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

Barazzuol L
(2019)
Distinct response of adult neural stem cells to low versus high dose ionising radiation.
in DNA repair

Barazzuol L
(2017)
A coordinated DNA damage response promotes adult quiescent neural stem cell activation.
in PLoS biology

Beucher A
(2009)
ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2.
in The EMBO journal



Brunton H
(2011)
Analysis of human syndromes with disordered chromatin reveals the impact of heterochromatin on the efficacy of ATM-dependent G2/M checkpoint arrest.
in Molecular and cellular biology

Casar Tena T
(2019)
Resting cells rely on the DNA helicase component MCM2 to build cilia.
in Nucleic acids research

Costantini S
(2007)
Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK.
in DNA repair

Covo S
(2009)
Translesion DNA synthesis-assisted non-homologous end-joining of complex double-strand breaks prevents loss of DNA sequences in mammalian cells.
in Nucleic acids research

Deckbar D
(2007)
Chromosome breakage after G2 checkpoint release.
in The Journal of cell biology
Description | diagnostic work |
Geographic Reach | National |
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 | National |
Policy Influence Type | Participation in advisory committee |
Impact | Report published for Health protection advice |
Description | radiation protection |
Geographic Reach | National |
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 | 05/2009 |
End | 06/2012 |
Description | Medical Research Council programme grant |
Amount | £42,662 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2011 |
End | 10/2012 |
Description | Radiation Protection Programme/ |
Amount | £347,481 (GBP) |
Organisation | Spanish National Research Council (CSIC) |
Sector | Public |
Country | Spain |
Start | 09/2006 |
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) |
Funding ID | 084704 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2008 |
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 | 07/2010 |
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 | Public |
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/politicians |
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 |