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.