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TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition

Oncogene volume 34, pages 1667–1678 (2015)Cite this article

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Abstract

Deregulation of the transforming acidic coiled-coil protein 3 (TACC3), an important factor in the centrosome–microtubule system, has been linked to a variety of human cancer types. We have recently reported on the oncogenic potential of TACC3; however, the molecular mechanisms by which TACC3 mediates oncogenic function remain to be elucidated. In this study, we show that high levels of TACC3 lead to the accumulation of DNA double-strand breaks (DSBs) and disrupt the normal cellular response to DNA damage, at least in part, by negatively regulating the expression of ataxia telangiectasia mutated (ATM) and the subsequent DNA damage response (DDR) signaling cascade. Cells expressing high levels of TACC3 display defective checkpoints and DSB-mediated homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, leading to genomic instability. Importantly, high levels of TACC3 confer cellular sensitization to radiation and poly(ADP-ribose) polymerase (PARP) inhibition. Overall, our findings provide critical information regarding the mechanisms by which TACC3 contributes to genomic instability, potentially leading to cancer development, and suggest a novel prognostic, diagnostic and therapeutic strategy for the treatment of cancer types expressing high levels of TACC3.

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Acknowledgements

This study was supported by the Program Development Startup from Loyola University Chicago.

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Author notes

  1. G-H Ha and J-L Kim: These authors contributed equally to this work.

Authors and Affiliations

  1. Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    G-H Ha, J-L Kim, A Petersson, M F Denning & E-K Breuer

  2. Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    G-H Ha, J-L Kim, A Petersson, S Oh & E-K Breuer

  3. Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    M F Denning

  4. Department of Molecular Pharmacology and Therapeutics Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    T Patel

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  1. G-H Ha
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Correspondence to E-K Breuer.

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Ha, GH., Kim, JL., Petersson, A. et al. TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition. Oncogene 34, 1667–1678 (2015). https://doi.org/10.1038/onc.2014.105

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  • DOI: https://doi.org/10.1038/onc.2014.105

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