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Published on: January 31, 2018
TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition
G-H Ha1, J-L Kim1, A Petersson1
11] 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.
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.
Insights
High levels of transforming acidic coiled-coil protein 3 (TACC3) disrupt DNA repair, causing genomic instability and increasing cancer risk. This suggests TACC3 as a potential target for cancer therapy.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Transforming acidic coiled-coil protein 3 (TACC3) is implicated in various cancers.
- The precise mechanisms of TACC3's oncogenic function are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying TACC3's role in cancer.
- To investigate how TACC3 influences DNA damage response and genomic stability.
Main Methods:
- Assessing DNA double-strand breaks (DSBs) in cells with varying TACC3 levels.
- Analyzing the expression of ataxia telangiectasia mutated (ATM) and DNA damage response (DDR) signaling.
- Evaluating homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways.
- Testing cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors.
Main Results:
- Elevated TACC3 levels correlate with increased DSBs and impaired DNA damage response.
- High TACC3 expression negatively regulates ATM expression and downstream DDR signaling.
- Cells with high TACC3 exhibit defective checkpoints and compromised HR/NHEJ repair, leading to genomic instability.
- Increased TACC3 sensitizes cells to radiation and PARP inhibition.
Conclusions:
- TACC3 contributes to genomic instability by disrupting DNA repair pathways.
- These findings highlight TACC3's role in cancer development.
- TACC3 may serve as a prognostic, diagnostic, and therapeutic target for TACC3-expressing cancers.
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