Ha G-H, Kim J-L, Petersson A, Oh S, Denning M F, Patel T, Breuer E-K
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.
Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
Oncogene. 2015 Mar 26;34(13):1667-78. doi: 10.1038/onc.2014.105. Epub 2014 Apr 28.
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.
转化酸性卷曲螺旋蛋白3（TACC3）是中心体-微管系统中的一个重要因子，其失调与多种人类癌症类型相关。我们最近报道了TACC3的致癌潜力；然而，TACC3介导致癌功能的分子机制仍有待阐明。在本研究中，我们发现高水平的TACC3会导致DNA双链断裂（DSB）的积累，并至少部分地通过负向调节共济失调毛细血管扩张症突变基因（ATM）的表达以及随后的DNA损伤反应（DDR）信号级联反应，破坏细胞对DNA损伤的正常反应。表达高水平TACC3的细胞表现出缺陷的检查点以及DSB介导的同源重组（HR）和非同源末端连接（NHEJ）修复系统，从而导致基因组不稳定。重要的是，高水平的TACC3使细胞对辐射和聚（ADP-核糖）聚合酶（PARP）抑制敏感。总体而言，我们的研究结果提供了关于TACC3导致基因组不稳定从而可能引发癌症发展的机制的关键信息，并为治疗表达高水平TACC3的癌症类型提出了一种新的预后、诊断和治疗策略。
