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  • Original Paper
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Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle

Oncogene volume 22, pages 1491–1500 (2003)Cite this article

Abstract

Werner's syndrome (WS) is an autosomal recessive disorder, characterized at the cellular level by genomic instability in the form of variegated translocation mosaicism and extensive deletions. Individuals with WS prematurely develop multiple age-related pathologies and exhibit increased incidence of cancer. WRN, the gene defective in WS, encodes a 160-kDa protein (WRN), which has 3′–5′exonuclease, DNA helicase and DNA-dependent ATPase activities. WRN-defective cells are hypersensitive to certain genotoxic agents that cause replication arrest and/or double-strand breaks at the replication fork, suggesting a pivotal role for WRN in the protection of the integrity of the genoma during the DNA replication process. Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage. However, we provide evidence that WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Finally, we show that WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase.

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Acknowledgements

The revision of the English of this manuscript by Mrs EM Lea is gratefully acknowledged. We thank Drs S Handeli and SL Schreiber for providing the cells expressing the wild-type and kinase-inactive form of ATR. We also thank the two anonymous reviewers who contributed to improve this manuscript. This work was partially supported by a MURST grant for young researchers and by a CNRS/EGIDE post-doc fellowship to PP.

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  1. CNRS, UPR2169 ‘Genetic Instability and Cancer’, Institut Gustave Roussy, 39 Rue Camille Desmoulins 94805 Villejuif, France

    Pietro Pichierri, Filippo Rosselli & Annapaola Franchitto

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  1. Pietro Pichierri
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Correspondence to Annapaola Franchitto.

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Pichierri, P., Rosselli, F. & Franchitto, A. Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Oncogene 22, 1491–1500 (2003). https://doi.org/10.1038/sj.onc.1206169

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