Restriction of Ku translocation protects telomere ends

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 Cam, Jean-Baptiste Charbonnier, Philippe Cuniasse () and Stéphane Marcand ()
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Stefano Mattarocci: UMR Stabilité Génétique Cellules Souches et Radiations
Sonia Baconnais: Gustave Roussy
Florian Roisné-Hamelin: UMR Stabilité Génétique Cellules Souches et Radiations
Sabrina Pobiega: UMR Stabilité Génétique Cellules Souches et Radiations
Olivier Alibert: Université Paris-Saclay
Vincent Morin: Institute for Integrative Biology of the Cell (I2BC)
Alice Deshayes: UMR Stabilité Génétique Cellules Souches et Radiations
Xavier Veaute: UMR Stabilité Génétique Cellules Souches et Radiations
Virginie Ropars: Institute for Integrative Biology of the Cell (I2BC)
Maelenn Chevreuil: Institut Pasteur
Johannes Mehringer: Kurt-Schwabe-Institute
Didier Busso: UMR Stabilité Génétique Cellules Souches et Radiations
Gerard Mazon: Gustave Roussy
Paloma Fernandez Varela: Institute for Integrative Biology of the Cell (I2BC)
Éric Cam: Gustave Roussy
Jean-Baptiste Charbonnier: Institute for Integrative Biology of the Cell (I2BC)
Philippe Cuniasse: Institute for Integrative Biology of the Cell (I2BC)
Stéphane Marcand: UMR Stabilité Génétique Cellules Souches et Radiations

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61864-1

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