The overall objective of the Group is to identify critical features of radiation-induced DNA damage such as clustered DNA damage, including complex DNA double strand breaks, which are

Lead Research Organisation: University of Oxford

Abstract

We are looking at the types of damage induced in the genetic material (DNA) of human cells by ionising radiation, such as X-rays, and the various ways cells use in the human body to put the damaged DNA back to its original state
Ionising radiation may be considered as a two-edged sword; on the one hand it may induce cancer and on the other it is also one of the most effective in cancer treatment. If the DNA damage is not restore to the correct genetic blueprint, changes in the genetic code may lead to age-related diseases including cancer. An important feature of ionising radiation is the very complex changes it causes to DNA.
Although we have identified in ‘test-tube’ experiments that some types of DNA damage are difficult to repair, very little is known about how the proteins detect where the damage is and how they travel to the damage before trying to repair it in human cells. Using lasers together with machines which produce ionising radiation we will look at the repair of DNA damage by the proteins as it occurs in living cells.
The research will help to develop new ways to enhance radiotherapy for cancer treatment and help reduce risks of radiation affecting a person’s health.

Technical Summary

Ionising radiation may be considered as a two-edged sword since it can induce cancer and other adverse responses in normal tissue or alternatively it may lead to cellular inactivation of tumour cells, of considerable importance in radiotherapy. Ionising radiation is also one of the most effective cancer treatments and it is believed that its therapeutic effect in part is attributed to DNA damage and specifically to complex DNA damage where several DNA lesions are induced in close proximity.

Therefore the overall objective is to identify critical features of radiation-induced DNA damage such as clustered DNA damage and complex DNA double strand breaks, which are seen as signatures of ionising radiation, and how they may compromise the cell’s ability to maintain genome stability, leading to mutations/tumourogenesis or cellular inactivation involving pathways that may be exploited for cancer therapy. These two outcomes are of relevance to radiation oncology and highlight the dual nature of the effects of radiation. Although information is emerging on the difficulties encountered in repairing clusters of lesions in mammalian cells, very little is known about how they are initially recognised in human cells. Additionally, genomic DNA is tightly packed with histones to form chromatin so that some DNA damage induced by IR may be masked from the surrounding environment. Depending on its location in the chromatin, unwinding or remodelling is required to reveal the damage and accessibility to DNA repair enzymes.

To address the objectives we plan to:-
• Identify the efficiency of the repair pathways and nucleosome remodelling factors involved in the repair of complex DNA damage when present in a mononucleosome model using biochemical approaches.
• i) extend understanding on the orchestrated recruitment of repair/signalling molecules to base damaged sites, particularly those pathways involved in repair of clusters, and ii) identify in real time those proteins recruited during the repair of complex DNA DSB in living mammalian cells.
• In collaboration with Boris Vojnovic’s Group, develop a novel application of confocal microscope coupled with the newly developed linear accelerator to explore real time recruitment of proteins to cellular damage induced by a millisecond pulse of ionising radiation. This development will provide an important technique for future real time studies in mammalian cells.
• To develop an understanding of radiosensitisation by nitric oxide based from our preliminary findings that radiation induces novel types of DNA damage.

The outcome of these studies may contribute to identification of repair pathways for therapeutic exploitation and to the potential health effects to normal tissue

Publications

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Folkes LK (2013) Modification of DNA damage mechanisms by nitric oxide during ionizing radiation. in Free radical biology & medicine

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Folkes LK (2013) DNA damage induced by nitric oxide during ionizing radiation is enhanced at replication. in Nitric oxide : biology and chemistry

 
Description Chair grants committee for NASA Space Radiation Program on Cancer
Geographic Reach North America 
Policy Influence Type Participation in a advisory committee
Impact Grant review for NASA to enhance protection of astronauts to cancer induction during missions.
 
Description EU SCENIHR - Working Group on Security Scanners
Geographic Reach Europe 
Policy Influence Type Membership of a guidance committee
Impact Use of scanners at airports - safety aspects for human health
 
Description EU Scientific Committee on Emerging and Newly Identified Health Risks; SCENIHR Working Group
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact Advice on radiation risks of airport scanners for consideration by EU parliament
 
Description MSc on Radiation Biology Course Director
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact sustainability of persons in the Radiation Biology
 
Description Member of MELODI Group on development of Strategic Research Agenda for EU radiation Protection Pogramme.
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact prorities research areas in low dose radiation risk for EU to impact radiation protection
 
Description NAS COMMITTEE FOR EVALUATION OF SPACE RADIATION CANCER RISK MODEL
Geographic Reach North America 
Policy Influence Type Participation in advisory committee
Impact Health Risk for Astronauts, assessment of risk model developed by NASA
 
Description President of the Radiation Research Society of North America
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Public Health England review panel of Centre for Radiation, Chemical and Environmental Hazards
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Advisory and research to improve advice to Government of Health effects of ionising radiation
 
Description Scientific Committee of MELODI
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact Define the research priorities for EURATOM funding
 
Description the Helmholtz Research School in Radiation Sciences,German Research Centre for Environmental Health
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact Sustainability of expertise in radiation protection
 
Description EU FP7 nuclear fusion programme
Amount € 330,000 (EUR)
Funding ID 269553 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2011 
End 03/2015
 
Description Low dose research initiative
Amount $396,153 (USD)
Funding ID DE-SC0002296 
Organisation U.S. Department of Energy 
Sector Public
Country United States
Start 09/2009 
End 12/2012
 
Description PHE studentship scheme
Amount £90 (GBP)
Organisation Public Health England 
Sector Public
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Japanese Collaboration 
Organisation Japan Atomic Energy Agency (JAEA)
Country Japan 
Sector Public 
PI Contribution trained Japanese collaborators collaborative research
Collaborator Contribution intellectual input equipment
Impact 22261346, 19708778, 17852554 , 17132657, 12137539 19540248, 19468043, 16893955, 14715924
 
Description NASA grant 
Organisation National Aeronautics and Space Administration (NASA)
Department Johnson Space Center (JSC)
Country United States 
Sector Public 
PI Contribution grants from DoE USA Low dose programme
Collaborator Contribution experiments equipment
Impact 22302045, 21362696, 20681786, 18220463, 17339233, 16546909, 6187760
 
Description PHE 
Organisation Public Health Agency (PHA)
Country United Kingdom 
Sector Public 
PI Contribution Fund a joint student
Collaborator Contribution intellectual input in vivo studies
Impact multi-disciplinary, biochemistry, biology,
Start Year 2010
 
Description Rutherford 
Organisation Rutherford Appleton Laboratory
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of laser facilities through Programme access
Collaborator Contribution Joint studentship
Impact 23012265, 22264527, 20079460, 18557822
 
Description German 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 International
Primary Audience Media (as a channel to the public)
Results and Impact Radio broadcast German radio on Fukushima



Inform public on radiation health risks
Year(s) Of Engagement Activity 2013
URL http://www.dradio.de/dlf/sendungen/wib/2035679/