Restriction of Ku translocation protects telomere ends

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-07-24 DOI:10.1038/s41467-025-61864-1

Stefano Mattarocci, Sonia Baconnais, Florian Roisné-Hamelin, Sabrina Pobiega, Olivier Alibert, Vincent Morin, Alice Deshayes, Xavier Veaute, Virginie Ropars, Maelenn Chevreuil, Johannes Mehringer, Didier Busso, Gerard Mazon, Paloma Fernandez Varela, Éric Le Cam, Jean-Baptiste Charbonnier, Philippe Cuniasse, Stéphane Marcand

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Abstract

Safeguarding chromosome ends against fusions via nonhomologous end joining (NHEJ) is essential for genome integrity. Paradoxically, the conserved NHEJ core factor Ku binds telomere ends. How it is prevented from promoting NHEJ remains unclear, as does the mechanism that allows Ku to coexist with telomere-protective DNA binding proteins, Rap1 in Saccharomyces cerevisiae. Here, we find that Rap1 directly inhibits Ku’s NHEJ function at telomeres. A single Rap1 molecule near a double-stand break suppresses NHEJ without displacing Ku in cells. Furthermore, Rap1 and Ku form a complex on short DNA duplexes in vitro. Cryo-EM shows Rap1 blocks Ku’s inward translocation on DNA – an essential step for NHEJ at DSBs. Nanopore sequencing of telomere fusions confirms this mechanism protects native telomere ends. These findings uncover a telomere protection mechanism where Rap1 restricts Ku’s inward translocation. This switches Ku from a repair-promoting to a protective role preventing NHEJ at telomeres.

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限制Ku易位保护端粒末端

通过非同源末端连接（NHEJ）保护染色体末端免受融合对基因组完整性至关重要。矛盾的是，保守的NHEJ核心因子Ku结合端粒末端。它是如何被阻止促进NHEJ的仍不清楚，就像在酿酒酵母中允许Ku与端粒保护DNA结合蛋白Rap1共存的机制一样。在这里，我们发现Rap1直接抑制Ku的端粒NHEJ功能。靠近双支架断裂的单个Rap1分子抑制NHEJ而不取代细胞中的Ku。此外，Rap1和Ku在体外形成短DNA双链复合体。Cryo-EM显示Rap1阻断Ku在DNA上的向内易位-这是NHEJ在dsb上的重要步骤。端粒融合的纳米孔测序证实了这种机制保护原生端粒末端。这些发现揭示了Rap1限制Ku向内移位的端粒保护机制。这将Ku从促进修复转变为防止端粒NHEJ的保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.