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Phosphorylation-dependent WRN-RPA interaction promotes recovery of stalled forks at secondary DNA structure

Author

Listed:
  • Alessandro Noto

    (Istituto Superiore di Sanità
    IRCCS Regina Elena National Cancer Institute)

  • Pasquale Valenzisi

    (Istituto Superiore di Sanità)

  • Flavia Feo

    (Istituto Superiore di Sanità)

  • Federica Fratini

    (Istituto Superiore di Sanità)

  • Tomasz Kulikowicz

    (NIH)

  • Joshua A. Sommers

    (NIH)

  • Benedetta Perdichizzi

    (Istituto Superiore di Sanità)

  • Maurizio Semproni

    (Istituto Superiore di Sanità)

  • Valentina Palermo

    (Istituto Superiore di Sanità)

  • Marco Crescenzi

    (Istituto Superiore di Sanità)

  • Robert M. Brosh Jr

    (NIH)

  • Annapaola Franchitto

    (Istituto Superiore di Sanità)

  • Pietro Pichierri

    (Istituto Superiore di Sanità
    Viale delle Medaglie d’Oro)

Abstract

The WRN protein is vital for managing perturbed replication forks. Replication Protein A strongly enhances WRN helicase activity in specific in vitro assays. However, the in vivo significance of RPA binding to WRN has largely remained unexplored. We identify several conserved phosphorylation sites in the acidic domain of WRN targeted by Casein Kinase 2. These phosphorylation sites are crucial for WRN-RPA interaction. Using an unphosphorylable WRN mutant, which lacks the ability to bind RPA, we determine that the WRN-RPA complex plays a critical role in fork recovery after replication stress countering the persistence of G4 structures after fork stalling. However, the interaction between WRN and RPA is not necessary for the processing of replication forks when they collapse. The absence of WRN-RPA binding hampers fork recovery, causing single-strand DNA gaps, enlarged by MRE11, and triggering MUS81-dependent double-strand breaks, which require repair by RAD51 to prevent excessive DNA damage.

Suggested Citation

  • Alessandro Noto & Pasquale Valenzisi & Flavia Feo & Federica Fratini & Tomasz Kulikowicz & Joshua A. Sommers & Benedetta Perdichizzi & Maurizio Semproni & Valentina Palermo & Marco Crescenzi & Robert , 2025. "Phosphorylation-dependent WRN-RPA interaction promotes recovery of stalled forks at secondary DNA structure," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55958-z
    DOI: 10.1038/s41467-025-55958-z
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