Reader in Molecular Genetics,
Head of Department, Life Health and Chemical Sciences
Chair, Research Degrees Committee (2010-2012)
Academic Co-ordinator, Research School (2008-2010)
Member of the BBSRC Genes and Developmental Biology Panel (2002-2007)
Member of the BBSRC Committee Pool
Member of the MRC College of Experts.
Executive Committee Member, British Society for Research on Ageing
Oriel 2008 Cellular Senescence Meeting organising committee member
Keywords: Drosophila, genetics, ageing, cell cycle, genome stability, DNA Repair, WRN, Werner Syndrome
Drosophila Molecular Genetics
My laboratory uses the fruit fly Drosophila melanogaster as a model for biological processes, and in particular the biology of oxidative stress resistance and ageing. The value of this organism stems largely from its highly developed background of genetic research, and the sophisticated techniques of genome manipulation which are available. The sequence of the Drosophila genome has been determined, and is publicly available via the web.
Role of WRN-related exonucleases in DNA damage repair
Our initial analysis of the Drosophila genome sequence for WRN homologues also revealed a second exonuclease, CG6744. Our mutational analysis in Drosophila has implicated this exonucleases in spermatogenesis and in genome stability.
Supported by an OU Charter Studentship, Pratima Chennuri
Werner's Syndrome Exonuclease
The progeroid condition Werner's Syndrome is caused by mutation of the WRN helicase. WRN is an unusual RecQ helicase, which also has an exonuclease function. In organisms other than vertebrates, however, it appears that these two activities reside on separate polypeptides. In collaboration with Dr Lynne Cox (University of Oxford), I am investigating the molecular genetics of the Drosophila WRN exonuclease homologue, DmWRNexo.
Supported by the BBSRC, project grant 2007-2010 (David Clancy) and Research into Ageing 2007-2010 (Ralph Lasala)
SysMIC - Mathematical and Systems Biology
SysMic is a consortium (UCL, Birkbeck, Edinburgh and the Open University) undertaking a project funded by the BBSRC as a resource for members of its research community: from graduates beginning their career through to established researchers wishing to improve their skills in mathematical and systems biology. The Open University contribution is from the Faculties of Mathematics Computing & Technology and Science.
SysMIC briefing for DTP students - Word file).
SysMIC goes live to registered members of the BBSRC research community in January 2013 – the first cohort of students are PhD students in the new Doctoral Training Partnerships.
Supported by the BBSRC
Past research projects
Glutathione Biosynthesis, Oxidative Stress and Ageing
Over the last five years, we have been investigating the relationship between oxidative stress and ageing, using Drosophila as a model system. We have focussed on the role of the tri-peptide glutathione, and have manipulated glutathione levels by expressing the enzyme glutamate cysteine ligase (GCL, which catalyses the rate-limiting step in glutathione biosynthesis), by using the Gal4-UAS expression system.
Glutamate cysteine ligase
We have cloned the genes encoding both subunits of the Drosophila homologue of GCL and, in collaboration with the laboratory of Lesley McLellan at the Biomedical Research Centre in Dundee University, are carrying out a detailed molecular genetic analysis of this enzyme with particular emphasis on the role of glutathione on organismal resistance to oxidative stress, and on ageing.We have found that elevation of glutathione levels extends lifespan, though only when in specific tissues. There appears to be a balance between enhanced oxidative stress resistance and negative effects of excess glutathione, as some combinations of GCL transgenes negatively impact on viability.
Funded by the BBSRC, 2001-2004 (Pushpa Kansagra & Claire Kotecki), and by a BBSRC quota studentship 2005-2007 (Claire Kotecki).
In parallel work, we have also investigated the molecular genetics of the enzyme that catalyses the second and final step in glutathione synthesis, Glutathione synthetase (GS). The GS locus encodes a complex set of transcripts. This project uses a combined approach of whole organisms genetics, molecular biology and cell culture. (Joanne Daniels)
Oxidative stress and ageing
The normal ageing process results from a number of causes, including chemical damage. Such chemical damage, oxidative stress, can result from the normal biochemical function of the cells of the body or from environmental sources, and generates a number of highly reactive chemical species, which in turn damage many cell components. All animals have antioxidant systems which have evolved to limit the damage caused by these processes. These systems can be switched on in response to oxidative stress, and there is some limited evidence that this "adaptive response" may increase life span. This research will help us understand the relationship between adaptation to oxidative stress and life span.
We aim to identify genes which are switched on by oxidative stress in the fruit fly Drosophila melanogaster, and to determine whether these genes can influence longevity. We are using functional genomic approaches to investigate oxidative stress resistance and its relationship to the ageing process. We will use microarrays to screen for genes whose expression levels are significantly altered in response to oxidative stress. In a related approach we will carry out a genetic screen for mutants with enhanced oxidative stress resistance. Our collaborators in Dundee are carrying out a related project in which a proteomic approach to the subject is being taken.
Supported by the BBSRC, 2002-2005 (Ruth Akhtar, Julie Bone)
Triplet Repeat Stability in Drosophila
This project is a collaboration with Mark Hirst, and seeks to examine the fate of Fragile X triplet repeat arrays inserted in the Drosophila genome.
S195 Introduction to Human Genetics
S204 Biology: Uniformity and Diversity
S377 Molecular and Cell Biology
S294 Cell Biology
S250 Science in Context
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