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Published on: June 12, 2017
Acetylation: a novel link between double-strand break repair and autophagy
Ghadeer Shubassi1, Thomas Robert, Fabio Vanoli
1Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
Abstract:
Histone deacetylase (HDAC) inhibitors are clinically relevant because they are used as anticancer drugs. Recent evidence sheds light on an intriguing connection among the DNA damage response (DDR), protein acetylation, and autophagy. HDAC inhibitors have been shown to counteract key steps in the cellular response to double-strand break formation by affecting checkpoint activation, homologous recombination-mediated repair of DNA lesions, and stability of crucial enzymes involved in resection of DNA ends. The degradation of the resection factors depends on autophagy, which plays a detrimental role when cells are in a hyperacetylated state and experience treatment with radiomimetic anticancer drugs. Future work will be required to further investigate the mechanisms underlying the link between acetylation, autophagy, and the DDR, as well as the significance of mTORC1 inhibitors, which are potent inducers of autophagy that are now used in cancer treatment.
Insights
Histone deacetylase (HDAC) inhibitors impact cancer drug efficacy by affecting DNA repair and autophagy. Understanding this link is crucial for developing new cancer treatments.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- Histone deacetylase (HDAC) inhibitors are clinically used as anticancer agents.
- Emerging evidence links the DNA damage response (DDR), protein acetylation, and autophagy.
- HDAC inhibitors interfere with cellular responses to DNA double-strand breaks.
Purpose of the Study:
- To elucidate the interplay between acetylation, autophagy, and the DDR in cancer cells.
- To investigate the role of autophagy in the efficacy of HDAC inhibitors and radiomimetic drugs.
Main Methods:
- The study reviews recent evidence on the molecular mechanisms involved.
- Analysis of how HDAC inhibitors affect DNA repair pathways (checkpoint activation, homologous recombination).
- Examination of the role of autophagy in the degradation of DNA resection factors.
Main Results:
- HDAC inhibitors disrupt key steps in the DNA damage response, including checkpoint activation and DNA repair.
- Autophagy degrades essential DNA resection factors, playing a detrimental role in hyperacetylated cells treated with radiomimetic anticancer drugs.
- The hyperacetylated state combined with autophagy induction compromises cellular resistance to DNA-damaging agents.
Conclusions:
- The intricate relationship between acetylation, autophagy, and the DDR is critical for understanding HDAC inhibitor action.
- Targeting autophagy, potentially with mTORC1 inhibitors, may enhance cancer therapy effectiveness.
- Further research is needed to fully unravel these complex mechanisms for therapeutic advancement.
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