TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition.
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.
1] Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA [2] Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Ha
1] Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA [2] Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Kim
1] Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA [2] Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Petersson
Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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1] Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA [2] Department of Pathology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Denning
Department of Molecular Pharmacology and Therapeutics Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Patel
1] Oncology Institute, Cardinal Bernardin Cancer Center, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA [2] Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Breuer
D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011836:Radiation Tolerance
D008869:Microtubule-Associated Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C120551:TACC3 protein, human