Department of Radiation Oncology, Dana-Farber Cancer Institute , Boston, MA, USA.
Center for DNA Damage and Repair, Dana-Farber Cancer Institute , Boston, MA, USA.
Cell Cycle. 2020 Jul;19(13):1565-1575. doi: 10.1080/15384101.2020.1758435. Epub 2020 May 18.
In the past decade, the study of the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and classical non-homologous end joining (C-NHEJ), has revealed a vast and intricate network of regulation. The choice between HR and C-NHEJ is largely controlled at the step of DNA end-resection. A pro-C-NHEJ cascade commencing with 53BP1 and culminating in the newly discovered REV7-Shieldin complex impedes end resection and therefore HR. Importantly, loss of any component of this pathway confers PARP inhibitor resistance in -deficient cells; hence, their study is of great clinical importance. The newest entrant on the scene of end resection regulation is the ATPase TRIP13 that disables the pro-C-NHEJ cascade by promoting a novel conformational change of the HORMA protein REV7. Here, we tie these new findings and factors with previous research on the regulation of DSB repair and HORMA proteins, and suggest testable hypotheses for how TRIP13 could specifically inactivate REV7-Shieldin to promote HR. We also discuss these biological questions in the context of clinical therapeutics.
在过去的十年中，对主要的 DNA 双链断裂 (DSB) 修复途径、同源重组 (HR) 和经典非同源末端连接 (C-NHEJ) 的研究揭示了一个广泛而复杂的调控网络。HR 和 C-NHEJ 之间的选择在很大程度上受 DNA 末端切除步骤的控制。以 53BP1 为起始、以新发现的 REV7-Shieldin 复合物为终点的促 C-NHEJ 级联反应阻碍了末端切除，从而抑制了 HR。重要的是，该通路的任何成分缺失都会导致 -缺陷细胞对 PARP 抑制剂产生抗性；因此，它们的研究具有重要的临床意义。末端切除调控的最新参与者是 ATP 酶 TRIP13，它通过促进 HORMA 蛋白 REV7 的一种新构象改变来阻止促 C-NHEJ 级联反应。在这里，我们将这些新发现和因素与 DSB 修复和 HORMA 蛋白的先前研究联系起来，并提出了可测试的假设，即 TRIP13 如何特异性地失活 REV7-Shieldin 以促进 HR。我们还将这些生物学问题置于临床治疗学的背景下进行讨论。
