RAD51AP1 通过染色质定向 TERRA 动态平衡调节 ALT-HDR。
RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA.
机构信息
Department of Pharmacology and Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
出版信息
Mol Cell. 2022 Nov 3;82(21):4001-4017.e7. doi: 10.1016/j.molcel.2022.09.025. Epub 2022 Oct 19.
Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.
端粒的非经典延长（ALT）是一种端粒延长的同源定向修复（HDR）机制，它控制着侵袭性癌症亚群的增殖。最近的研究表明，端粒重复 RNA（TERRA）促进 ALT 相关 HDR（ALT-HDR）。在这里，我们报告说，关键的 ALT 因子 RAD51AP1 与 TERRA 相互作用，并利用它来产生 D-和 R-环 HR 中间体。我们还表明，RAD51AP1 结合并可能稳定含有 TERRA 的 R 环，因为 RAD51AP1 的耗竭会减少端粒 DNA 断裂处的 R 环形成。蛋白质组学分析揭示了 RAD51AP1 介导的 TERRA R 环动态平衡在一种染色质指导的 TERRA 抑制机制和 ALT-HDR 期间转录-复制碰撞（TRC）的预防中的作用。有趣的是，我们发现 TERRA 结合和 RAD51AP1 的这种非经典功能都需要其内在的 SUMO-SIM 调节轴。这些发现为 RAD51AP1 在 ALT 机制和 TERRA 调控中的多语境功能提供了深入了解。
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