Research
DNA damage repair, in particular base excision repair, in response to endogenous (intracellular) and exogenous (ionising radiation) stress.
Our cellular DNA is under constant attack from both endogenous and exogenous mutagens, and consequently the base excision repair (BER) pathway plays a vital role in repairing damaged DNA bases, sites of base loss (apurinic/apyrimidinic sites) and DNA single strand breaks of varying complexity. BER thus maintains genome stability, and prevents the development of human diseases, such as premature aging, neurodegenerative diseases and cancer. Indeed, there is accumulating evidence that misregulation of BER protein levels is observed in cells and tissues from patients with these diseases, which has implications for disease development, but also devising effective strategies for the treatment and cure of the diseases. We have pioneered ongoing novel research demonstrating that post-translational modifications, particularly ubiquitylation, perform a key role in controlling BER protein stability. Indeed, we have identified E3 ubiquitin ligases and deubiquitylation enzymes that modulate ubiquitylation-dependent proteasomal degradation of key BER proteins, and therefore play vital roles in the cellular DNA damage response, and in maintenance of genome stability.
Base excision repair proteins as prognostic and predictive molecular biomarkers in head and neck cancer.
Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cancer by incidence worldwide, with nearly 600,000 new cases per year reported. There has also been a rapid increase in the incidence of human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) in the last three decades. Interestingly, there are improved survival rates for patients with HPV-positive OPSCC in comparison to their HPV-negative counterparts whose outcome is very poor. Furthermore, HPV-positive tumours are also more sensitive to radiotherapy and chemotherapy. However, the molecular mechanisms which underlie the improved survival and radiosensitivity of HPV-positive OPSCC versus HPV-negative OPSCC are currently unknown. We are currently investigating the role of base excision repair (BER) proteins both as prognostic biomarkers in the development of HNSCC, but also as predictive biomarkers of the response of HPV-positive and HPV-negative OPSCC to radiotherapy (ionising radiation).
DNA damage complexity induced by ionising radiation, and the radiobiology of proton therapy
The critical cellular target for ionising radiation is DNA and DNA damage accumulation is implicated in the development of premature ageing, neurodegenerative diseases and cancer. However ionising radiation, such as conventional x-ray irradiation but also proton beam therapy, is also the most effective cancer treatment and it is believed that its therapeutic effect is partially attributable to complex DNA damage (CDD), where several DNA lesions are induced in close proximity. We are currently examining CDD formation induced by proton irradiation (at the Clatterbridge Cancer Centre), relative to x-rays and densely ionising radiation including alpha particles (collaboration with the Oxford Institute for Radiation Oncology), but also the cellular response to this particular type of DNA damage. Our goal is to improve our basic understanding of radiation biology and ultimately to identify new cellular targets for drugs and inhibitors that may enhance the efficacy of radiotherapy in cancer treatment.
Research grants
Examining the Impact of Proton Beam therapy on DNA Replication Efficiency and Stress in Head and Neck Cancer and Glioblastoma cell models
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
November 2021 - October 2022
Research fees for 201489396 Aderonke Adebowun Abah
TERTIARY EDUCATION TRUST FUND (NIGERIA)
April 2021 - September 2025
New Insights into the cellular response to complex DNA damage induced by proton beam therapy
MEDICAL RESEARCH COUNCIL
September 2021 - August 2024
A Research Surgical Fellowship for Hayley Fowler
ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)
October 2020 - September 2021
Examining the Impact of FLASH Proton Beam Therapy
THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST (UK)
April 2020 - April 2022
Surgical Research Fellowship for Rachael Clifford
ROYAL COLLEGE OF SURGEONS OF ENGLAND(UK)
August 2019 - January 2021
Does inhibiting acid ceramidase improve radiosensitivity in an in vitro model of colorectal cancer?
ROYAL COLLEGE OF SURGEONS OF EDINBURGH
February 2017 - January 2018
The radiobiology of proton therapy
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
March 2016 - June 2019
To address DNA repair mechanisms in uveal melanoma
ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST CHARITABLE FUNDS (UK)
October 2015 - March 2020
The cellular response to complex DNA damage induced by ionising radiation
MEDICAL RESEARCH COUNCIL
November 2014 - November 2017
The cellular response to DNA damage: Ubiquitylation-dependent regulation of 8-oxoguanine DNA glycosylase (OGG1)
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
September 2013 - September 2018
Molecular mechanism of regulation of the cellular protein levels of endonuclease III homologue (NTH1), in response to DNA damage
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
October 2014 - September 2017