DNA damage responses in mammalian cells and their contribution to human health disorders

Lead Research Organisation: University of Sussex
Department Name: Brighton and Sussex Medical School

Abstract

DNA damage responses encompass DNA repair processes and signal transduction mechanisms. The grant focuses on the response to DNA double strand breaks (DSBs), an important lethal and carcinogenic lesion. DSBs arise from endogenous oxidative damage, during certain metabolic processes including V(D)J recombination, a step during immune development, and following exposure to ionising radiation. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent DSB repair pathways and Ataxia telangiectasia mutated (ATM) regulates the major DSB signalling response. This programme aims to understand how DSBs are processed and rejoined by NHEJ and its contribution to human disease. Three disorders conferred by defects in NHEJ have known and all are associated with immunodeficiency and radiosensitivity. ATM signalling is dispensable for most DSB repair. However, a subset of DSBs require ATM signalling proteins and a nuclease, Artemis. We will examine the roles of Artemis and ATM in DSB repair. ATR regulates a related signalling process that is activated by stalled replication forks and bulky lesions. Seckel Syndrome is characterised by defects in the ATR signalling pathway, although not all defective genes have been identified. This programme will also aim to gain insight into ATR signalling and its contribution to disorders affecting human health.

Technical Summary

DNA damage responses encompass DNA repair processes and signalling transduction mechanisms. DNA non-homologous end-joining (NHEJ) is the major process that repairs DNA double strand breaks (DSBs) induced by ionising radiation. Recent studies have shown that the ATM-dependent signal transduction pathway also impacts upon DNA repair by activating mechanisms required for DNA end-processing and cell cycle checkpoint arrest. NHEJ is required for efficient V(D)J recombination and also functions during development. One aim of this programme is to gain insight into how DSBs are processed and rejoined by NHEJ and the contribution of NHEJ to human health disorders. ATR regulates a related signal transduction process that is activated by stalled replication forks and bulky lesions. We have shown that Seckel Syndrome is characterised by defects in the ATR signalling pathway. This programme will also aim to gain insight into ATR signalling and its contribtuion to disorders affecting human health.

Publications

10 25 50
 
Description diagnostic work
Geographic Reach UK 
Policy Influence Type Influenced training of practitioners or researchers
Impact interface with clinicians to exploit basic research findings for diagnosis
 
Description genetic susceptibility to radiation
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
 
Description high dose radiation exposure
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact Report published for Health protection advice
 
Description radiation protection
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact advice provided for issues of radiation rpotection
 
Description AICR Project Grant
Amount £169,127 (GBP)
Organisation Association for International Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 06/2012
 
Description Medical Research Council programme grant
Amount £42,662 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 10/2012
 
Description Radiation Protection Programme/
Amount £347,481 (GBP)
Organisation Spanish National Research Council (CSIC) 
Sector Public
Country European Union (EU)
Start 10/2006 
End 10/2009
 
Description Wellcome Trust Project Grant (Impact of DNA non homologous end joining on stem cell function in vivo)
Amount £246,628 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 10/2011
 
Description pEMF biological trust project grant/EMF biological research trust
Amount £120,000 (GBP)
Organisation The EMF Biological Research Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2010 
End 08/2011
 
Title Identification of repair defective disorders 
Description Idetnified genes in human disorders - LIG4 syndromes, genes defective in Seckel Syndrome. Have enhanced the ability to diagnose these disorders. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact Now carry out routine diagnosis 
 
Title cell bank for repair defective individuals 
Description Have expanded a cell bank for repair defective individuals 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Idetnification of genetic defects in patients 
 
Description Collaboration wtih Markus Lobrich 
Organisation Technical University of Darmstadt
Country Germany 
Sector Academic/University 
PI Contribution We coontributed experiments and dieas
Collaborator Contribution Collaborative research. Increased output in terms of journals. The Technical University of Darmstadt has a high LET irradiation source which has helped our work
Impact Pubications - multiple. See publiciaton list wtih joint publications between Jeggo and Lobrich
Start Year 2010
 
Description identificaiton of defects in Seckel Syndrome 
Organisation Nagasaki University
Department Tomoo Ogi Department of Molecular Medicine
Country Japan 
Sector Academic/University 
PI Contribution We carried out cellular analysis of patient cell lines
Collaborator Contribution identificaiton of genes causing seckel syndrome; collaborative publication
Impact collaborative paper
Start Year 2006
 
Description identificaiton of defects in Seckel Syndrome 
Organisation University of Sussex
Department Genome Damage and Stability Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We carried out cellular analysis of patient cell lines
Collaborator Contribution identificaiton of genes causing seckel syndrome; collaborative publication
Impact collaborative paper
Start Year 2006
 
Description identification of genes causing SEckel Syndrome 
Organisation Medical Research Council (MRC)
Country United Kingdom 
Sector Academic/University 
PI Contribution we carried out analysis of cell lines from the paitents
Collaborator Contribution Identification of genetic defects causing Seckel Syndrome and collaborative publication
Impact joint publication
Start Year 2006
 
Description health regulators 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Policymakers/parliamentarians
Results and Impact Talked to regulators and scientists at a meeting for radiation protection

none
Year(s) Of Engagement Activity 2008
 
Description participated in two science week programme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact helped the MRC with their stand

no further impacts
Year(s) Of Engagement Activity 2009,2010,2011,2012