PARP inhibitors (PARPi) show selective efficacy in tumors with homologous recombination repair (HRR)-defects but the activation mechanism of HRR pathway in PARPi-treated cells remains enigmatic. To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.

中文翻译：

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PARP1-TRIM44-MRN 环决定对 PARP 抑制剂的反应


PARP 抑制剂 （PARPi） 在具有同源重组修复 （HRR） 缺陷的肿瘤中显示出选择性效力，但 HRR 通路在 PARPi 处理的细胞中的激活机制仍然是个谜。为了揭示它，我们通过筛选 211 种人类泛素相关蛋白来寻找桥接 PARP1 和 ATM 通路的介质。我们发现 TRIM44 是一种重要的介质，可将 MRN 复合物募集到受损的染色质上，与 PARP1 活性无关。TRIM44 结合 PARP1 并调节 PARP1 的泛素化-PARylation 平衡，这有助于及时募集 MRN 复合物进行 DSB 修复。暴露于 PARPi 后，TRIM44 通过其 ZnF UBP 结构域将其结合从 PARP1 转移到 MRN 复合物。在细胞中敲低 TRIM44 显着增强了对奥拉帕尼的敏感性，并克服了 53BP1 缺陷诱导的对奥拉帕尼的耐药性。这些观察结果强调了 TRIM44 在将 PARP1 拴留在 ATM 介导的修复途径中的核心作用。抑制 TRIM44 可能会提高 PARPi 的有效性，并扩大其用途，甚至扩大到精通 HR 的肿瘤。