 | Robert D C SaundersReader in Molecular
Genetics
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Subject Specialities: | 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 (Previous Research Interests, below), and is publicly available via the web. |
| 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 polypeptided. 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 (Dave Clancy) Supported by Research into Ageing 2007-2010 (Ralph Lasala, Research Student) |  Clones of mwh cells in a mwh DmWRNexo / DmWRNexo wing blade. Click on thumbnail for larger image. | |
| 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. |
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| 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 University of Dundee, 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. Supported by the BBSRC, 2001-2004 (Pushpa Kansagra & Claire Kotecki), and by a BBSRC quota studentship 2005-2008 (Claire Kotecki). |
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| Glutathione
Synthetase 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 Gilfillan) |
 Comet assay reveals DNA damage following GS/GCL knockdown in S2 cells |
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| 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) |
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| 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. Maria Tynan |
External Activities: | Member of the BBSRC
Genes
and Developmental Biology Panel (2002-2007) Member of the MRC College of Experts. Invited speaker at the 35th Annual Meeting of the American Aging Association, held in Boston June 2006. UK-Japan Werner Syndrome consortium meeting, Tokyo, March 2007 Executive committee member, British Society for Research on Ageing External examiner for Brunel University 2009-2012 |
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Other Activities | Academic
Coordinator in the research school (2008-2009). In this role, I
oversaw the development and presentation of the University's Research
Career Development programme. For more information, see the Research Career Development website. Chair of Research Degrees Committee (2010-date) Member of Senate (2010-date) Director, Biomedical Research Network (2009-date) | Programme of events for academic year 2008-9 |
Selected Publications | ||
WRN exonucleases in Drosophila: | Saunders, R. D. C., Boubriak, I., Clancy, D. J., Cox, L. S. (2008) Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. Aging Cell 7; 418-425 | pdf |
| Cox, L. S., Clancy, D. J., Boubriak, I., Saunders, R. D. C. (2007) Modeling Werner Syndrome in Drosophila melanogaster. Ann. N. Y. Acad. Sci. 1119; 274-288. | ||
| Boubriak,
I., Mason, P. A., Clancy, D. J., Dockray, J., Saunders, R. D. C., Cox.
L. S. 92009) DmWRNexo is a 3′–5′ exonuclease: phenotypic and
biochemical characterization of mutants of the Drosophila orthologue of
human WRN exonuclease. Biogerontology 10; 267-277 | ||
GCL, Oxidative Stress and Lifespan: | Mathers, J., Fraser, J. A., McMahon, M., Saunders, R. D. C., Hayes, J. D., & McLellan, L. I. (2004) Antioxidant and Cytoprotective Responses to Redox Stress. Biochem. Soc. Symp. 71, 157–176. | |
| Fraser, J. A, Kansagra, P., Kotecki, C., Saunders, R. D. C., McLellan, L. I. (2003) The Modifier Subunit of Drosophila Glutamate-Cysteine Ligase Regulates Catalytic Activity by Covalent and Noncovalent Interactions and Influences Glutathione Homeostasis in vivo. J. Biol. Chem., Vol. 278; 46369-46377 | ||
| Fraser, J. A., Saunders, R. D. C. & McLellan, L. I. (2002) Drosophila melanogaster glutamate cysteine ligase activity is regulated by a modifier subunit with a similar mechanism of action to the mammalian form. Journal of Biological Chemistry 277; 1158-1165 | ||
| Saunders, R. D. C. and McLellan, L. I. (2000) Molecular cloning of Drosophila γ-glutamylcysteine synthetase by functional complementation of a yeast mutant. FEBS Lett. 467; 337-340. | ||
Genome analysis in Drosophila: | Peter, A. et al (2002) Identification and mapping of vital gene functions of the Drosophila X-chromosome EMBO Reports 3; 34-38. | |
| Benos et al (2001) From first base: The sequence of the tip of the X chromosome of D. melanogaster: a comparison of two sequencing strategies. Genome Research 11; 710-730. | ||
| Benos, P. V. et al (2000) From sequence to chromosome: the tip of the X chromosome of D. melanogaster. Science 287; 2220-2222. | ||
| Adams, M. D. et al (2000) The genome sequence of Drosophila melanogaster. Science 287; 2185-2195. | ||
| Saunders, R. D. C. (1999) In situ hybridisation to polytene chromosomes. Chapter 7, pp103-113 In "In situ Hybridization Protocols. Methods in Molecular Biology vol. 123" Ed. I. A. Darby Pub. Humana Press. | ||
| Saunders, R. D. C. (1998) Drosophila genome maps. In ICRF Handbook of Genome Analysis Volume 2, pp667-686. Eds Spurr, N. K., Young, B. D. & Bryant, S. P. Pub. Blackwells. | ||
| Deák, P., Omar, M. M., Saunders, R. D. C., Pál, M., Komonyi, O., Szidonya, J. Maróy, P., Zhang, Y., Ashburner, M., Benos, P., Savakis, C., Sidén-Kiamos, I., Louis, C., Bolshakov, V., Kafatos, F. C., Madueño, E., Modolell, J. & Glover, D. M. (1997) P element insertion alleles of essential genes on the third chromosome of Drosophila melanogaster: Correlation of physical and cytogenetic maps in the chromosomal region 86E-87F. Genetics, 147; 1697-1722. | ||
| E. Madueno, et al (1995) A
Physical Map of the X Chromosome of Drosophila melanogaster: Cosmid
Contigs and Sequence Tagged Sites Genetics 1995 139: 1631-1647. |
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Other publications: | Kress, H., Jarrin, A., Thuroff, E., Saunders, R., Weise, C., Schmidt am Busch, M., Knapp, E. W., Wedde, M., Vilcinskas, A. (2004) A Kunitz type protease inhibitor related protein is synthesized in Drosophila prepupal salivary glands and released into the moulting fluid during pupation. Insect Biochem and Mol Biol. 34; 855-869. | |
| Renault, A. D., Zhang, X.-H., Alphey, L. S., Frenz, L. M., Glover, D. M., Saunders, R. D. C. & Axton, J. M. (2003) gnu is essential in the cell cycle transition from meiosis to mitosis. Development, 130; 2997-3005. | | |
| Yamamoto, R. Axton, J.M., Yamamoto, Y. Saunders, R.D.C., Glover, D.M. and Henderson, D.S. (2000) The Drosophila mus101 Gene, Which Links DNA Repair, Replication and Condensation of Heterochromatin in Mitosis, Encodes a Protein With Seven BRCA1 C-Terminus Domains. Genetics 156: 711-721. |
