TRF1 relies on fork reversal to prevent fragility at human telomeres

Mélina Vaurs, Eloïse Claude, Elia Zanella, Joana Rodrigues, Joe Nassour, Jan Karlseder, Claus M. Azzalin, Ylli Doksani and Anabelle Decottignies ()
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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
Jan Karlseder: Salk Institute for Biological Studies
Claus M. Azzalin: GIMM - Gulbenkian Institute for Molecular Medicine
Ylli Doksani: IFOM ETS - The AIRC Institute of Molecular Oncology
Anabelle Decottignies: UCLouvain

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61828-5

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