 缺失细胞对电离辐射和 PARP 抑制的敏感性，突出了 53BP1-LC8 模块在对抗 DDR 中 BRCA1 依赖性功能方面的作用。总之，这些数据确立了 LC8 作为 53BP1 依赖性 DSB 反应的一个重要介质。
