Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence.

Fabbrizi, Maria Rita, Nickson, Catherine M, Hughes, Jonathan R, Robinson, Emily A, Vaidya, Karthik, Rubbi, Carlos P, Kacperek, Andrzej, Bryant, Helen E, Helleday, Thomas and Parsons, Jason L ORCID: 0000-0002-5052-1125 (2024) Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence. Cell death & disease, 15 (2). p. 150.

Access the full-text of this item by clicking on the Open Access link.

Official URL: http://dx.doi.org/10.1038/s41419-024-06541-9

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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Head and Neck Neoplasms, DNA Damage, Protons, DNA Glycosylases, Glycoside Hydrolases, Linear Energy Transfer
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	28 Feb 2024 10:35
Last Modified:	28 Feb 2024 10:35
DOI:	10.1038/s41419-024-06541-9
Open Access URL:	https://doi.org/10.1038/s41419-024-06541-9
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178949