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

Alessandro Noto, Pasquale Valenzisi, Flavia Feo, Federica Fratini, Tomasz Kulikowicz, Joshua A. Sommers, Benedetta Perdichizzi, Maurizio Semproni, Valentina Palermo, Marco Crescenzi, Robert M. Brosh, Annapaola Franchitto () and Pietro Pichierri ()
Additional contact information
Alessandro Noto: Istituto Superiore di Sanità
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: NIH
Annapaola Franchitto: Istituto Superiore di Sanità
Pietro Pichierri: Istituto Superiore di Sanità

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55958-z

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