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TRF1 relies on fork reversal to prevent fragility at human telomeres

Author

Listed:
  • Mélina Vaurs

    (UCLouvain)

  • Eloïse Claude

    (UCLouvain)

  • Elia Zanella

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Joana Rodrigues

    (GIMM - Gulbenkian Institute for Molecular Medicine)

  • Joe Nassour

    (Salk Institute for Biological Studies
    School of Medicine)

  • Jan Karlseder

    (Salk Institute for Biological Studies)

  • Claus M. Azzalin

    (GIMM - Gulbenkian Institute for Molecular Medicine
    Faculdade de Medicina da Universidade de Lisboa)

  • Ylli Doksani

    (IFOM ETS - The AIRC Institute of Molecular Oncology)

  • Anabelle Decottignies

    (UCLouvain)

Abstract

Telomeres pose challenges during replication, with converging forks unlikely to resolve issues. Depleting TRF1 results in fragile telomeres, yet its exact role in telomere replication remains unclear. In our cellular model, insufficient TRF1 density at long telomeres leads to telomere fragility that is alleviated by restoring telomeric TRF1 levels. Our findings indicate that TRF1 mitigates lagging strand telomere fragility through fork reversal in a process involving telomerase activity, rather than merely alleviating fork barriers. Additionally, TFIIH, a crucial partner of TRF1, aids in restarting replication on the leading strand after fork reversal. When fork reversal is compromised, PrimPol-mediated repriming rescues fragility at leading strand telomeres, revealing a new role for this enzyme in human telomere replication. Lastly, our findings indicate that the TRF1-mediated decrease in telomere fragility is dependent on RNA:DNA hybrids, likely facilitating fork restart.

Suggested Citation

  • Mélina Vaurs & Eloïse Claude & Elia Zanella & Joana Rodrigues & Joe Nassour & Jan Karlseder & Claus M. Azzalin & Ylli Doksani & Anabelle Decottignies, 2025. "TRF1 relies on fork reversal to prevent fragility at human telomeres," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61828-5
    DOI: 10.1038/s41467-025-61828-5
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    References listed on IDEAS

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