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限制Ku易位可保护端粒末端。

Restriction of Ku translocation protects telomere ends.

作者信息

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

机构信息

Université Paris-Saclay, Université Paris Cité, CEA, Inserm, Institut de biologie François Jacob, UMR Stabilité Génétique Cellules Souches et Radiations, Fontenay-aux-Roses, France.

Genome Integrity and Cancer, UMR 9019 CNRS, Université Paris-Saclay, Gustave Roussy, Villejuif, France.

出版信息

Nat Commun. 2025 Jul 24;16(1):6824. doi: 10.1038/s41467-025-61864-1.

DOI:10.1038/s41467-025-61864-1
PMID:40707444
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12289973/
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.

摘要

通过非同源末端连接（NHEJ）保护染色体末端不发生融合对于基因组完整性至关重要。矛盾的是，保守的NHEJ核心因子Ku会结合端粒末端。目前尚不清楚它是如何被阻止促进NHEJ的，与Ku如何与端粒保护DNA结合蛋白（酿酒酵母中的Rap1）共存的机制一样不清楚。在这里，我们发现Rap1直接抑制Ku在端粒处的NHEJ功能。双链断裂附近的单个Rap1分子可抑制NHEJ，而不会在细胞中取代Ku。此外，Rap1和Ku在体外短DNA双链体上形成复合物。冷冻电镜显示Rap1会阻止Ku在DNA上向内移位——这是DSB处NHEJ的关键步骤。端粒融合的纳米孔测序证实了这种机制可保护天然端粒末端。这些发现揭示了一种端粒保护机制，其中Rap1限制了Ku的向内移位。这将Ku从促进修复的角色转变为防止端粒处NHEJ的保护角色。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/451209f1deb6/41467_2025_61864_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/d977267f2f92/41467_2025_61864_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/5061fed8bd7a/41467_2025_61864_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/5454a163bbbe/41467_2025_61864_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/77fc0fb76ff0/41467_2025_61864_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/451209f1deb6/41467_2025_61864_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/d977267f2f92/41467_2025_61864_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/5061fed8bd7a/41467_2025_61864_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/5454a163bbbe/41467_2025_61864_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/77fc0fb76ff0/41467_2025_61864_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5280/12289973/451209f1deb6/41467_2025_61864_Fig5_HTML.jpg

相似文献

[1]
Restriction of Ku translocation protects telomere ends.

Nat Commun. 2025-7-24

[2]
Ku DNA End-Binding Activity Promotes Repair Fidelity and Influences End-Processing During Nonhomologous End-Joining in .

Genetics. 2018-3-2

[3]
Chromosome end protection by RAP1-mediated inhibition of DNA-PK.

Nature. 2025-4-16

[4]
Comparison of Telomere Structure in Eukaryotes.

Arch Razi Inst. 2024-12-31

[5]
Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends.

Genes Dev. 2003-10-1

[6]
Ku Binding on Telomeres Occurs at Sites Distal from the Physical Chromosome Ends.

PLoS Genet. 2016-12-8

[7]
TRF2 interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres.

Cell Rep. 2013-10-3

[8]
Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in .

Elife. 2022-1-19

[9]
Rap1 prevents telomere fusions by nonhomologous end joining.

EMBO J. 2005-9-7

[10]
Ccq1 restrains Mre11-mediated degradation to distinguish short telomeres from double-strand breaks.

Nucleic Acids Res. 2024-4-24

本文引用的文献

[1]
Telomeres stall DNA loop extrusion by condensin.

Cell Rep. 2025-7-22

[2]
Chromosome end protection by RAP1-mediated inhibition of DNA-PK.

Nature. 2025-4-16

[3]
Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres.

Nucleic Acids Res. 2024-7-22

[4]
DNA-PK and the TRF2 iDDR inhibit MRN-initiated resection at leading-end telomeres.

Nat Struct Mol Biol. 2023-9

[5]
Human POT1 protects the telomeric ds-ss DNA junction by capping the 5' end of the chromosome.

Science. 2023-8-18

[6]
Homology directed telomere clustering, ultrabright telomere formation and nuclear envelope rupture in cells lacking TRF2 and RAP1.

Nat Commun. 2023-4-14

[7]
Cryo-EM of NHEJ supercomplexes provides insights into DNA repair.

Mol Cell. 2021-8-19

[8]
Inhibition of MRN activity by a telomere protein motif.

Nat Commun. 2021-6-22

[9]
A new assay capturing chromosome fusions shows a protection trade-off at telomeres and NHEJ vulnerability to low-density ionizing radiation.

Nucleic Acids Res. 2021-7-9

[10]
Budding yeast Rap1, but not telomeric DNA, is inhibitory for multiple stages of DNA replication in vitro.

Nucleic Acids Res. 2021-6-4

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