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Restriction of Ku translocation protects telomere ends

Author

Listed:
  • 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)

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.

Suggested Citation

  • Stefano Mattarocci & Sonia Baconnais & Florian Roisné-Hamelin & Sabrina Pobiega & Olivier Alibert & Vincent Morin & Alice Deshayes & Xavier Veaute & Virginie Ropars & Maelenn Chevreuil & Johannes Mehr, 2025. "Restriction of Ku translocation protects telomere ends," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61864-1
    DOI: 10.1038/s41467-025-61864-1
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