The cellular response to complex DNA damage induced by ionising radiation
Lead Research Organisation:
University of Liverpool
Department Name: Institute of Translational Medicine
Abstract
DNA in our chromosomes encodes genetic information that is essential to life. However, damage to our DNA by ionising radiation from the environment is a constant daily occurrence and DNA damage accumulation is thought to be involved in the development of ageing, neurodegenerative diseases and cancer. To combat this, our cells usually contain efficient DNA repair mechanisms that act to prevent the development of these human diseases. Conversely radiotherapy, in the form of ionising radiation, is also still the most effective treatment for killing cancer cells, although it's effectiveness is variable in different cancers and side effects can be common. Despite this knowledge, complete information on how our cells repair DNA damage induced by ionising radiation in our chromosomes is still unclear and is the focus of the proposed research. This proposal is therefore essential for our understanding of the basic biological mechanisms our cells use to prevent DNA damage accumulation caused by ionising radiation, and thus act to stop the formation of human diseases. Furthermore, this proposal aims to provide leads to the development of new strategies in combination with radiotherapy, for the effective treatment of cancer.
Technical Summary
The critical cellular target for ionising radiation (IR) is DNA and DNA damage accumulation is implicated in the development of ageing, neurodegenerative diseases and cancer. However, IR 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. However, very little is known about how CDD is initially recognised and/or processed in human cells. Since genomic DNA is tightly packed with histones to form chromatin there is emerging evidence, particularly during double strand break repair, that histone modifications (eg. ubiquitylation) are required to unwind or remodel chromatin to increase accessibility of the DNA damage to repair enzymes. However, the role of these modifications in the signalling and/or repair of CDD induced by IR is unknown. Therefore, I propose to understand whether histone modifications (with an initial focus on histone ubiquitylation/deubiquitylation) play an important role in the cellular response to IR-induced CDD. Using IR of different ionisation densities (ie. gamma-irradiation and alpha-particle/proton irradiation), which increases the complexity of DNA damage, together with various biochemical and molecular biology techniques, I propose to identify whether site specific histone ubiquitylation (eg. H2A-K119, H2B-K120 and H2AX-K119) is modulated in human cells at CDD sites. Furthermore, I will identify the enzymes involved using a candidate approach of known histone ubiquitylation/deubiquitylation enzymes, a screening approach by overexpressing/siRNA knockdowns of deubiquitylation enzymes, and a biochemical approach incorporating mononucleosomes containing DNA damage sites and protein fractionation. The goal is to improve our understanding of radiobiology, and ultimately identify new cellular targets for drugs and inhibitors that may enhance the efficacy of radiotherapy in cancer treatment.
Planned Impact
This proposal aims to discover the cellular enzymes and epigenetic mechanisms involved in the recognition/processing of complex DNA damage induced by ionising radiation. This novel and niche area of research is aimed at understanding fundamental radiobiology research that is world leading. Critically, since DNA damage accumulation has been linked with the development of ageing, neurodegenerative diseases and cancer, this research may reveal novel cellular mechanisms that prevent these processes and stimulate further research in this area to understand the association with ageing and human diseases. The long term goal is therefore to enhance the health and quality of life for the ageing population and provide leads to strategies for preventing the incidence of neurodegenerative diseases and cancer.
Furthermore, since ionising radiation is also a key treatment used in cancer therapy, this proposal aims to identify novel cellular targets, and the subsequent development of drugs and small molecule inhibitors against these targets, that can improve the efficacy of radiotherapy in cancer treatment. Consequently, the proposed work may be translatable to the benefit of cancer patients by increasing cure rates and also reducing acute and long-term sides effects commonly associated with radiotherapy, leading to an overall increase in the quality of life for these patients. This will also represent commercial opportunities with the development of these novel drugs and small molecule inhibitors targeting the signalling/processing of complex DNA damage induced by ionising radiation, and therefore will be of huge interest to the pharmaceutical industry worldwide. I propose, in the future, to focus the results of this research on improving the efficacy of radiotherapy in squamous cell carcinoma of the head and neck (SCCHN), which is a priority translational research area for the Liverpool Cancer Research Centre. Importantly SCCHN is primarily treated with radiotherapy, although because of the common occurrence of acute and long-term adverse effects, novel agents and strategies are increasingly being sought for the effective treatment of these tumours. Therefore my research aims to achieve this long term goal, although realistically, the timescale for these benefits to be realised may take several decades.
Nevertheless, this fundamental radiobiology research proposal shows considerable promise in improving our understanding of the biological effects of ionising radiation, the association with ageing and the development of human diseases, and designing better strategies for the treatment of cancer. The staff working on this project (in addition to the included collaborators at the Universities of Liverpool and Oxford) will therefore be performing cutting-edge radiobiology research that is world-leading, whilst also developing communication skills through participation and presentation at national and international conferences, and these skills are highly applicable for future employment both in the UK and throughout the World.
Furthermore, since ionising radiation is also a key treatment used in cancer therapy, this proposal aims to identify novel cellular targets, and the subsequent development of drugs and small molecule inhibitors against these targets, that can improve the efficacy of radiotherapy in cancer treatment. Consequently, the proposed work may be translatable to the benefit of cancer patients by increasing cure rates and also reducing acute and long-term sides effects commonly associated with radiotherapy, leading to an overall increase in the quality of life for these patients. This will also represent commercial opportunities with the development of these novel drugs and small molecule inhibitors targeting the signalling/processing of complex DNA damage induced by ionising radiation, and therefore will be of huge interest to the pharmaceutical industry worldwide. I propose, in the future, to focus the results of this research on improving the efficacy of radiotherapy in squamous cell carcinoma of the head and neck (SCCHN), which is a priority translational research area for the Liverpool Cancer Research Centre. Importantly SCCHN is primarily treated with radiotherapy, although because of the common occurrence of acute and long-term adverse effects, novel agents and strategies are increasingly being sought for the effective treatment of these tumours. Therefore my research aims to achieve this long term goal, although realistically, the timescale for these benefits to be realised may take several decades.
Nevertheless, this fundamental radiobiology research proposal shows considerable promise in improving our understanding of the biological effects of ionising radiation, the association with ageing and the development of human diseases, and designing better strategies for the treatment of cancer. The staff working on this project (in addition to the included collaborators at the Universities of Liverpool and Oxford) will therefore be performing cutting-edge radiobiology research that is world-leading, whilst also developing communication skills through participation and presentation at national and international conferences, and these skills are highly applicable for future employment both in the UK and throughout the World.
Organisations
- University of Liverpool (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- The Clatterbridge Cancer Centre NHS Foundation Trust (Collaboration)
- Stanford University (Collaboration)
- LIVERPOOL JOHN MOORES UNIVERSITY (Collaboration)
- UNIVERSITY OF LIVERPOOL (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
Publications
Carter RJ
(2016)
Base Excision Repair, a Pathway Regulated by Posttranslational Modifications.
in Molecular and cellular biology
Fabbrizi M
(2022)
Cell death mechanisms in head and neck cancer cells in response to low and high-LET radiation
in Expert Reviews in Molecular Medicine
Carter RJ
(2019)
Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage.
in International journal of radiation oncology, biology, physics
Carter RJ
(2018)
Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response.
in International journal of radiation oncology, biology, physics
Williams SC
(2018)
NTH1 Is a New Target for Ubiquitylation-Dependent Regulation by TRIM26 Required for the Cellular Response to Oxidative Stress.
in Molecular and cellular biology
Edmonds MJ
(2014)
Regulation of base excision repair proteins by ubiquitylation.
in Experimental cell research
Wilkinson B
(2023)
The Cellular Response to Complex DNA Damage Induced by Ionising Radiation
in International Journal of Molecular Sciences
Fabbrizi MR
(2021)
The Enzyme-Modified Neutral Comet (EMNC) Assay for Complex DNA Damage Detection.
in Methods and protocols
Martin PR
(2017)
The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure.
in Scientific reports
Singh AN
(2019)
The p97-Ataxin 3 complex regulates homeostasis of the DNA damage response E3 ubiquitin ligase RNF8.
in The EMBO journal
Vitti ET
(2019)
The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair.
in Cancers
Edmonds MJ
(2017)
Ubiquitylation-dependent regulation of NEIL1 by Mule and TRIM26 is required for the cellular DNA damage response.
in Nucleic acids research
Nickson CM
(2021)
USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation.
in Frontiers in oncology
| Description | Advanced technologies for radiobiology and clinical radiotherapy |
| Amount | £62,328 (GBP) |
| Funding ID | ST/T002158/1 |
| Organisation | Science and Technologies Facilities Council (STFC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2019 |
| End | 09/2021 |
| Description | Does acid ceramidase improve the radiosensitivity in an in vitro model of colorectal cancer |
| Amount | £8,900 (GBP) |
| Organisation | The Royal College of Surgeons of Edinburgh |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2017 |
| End | 03/2018 |
| Description | Examining the impact of FLASH proton beam therapy |
| Amount | £30,000 (GBP) |
| Organisation | The Clatterbridge Cancer Centre NHS Foundation Trust |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2020 |
| End | 04/2022 |
| Description | Examining the impact of proton beam therapy on DNA replication efficiency and stress in head and neck cancer and glioblastoma cell models |
| Amount | £10,000 (GBP) |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2021 |
| End | 10/2022 |
| Description | Improving the biological response of proton beam therapy in head and neck cancer |
| Amount | £202,129 (GBP) |
| Funding ID | CR1197 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2019 |
| End | 05/2022 |
| Description | Investigation into the effective use of proton beam therapy for the treatment of glioblastoma |
| Amount | £8,000 (GBP) |
| Organisation | The Clatterbridge Cancer Centre NHS Foundation Trust |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 04/2018 |
| Description | Isolation and identification of the chromatin remodelling enzymes required for base excision repair |
| Amount | £109,991 (GBP) |
| Funding ID | CR1145 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2017 |
| End | 09/2020 |
| Description | Molecular mechanism of regulation of the cellular protein levels of endonuclease III homologue (NTH1), in response to DNA damage |
| Amount | £113,754 (GBP) |
| Funding ID | CR1016 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2014 |
| End | 09/2017 |
| Description | New insights into the cellular response to complex DNA damage induced by proton beam therapy |
| Amount | £504,521 (GBP) |
| Funding ID | MR/V028944/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2021 |
| End | 08/2024 |
| Description | North West Cancer Research Project Grant (Supplement to current funding) |
| Amount | £26,197 (GBP) |
| Funding ID | CR972 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2015 |
| End | 09/2018 |
| Description | Novel strategies for radioresistant head and neck cancers through targeting the DNA damage response in combination with high-precision proton beam the |
| Amount | £70,000 (GBP) |
| Funding ID | 2600797 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2021 |
| End | 03/2025 |
| Description | Nrf2: a novel chemoradiotherapy resistance biomarker and interventional target for rectal cancer |
| Amount | £13,500 (GBP) |
| Organisation | Bowel Disease Research Foundation (BDRF) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 04/2019 |
| Description | Profiling ADP-ribosylation enzymes and PARP inhibition in head and neck squamous cell carcinoma |
| Amount | £448,683 (GBP) |
| Funding ID | CDF2019.05 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 11/2019 |
| End | 11/2024 |
| Description | Realizing the radiobiological impact of protons and high-LET particles in head and neck cancer and glioblastoma models |
| Amount | $1,770,799 (USD) |
| Funding ID | 1R01CA256854-01 |
| Organisation | National Institutes of Health (NIH) |
| Sector | Public |
| Country | United States |
| Start | 07/2021 |
| End | 04/2026 |
| Description | The impact of hypoxia on cellular radiosensitivity following proton beam therapy |
| Amount | £7,109 (GBP) |
| Organisation | Royal Liverpool and Broadgreen University Hospitals NHS Trust |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2017 |
| End | 06/2018 |
| Description | The radiobiology of proton therapy |
| Amount | £186,096 (GBP) |
| Funding ID | CR1074 |
| Organisation | North West Cancer Research (NWCR) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2016 |
| End | 02/2019 |
| Description | To address DNA repair mechanisms in uveal melanoma |
| Amount | £33,200 (GBP) |
| Funding ID | A0916/CF |
| Organisation | Royal Liverpool and Broadgreen University Hospitals NHS Trust |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2015 |
| End | 09/2018 |
| Title | Method for quantifying levels of complex DNA damage in cells following irradiation |
| Description | We have established a specific method, entitled the Enzyme-Modified Neutral Comet (EMNC) assay, for quantitatively examining the levels of complex DNA damage (CDD) induced by ionising radiation. This is now a commonly used technique by Dr Jason Parsons and his Team to further our understanding of radiobiology within cultured cell lines. Specifically, the EMNC allows an assessment of CDD induced by ionising radiation of increasing linear energy transfer (LET), and have proven this can capture such sites in cultured cells following proton beam therapy. This will enable further investigations into the molecular and cellular biology of radiation-induced CDD, with the future goal of developing optimal strategies for the effective use of protons and other high-LET radiation in cancer treatment. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | The EMNC assay has only been reported this year, although we have previously used this methodology to further our understanding of the radiobiology of protons, as evidenced here (PMID: 30851349; 29413288). Further impact will no doubt be developed more in the future. |
| URL | https://www.mdpi.com/2409-9279/4/1/14 |
| Title | Research Laboratory Examining Proton Irradiation |
| Description | In association with our collaborators at the Clatterbridge Cancer Centre, we have established a research laboratory at the Centre (with generous funding of ~£40k) dedicated for examining the molecular and cellular effects of proton beam therapy. This is now heavily used by Dr Jason Parsons and his Team to further an understanding of the radiobiology of proton irradiation on cancer cells, although is open and indeed being utilised for collaborative radiobiology research particularly with other UK Centres (e.g. University of Birmingham, University of Oxford, University College London, and Imperial College London). The future goal is the development of optimal strategies for the effective use of protons in cancer treatment. This research is vital given that the Clatterbridge Cancer Centre currently houses the only accessible proton beam therapy facility, and now the only research laboratory, in the UK but that new proton facilities are now active in Manchester and London (from 2021). Therefore this facility is currently at the forefront of radiobiology research into proton beam therapy. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2016 |
| Provided To Others? | Yes |
| Impact | The establishment of the new research laboratory at the Clatterbridge Cancer Centre is crucial in furthering our understanding of the radiobiology of proton beam therapy in cancer cells, and since this is currently the only such accessible and collaborative facility in the UK, we are at the forefront of research in this area. |
| Title | Cellular sensitivity to ionising radiation |
| Description | My Postdoctoral Research Scientist (Dr Rachel Carter) funded by the MRC Award (MR/M000354/1) has completed both a plasmid overexpression, and an siRNA knockdown screen in cells and analysed the cellular response to different sources of ionising radiation. This has examined the effect of (~90) deubiquitylation enzymes on the survival of cells following either low-LET x-ray irradiation or high-LET alpha particle irradiation (collaboration with the CRUK/MRC Oxford Institute for Radiation Oncology). Work has also been extended to examining the cellular response of these enzymes following proton beam therapy, at both high and low-LET (collaboration with the Clatterbridge Cancer Centre). This is aimed at improving our understanding and knowledge of radiobiology. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| Impact | This collection of data has given us valuable insights into the roles of deubiquitylation enzymes in the cellular response to different sources of ionising radiation, with a particular focus on those enzymes playing a role in the identification and/or processing of complex DNA damage induced by high-LET alpha particle and proton irradiation. We are in the continual process of validating candidate enzymes, leading to the identification of cellular enzymes and their novel roles in radiation biology. Our future goal is to examine validated enzymes as novel targets for drugs and/or small molecule inhibitors for improving the efficacy of radiotherapy in cancer treatment. |
| Description | Collaboration with Chemistry, Liverpool |
| Organisation | University of Liverpool |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My Group and I are providing our expertise in radiobiology to Prof Steve Rannard and Dr Marco Giardiello in the Department of Chemistry, University of Liverpool, UK. This collaboration has involved us examining the impact of nanoparticles on the response of head and neck tumour cells to ionising radiation, including both conventional (photon) irradiation and proton beam therapy. We also provide intellectual input into research results and in designing the future direction of the work. |
| Collaborator Contribution | Our partners, Prof Steve Rannard and Dr Marco Giardiello, have provided input into the synthesis and chemical composition of the nanoparticles. We have ongoing discussions about the evaluation of results obtained, as well as the optimisation of nanoparticle composition to enhance tumour cell radiosensitisation, and therefore about the progression of the collaborative research. |
| Impact | No outputs or outcomes have yet resulted.This collaboration, however, is multidisciplinary involving the respective Groups with expertise in chemistry (Prof Rannard and Dr Giardiello) and radiation biology (Dr Parsons). |
| Start Year | 2018 |
| Description | Collaboration with Clatterbridge Cancer Centre |
| Organisation | The Clatterbridge Cancer Centre NHS Foundation Trust |
| Country | United Kingdom |
| Sector | Public |
| PI Contribution | My research team and I have regular visits to Dr Andrzej Kacperek and the Eye Proton Therapy Team at the Clatterbridge Cancer Centre, Bebington, UK in order to perform cell irradiation experiments using the 60 MeV proton beam. We also have regular contact and discussion with our collaborators on experimental design, results and evaluation in order for the research to proceed effectively. |
| Collaborator Contribution | Our partners at the Clatterbridge Cancer Centre, including Dr Andrez Kacperek, assist in the dosimetry and delivery of proton beam irradiation of cells. They also advise on experimental design, and interpretation of results. |
| Impact | As a consequence of this collaboration, we have now established a radiobiology research laboratory at the Clatterbridge Cancer Centre (funded by the Centre to a cost of ~£40k) which is dedicated for further examining the cellular response to proton beam therapy, and majorly used by Dr Jason Parsons and his research team. This research laboratory, and indeed the proton beam facility itself, are currently the only facilities available in the UK for studying the effects of protons on cancer cells and crucial for the increased future use of proton beam therapy for cancer treatment. Also published research in three peer-reviewed manuscripts (PMID: 29413288; PMID: 30851349, PMID: 34277417). |
| Start Year | 2014 |
| Description | Collaboration with Imperial College London |
| Organisation | Imperial College London |
| Department | Department of Physics |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My Group and I are providing our expertise in radiation biology to Prof Ken Long and the The Laser hybrid Accelerator for Radiobiological Applications (LhARA) consortium at Imperial College London, UK. We have been providing our expertise into the development of a radiobiology research facility as part of the LhARA project, and also guidance on the future progress of the initiative. |
| Collaborator Contribution | Our collaborator, Prof Ken Long, leads on the collaborative LhARA project aiming to establish a laser accelerator facility for in vitro and in vivo radiobiology research. Therefore Prof Long provides his intellectual input into the development of the laser accelerator, and in designing the future direction of the project. |
| Impact | No outputs or outcomes have yet resulted. This collaboration, however, is multidisciplinary involving the respective Groups with expertise in physics (Prof Long) and radiation biology (Dr Parsons). |
| Start Year | 2019 |
| Description | Collaboration with Integrative Biology, Liverpool |
| Organisation | University of Liverpool |
| Department | Institute of Integrative Biology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My postdoctoral research scientist (Dr Rachel Carter) employed on the MRC Award, and I, have collaborated with Prof Rob Beynon at the Institute of Integrative Biology, University of Liverpool, UK to identify the histone modifications induced in the cellular response to ionising radiation. We have provided purified histone samples prepared from cells irradiated with either low-LET x-ray irradiation or high-LET alpha particle irradiation, so that these can be analysed by mass spectrometry. We have also had regular contact and discussions with Prof Beynon and his team, to ensure that the research progresses well. |
| Collaborator Contribution | Our partner, Prof Rob Beynon, and his team from the Centre for Proteome Research have performed mass spectrometry analysis on purified histone samples, and provided quantitative data analysis on the types of histone modifications induced in cells in response to either low-LET x-ray and proton irradiation, and high-LET alpha particle and proton irradiation. |
| Impact | No outputs or outcomes have yet resulted |
| Start Year | 2014 |
| Description | Collaboration with Liverpool John Moores University |
| Organisation | Liverpool John Moores University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My Group and I are providing our expertise in DNA damage repair to Dr Kehinde Ross at Liverpool John Moores University, UK. We have been providing our laboratory resources and technical expertise into analysing the DNA damage response in keratinocyte differentiation. We also provide intellectual input into research results and guidance on the future progress of the research. |
| Collaborator Contribution | Our collaborator, Dr Kehinde Ross, leads on this collaborative project aiming to further understand keratinocyte differentiation, examining the roles of micro RNAs in this process, and the relationship to the DNA damage response. Therefore Dr Ross provides his intellectual input into the results obtained from experimental research, and in designing the future direction of the work. |
| Impact | The collaborative research has led to one peer-reviewed manuscript (PMID: 31985037) |
| Start Year | 2018 |
| Description | Collaboration with Physiology, Liverpool |
| Organisation | Stanford University |
| Department | Department of Molecular and Cellular Physiology |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | My postdoctoral research scientist (Dr Rachel Carter) employed on the MRC Award, and I, have had regular contact and discussions with our collaborators Prof Michael Clague and Prof Sylvie Urbe in the Department of Cellular and Molecular Physiology, at the University of Liverpool, UK. This collaboration is aimed at investigating the role of deubiquitylation enzymes in the cellular response to ionising radiation, with a particular focus on those involved in complex DNA damage, and therefore we share details of experimental results as well as discussion of future research strategies. |
| Collaborator Contribution | Our partners, Prof Michael Clague and Prof Sylvie Urbe, have kindly provided us with mammalian expression plasmids for the majority of the deubiquitylation enzyme family (~70 in total). These, as well as fruitful discussions, have enabled us to further examine the role of this enzyme family in mediating the response of cells to low-LET x-ray and proton irradiation, as well as and high-LET alpha particle and proton irradiation. |
| Impact | This collaboration has been acknowledged in one peer-reviewed manuscript (PMID: 30851349). |
| Start Year | 2014 |
| Description | Collaboration with University of Oxford |
| Organisation | University of Oxford |
| Department | Department of Oncology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My postdoctoral research scientist (Dr Rachel Carter) employed on the MRC Award had regular visits to the CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK in order to perform irradiation experiments (using high-LET alpha particles) in collaboration with Dr Mark Hill. Myself and Dr Carter also had regular contact and discussions with our collaborators, including both Dr Mark Hill and Prof Peter O'Neill, which also involved Institute visits every 6 months to discuss the effective progress of the research. |
| Collaborator Contribution | Our partners, led by Dr Mark Hill and his Postdoctoral Research Scientist Dr Jamie Thompson, assist in the dosimetry and delivery of alpha particle irradiation to cells using their laboratory facilities. Prof Peter O'Neill has been advising on design of irradiation studies, as well as on in vitro biochemical experiments using mononucleosome substrates. Both were also actively involved in the evaluation and discussion of results, and to plan the future direction of the work.. |
| Impact | Published research in three peer-reviewed manuscripts (PMID: 29413288; PMID: 30851349, PMID: 34277417). Also published one expert review (PMID: 36902352). |
| Start Year | 2014 |
| Description | Collaboration with University of Oxford |
| Organisation | University of Oxford |
| Department | Department of Oncology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My Group and I are providing our expertise in radiobiology and DNA damage repair to Prof Kristijan Ramadan at the CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. This has involved us examining the impact of siRNA-mediated depletion of key enzymes involved in deubiquitylation on the kinetics of DNA damage and repair in response to ionising radiation using, in particular, our technical expertise in multiple versions of the single cell gel electrophoresis (comet) assay. We also provide intellectual input into research results and in designing the future direction of the work. |
| Collaborator Contribution | Our collaborator, Prof Kristijan Ramadan, has provided reagents and his expertise in the ubiquitin proteasome system to contribute to the research aims, which are to identify the roles of specific deubiquitylation enzymes in the cellular response to DNA damage. Prof Ramadan is also utilising his technical expertise and resources in the formation and repair of DNA-protein cross links, where we are collaborating further to investigate whether DNA-protein cross links are formed under different conditions of low and high-LET proton irradiation, which we've demonstrated are generating different degrees of complex DNA damage. |
| Impact | Published research in one peer-reviewed manuscript (PMID: 31613024) |
| Start Year | 2017 |
| Description | Interview with the Liverpool Echo |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | My Research Group and I conducted a laboratory tour of the North West Cancer Research (NWCR) Centre at the University of Liverpool for media from the Liverpool Echo. We spoke about our research into the effects of ionising radiation in cancer cells, including head and neck squamous cell carcinoma, and also about the laboratory environment we work in. The visit was subsequently publicized in the Liverpool Echo and gave the media and the general public a valuable insight into the important research we are conducting. |
| Year(s) Of Engagement Activity | 2016 |
| URL | http://www.liverpoolecho.co.uk/news/health/meet-liverpool-scientists-trying-find-10888584 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Proton Physics Research Implementation Group (PPRIG), London, UK. The seminar covered the cellular DNA damage response to proton irradiation, with a specific focus on the formation of complex DNA damage, and its recognition and repair by enzymes of the ubiquitin proteasome pathway. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. The seminar covered the radiobiology of proton beam therapy, and in particular the associations with the induction of complex DNA damage and the repair of this by enzymes of the ubiquitin proteasome pathway. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Gustave-Roussy Cancer Campus, France. The seminar covered the cellular DNA damage response to proton beam therapy in head and neck cancers, and in particular the associations with the induction of complex DNA damage and the signalling and repair of this damage by enzymes of the ubiquitin proteasome pathway and the cellular DNA damage response. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the 58th annual conference of the Particle Therapy Co-operative Group (PTCOG), Manchester, UK. The seminar covered the cellular response to complex DNA damage induced by high linear energy transfer (LET) protons, in particular proton beam therapy, and how the repair of this damage is co-ordinated through enzymes involved in the ubiquitin proteasome pathway (particularly RNF20/40, MSL2 and USP6). This is important for our understanding of the molecular and cellular responses to DNA damage induced by proton beam therapy, and for the identification and development of optimal strategies utilising this radiotherapy modality for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the 30th European Congress of Pathology 2018 in Bilbao, Spain. The seminar covered the current concepts of radiobiology and the impact of ionising radiation on head and neck cancers, with a particular focus on proton beam therapy and identification of the cellular DNA damage response. This is important for our understanding of the development of optimal strategies utilising ionising radiation, particularly proton beam therapy, for effective head and neck cancer treatment |
| Year(s) Of Engagement Activity | 2018 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the British Institute for Radiology-Practical Radiobiology for modern everyday radiotherapy (virtual). The seminar covered the radiobiology of photons and protons in head and neck tumour cell models, but also our experiences of optimising the radiotherapy response through targeting DNA damage and repair which can be translated for cancer treatment. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.mybir.org.uk/CPBase__event_detail?id=a173Y00000Fol3pQAB&site=a0N2000000COvFsEAL |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (NCRI CTRad) Radiotherapy DNA Damage Repair inhibitor (DDRi) combinations Workshop, Manchester, UK. The seminar covered the radiobiology of proton beam therapy, but particularly targeting the DNA damage reponse in combination with proton therapy for effective killing of tumour cells. This is important for the identification and development of optimal strategies (e.g. targeting the DDR) utilising this radiotherapy modality for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the CRUK Manchester Institute, Manchester, UK. The seminar covered the radiobiology of proton beam therapy, and the associations with complex DNA damage and the cellular DNA damage response. This is important for our understanding of the molecular and cellular responses to DNA damage induced by proton beam therapy, and for the identification and development of optimal strategies utilising this radiotherapy modality for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Particle Therapy Co-operative Group (PTCOG)-59th Annual Conference (virtual). The seminar covered the response of head and neck cancer cells to photon and proton radiotherapy, but particularly targeting the DNA damage response in combination with these therapies for effective killing of the tumour cells. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.ptcog59.org/ |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the 68th Annual Meeting of the Radiation Research Society (RRS), Hawaii, USA. The seminar covered the radiobiology of protons and high-LET radiation in head and neck cancer and glioblastoma cell models, but also our ongoing strategies to optimise radiation-induced tumour cell killing through targeting the DNA damage response that can be translated clinically. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://na.eventscloud.com/website/37917/ |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Institute of Cancer and Genomic Sciences, University of Birmingham, UK. The seminar covered the radiobiology of proton beam therapy and also the response of human papillomavirus type-16 (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) to ionising radiation. This particularly focussed on our research demonstrating that the radiosensitivity of OPSCC cells is caused by defects in DNA damage and repair pathways, but also the formation and subsequent repair of complex DNA damage induced by proton irradiation. The latter is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at University College London (UCL), UK. The seminar covered the radiobiology of proton beam therapy, and in particular the cellular response to complex DNA damage through DNA damage signalling pathways and via key deubiquitylation enzymes. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | Invited speaker to the MRC Oxford Institute for Radiation Oncology, for the Scholars Seminar. The seminar covered my experience at developing an academic and radiobiology research career. This also covered our most recent research relating to the radiobiology of proton beam therapy in tumour models, and identifying optimal radiosensitisation strategies. |
| Year(s) Of Engagement Activity | 2021 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the 15th international workshop on radiation damage to DNA, Aussois, France. The seminar covered the cellular response to complex DNA damage induced by ionising radiation, in particular proton beam therapy, and how the repair of this damage is co-ordinated through enzymes involved in the ubiquitin proteasome pathway. This is important for our understanding of the molecular and cellular responses to ionising radiation, particularly proton beam therapy, and for the identification and development of optimal strategies utilising radiotherapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response (virtual). The seminar covered the radiobiology of proton beam therapy, but particularly targeting the DNA damage response in combination with proton therapy for effective killing of tumour cells. This is important for the identification and development of optimal strategies (e.g. targeting the DDR) utilising this radiotherapy modality for cancer treatment. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://iecc2021.sciforum.net/ |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at Imperial College London (ICL), UK. The seminar covered the radiobiology of proton beam therapy, and in particular the impact on DNA damage and how this is repaired through DNA damage signalling pathways. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at PARP 2019 conference focused on "New avenues in basic and translational PARP research" in Budapest, Hungary. The seminar covered the vital role of PARP-1 in the cellular response to complex DNA damage induced by proton beam therapy, and also the role of PARP inhibitors in radiosensitising cells to proton irradiation. This is important for our understanding of the role of PARP in cellular and biological response of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy in combination with PARP inhibitors for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Physics of Cancer Conference, Liverpool, UK. The seminar covered the radiobiology of proton beam therapy, and the associations with complex DNA damage and the cellular DNA damage response. This is important for our understanding of the molecular and cellular responses to DNA damage induced by proton beam therapy, and for the identification and development of optimal strategies utilising this radiotherapy modality for cancer treatment. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Invited seminar speaker |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Other audiences |
| Results and Impact | Invited seminar speaker at the Centre for Gene Regulation and Expression, University of Dundee, UK. The seminar covered the radiobiology of proton beam therapy, and in particular the cellular response to complex DNA damage through DNA damage signalling pathways and via key deubiquitylation enzymes. This is important for our understanding of the molecular, cellular and biological responses of cells to proton beam therapy and for the development of optimal strategies utilising this mode of therapy for cancer treatment. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Laboratory tours |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Industry/Business |
| Results and Impact | My Research Group and I have conducted regular laboratory tours (~15 in the last year) of the North West Cancer Research (NWCR) Centre at the University of Liverpool to schools, businesses, charitable donors, the general public and the media. These events, co-ordinated in association with NWCR, have involved talking about our research activities into radiation biology (particularly in head and neck squamous cell carcinoma), how this is funded, and also about the research environment we work in. We regularly answer questions from the visitors on these aspects, and very positive feedback on their experiences have been reported. This activity has usually enlightened the visitors on the important research that we perform. |
| Year(s) Of Engagement Activity | 2015,2016,2017,2018 |
| Description | Press release |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Release of the details of our peer-reviewed publication in The Red Journal (PMID: 29413288). This correlative research project led by my Group at the University of Liverpool, but also involving partners at the University of Oxford and The Clatterbridge Cancer Centre, has revealed new biological details on how cancer cells respond to proton beam therapy. Specifically, this research has shown that cancer cells have specific mechanisms capable of repairing the DNA damage caused by proton irradiation, and which is vital for our understanding of the optimal treatment strategies utilising proton beam therapy for effective cancer treatment. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://news.liverpool.ac.uk/2018/02/15/new-research-highlights-cancer-cells-repair-following-proton... |
| Description | Radio interview |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Myself and Anne Jackson, Chief Executive Officer of North West Cancer Research (NWCR), were invited to a live interview at BBC Radio Merseyside with Tony Snell. I was particularly asked questions about our current scientific research, but also my research experiences to date. This was broadcast live throughout the Merseyside region, and gave the general public an insight into our research. |
| Year(s) Of Engagement Activity | 2016 |
| URL | http://www.bbc.co.uk/programmes/p03g459v |