Mre11-Rad50 oligomerization promotes DNA double-strand break repair.
Mre11-Rad50 oligomerization promotes DNA double-strand break repair.
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DOI：
10.1038/s41467-022-29841-0
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发表时间：
2022-05-02
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
保守的Mre 11-Rad 50复合物对于DNA双链断裂的检测、信号传导、末端束缚和处理至关重要。虽然已知DNA损伤处的Mre 11-Rad 50灶形成伴随修复，但潜在的分子组装机制和功能意义仍不清楚。结合电子显微镜、生化分析和遗传学研究的途径重建，我们发现S。有或没有Xrs 2的酿酒酵母Mre 11-Rad 50在溶液中和DNA上形成高阶组装体。Rad 50介导这种寡聚化，并且保守Rad 50 β折叠中的突变增强或破坏寡聚化。我们证明，Mre 11-Rad 50-Xrs 2寡聚化促进病灶形成，DNA损伤信号，修复和端粒维持在体内。Mre 11-Rad 50寡聚化不影响其核酸外切酶活性，但在双链断裂附近的5′-DNA链上的多个位点驱动核酸内切裂解。有趣的是，人类RAD 50 β折叠中的突变与遗传性癌症易感性有关，我们的研究结果可能会深入了解它们在化疗耐药性中的潜在作用。Mre 11-Rad 50（MR）复合物在DNA断裂的检测、信号传导和修复中具有关键功能。在这里，作者使用透射电子显微镜显示MR寡聚化是由一个小的β-片层从Rad 50的头部结构域在MR结构的基础上突出，并揭示MR头部结构域寡聚化是有效的DNA末端切除所必需的。
The conserved Mre11-Rad50 complex is crucial for the detection, signaling, end tethering and processing of DNA double-strand breaks. While it is known that Mre11-Rad50 foci formation at DNA lesions accompanies repair, the underlying molecular assembly mechanisms and functional implications remained unclear. Combining pathway reconstitution in electron microscopy, biochemical assays and genetic studies, we show that S. cerevisiae Mre11-Rad50 with or without Xrs2 forms higher-order assemblies in solution and on DNA. Rad50 mediates such oligomerization, and mutations in a conserved Rad50 beta-sheet enhance or disrupt oligomerization. We demonstrate that Mre11-Rad50-Xrs2 oligomerization facilitates foci formation, DNA damage signaling, repair, and telomere maintenance in vivo. Mre11-Rad50 oligomerization does not affect its exonuclease activity but drives endonucleolytic cleavage at multiple sites on the 5′-DNA strand near double-strand breaks. Interestingly, mutations in the human RAD50 beta-sheet are linked to hereditary cancer predisposition and our findings might provide insights into their potential role in chemoresistance. The Mre11-Rad50 (MR) complex has key functions in the detection, signaling and repair of DNA breaks. Here the authors use transmission electron microscopy to show MR oligomerization is governed by a small beta-sheet protruding from the head domain of Rad50 at the base of the MR structure, and reveal MR head domain oligomerization is required for efficient DNA end resection.
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