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Abstract
Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation.
Original language | English |
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Article number | 150 |
Number of pages | 11 |
Journal | Cell Death and Disease |
Volume | 15 |
Issue number | 2 |
DOIs | |
Publication status | Published - 17 Feb 2024 |
Bibliographical note
Copyright:© 2024. Crown.
Acknowledgements:
We would like to thank Prof. T Carey for providing the UMSCC6 and UMSCC74A cells. The authors also thank Emma Melia for assistance with cell cycle analysis, and the team at the Clatterbridge Cancer Centre for technical assistance with proton irradiation of cells. This work was supported by funding from North West Cancer Research [CR1197], the Medical Research Council [MR/V028944/1] and the National Institutes of Health [1R01CA256854-01]. The Swedish Cancer Foundation (22-2108 S) is also gratefully acknowledged.
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New Insights into the cellular response to complex DNA damage induced by proton beam therapy
Parsons, J. (Principal Investigator)
1/04/23 → 30/04/25
Project: Research Councils