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The RAD9–RAD1–HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling

Oncogene volume 31, pages 2809–2823 (2012)Cite this article

Abstract

The WRN protein belongs to the RecQ family of DNA helicases and is implicated in replication fork restart, but how its function is regulated remains unknown. We show that WRN interacts with the 9.1.1 complex, one of the central factors of the replication checkpoint. This interaction is mediated by the binding of the RAD1 subunit to the N-terminal region of WRN and is instrumental for WRN relocalization in nuclear foci and its phosphorylation in response to replication arrest. We also find that ATR-dependent WRN phosphorylation depends on TopBP1, which is recruited by the 9.1.1 complex in response to replication arrest. Finally, we provide evidence for a cooperation between WRN and 9.1.1 complex in preventing accumulation of DNA breakage and maintaining genome integrity at naturally occurring replication fork stalling sites. Taken together, our data unveil a novel functional interplay between WRN helicase and the replication checkpoint, contributing to shed light into the molecular mechanism underlying the response to replication fork arrest.

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Acknowledgements

We are grateful to Drs L Comai and M Lalle for providing recombinant proteins and Drs D Toniolo and M Rocchi for providing BACs for FISH analysis. This work was supported by Fondazione Telethon to PP (Grant no. GGP04094) and, in part, by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) to PP (Grant no. IG9294) and AF (Grant no. IG4400).

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  1. L Cignolo

    Present address: 2Current address: Sanford-Burnham Medical Research Institute, San Diego, CA, USA,

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  1. Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy

    P Pichierri, S Nicolai, L Cignolo, M Bignami & A Franchitto

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Correspondence to P Pichierri.

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Pichierri, P., Nicolai, S., Cignolo, L. et al. The RAD9–RAD1–HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling. Oncogene 31, 2809–2823 (2012). https://doi.org/10.1038/onc.2011.468

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