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Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress

Oncogene volume 32, pages 3744–3753 (2013)Cite this article

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Abstract

It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51-mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations.

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Acknowledgements

OM is supported by an EMBO Long-Term Fellowship. We thank Cancer Research UK for supporting this work financially, Dr Anastasia Zlatanou for cells and materials and Dr Agnieszka Gambus for helpful discussions.

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Author notes

  1. O Mortusewicz

    Present address: 5Current address: Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Karolinska Institute, S-171 21 Stockholm, Sweden.,

Authors and Affiliations

  1. School of Cancer Sciences, College of Medical and Dental Sciences, Institute for Biomedical Research, University of Birmingham, Birmingham, UK

    R M Jones, I Afzal & E Petermann

  2. Department of Oncology, Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK

    O Mortusewicz

  3. School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    M Lorvellec & P García

  4. Department of Medical Biochemistry and Biophysics, Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden

    T Helleday

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  1. R M Jones
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Correspondence to T Helleday or E Petermann.

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Jones, R., Mortusewicz, O., Afzal, I. et al. Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress. Oncogene 32, 3744–3753 (2013). https://doi.org/10.1038/onc.2012.387

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