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The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation

Oncogene volume 32, pages 610–620 (2013)Cite this article

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Abstract

Oncogene-induced replication stress is recognized as the primary cause of accumulation of DNA damage and genome instability in precancerous cells. Although the molecular mechanisms responding to such type of replication perturbation are not fully characterized, it has been speculated that their dysfunction may enhance genome instability and accelerate tumor progression. Here, we show that the WRN protein, a member of the human RecQ helicases, is necessary to sustain replication fork progression in response to oncogene-induced replication stress. Loss of WRN affects cell cycle progression and results in enhanced accumulation of double-strand breaks and instability at common fragile sites in cells experiencing oncogene-induced replication stress. Moreover, we demonstrate that double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death. Overall, our findings give insights into the mechanisms protecting replication forks in cells experiencing oncogene-induced replication stress, and identify factors that, when mutated or dysfunctional, may enhance genome instability in precancerous cells. In addition, because concomitant depletion of WRN and MUS81 causes synthetic sickness in cells growing under oncogene-induced replication stress, our results support the possibility of targeting cancer cells with an impaired replication fork recovery pathway by a specific inactivation of the other parallel pathway.

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Acknowledgements

We are grateful to Dr Pavel Janscak for providing the siRNAs and antibody against RECQ5. We also thank Drs D Toniolo and M Rocchi for providing bacterial artificial chromosomes for FISH analysis. This work was supported by a grant from the Association for International Cancer Research (Grant 07-497) to P.P. and by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC) to P.P. (IG 9294) and A.F. (IG 4400).

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  1. I Murfuni and S Nicolai: These authors contributed equally to this work

Authors and Affiliations

  1. Section of Experimental and Computational Carcinogenesis, Istituto Superiore di Sanità, Rome, Italy

    I Murfuni, S Nicolai, M Bignami & P Pichierri

  2. Section of Molecular Epidemiology at the Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy

    S Baldari & A Franchitto

  3. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy

    M Crescenzi

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  1. I Murfuni
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Correspondence to A Franchitto or P Pichierri.

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Murfuni, I., Nicolai, S., Baldari, S. et al. The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation. Oncogene 32, 610–620 (2013). https://doi.org/10.1038/onc.2012.80

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