Professor Lynne Cox
I hold the position of George Moody Fellow and Tutor in Biochemistry at Oriel.
My lab studies the molecular basis of human ageing, with the aim of reducing the morbidity and frailty associated with old age. Replicative senescence is loss of ability of cells to copy their DNA, that underlies and is thought to cause human ageing. We study progeroid Werner's syndrome (WS), where cell senescence and early onset of many age-related symptoms in the patients result from loss of a single protein, the WRN helicase/exonuclease that is involved in DNA replication, recombination and repair. We have shown that DNA replication is aberrant in human cells when WRN protein is mutated.
Using a powerful confocal microscopy approach, we have examined individual DNA molecules in the process of replicating, and find that in WS cells, the majority of DNA replication forks show abnormalities characteristic of fork stalling and collapse. Such collapse is thought to result in the DNA forming unusual 4-way junctions called Holliday junctions, ad we have recently demonstrated that we can overcome some of the severe defects in WS cells by over-expressing a bacterial protein that cuts Holliday junctions.
Although these findings provide clues to WRN’s action in cells, it is hard to dissect out the precise role as the patient cells we use are already genetically unstable and some problems may not be due solely to loss of WRN. We are therefore developing “isogenic” models of WS, including a cell culture model and a fly model.
To further study the role of WRN, we have established a fly model of Werner's syndrome. Our recent discovery that flies share the WRN exonuclease with humans was very exciting as it now allows us to test the impact of specific mutations in the WRN gene on development and ageing in a whole organism. Moreover, we have purified the Drosophila WRN protein, shown that it has exonuclease activity in vitro and are now examining its structure. By combining core biochemical and biophysical methods with fly genetics and developmental biology, we have generated a very powerful tool to discover precisely what WRN does in cells and how it prevents premature ageing.
My research interests lie in DNA, how it is copied accurately and how this is co-ordinated within the cell division cycle. Such interests allow me to teach at a research level all aspects of DNA metabolism, including DNA replication, repair, recombination, transcription, translation and cell biology including cell cycle and cancer. I therefore cover Paper III and much of Paper IV for Part I, together with the Human Disease course in Part II, and molecular and cell biology aspects of the first year MCB paper.
Mason, P.A., Boubriak, I., Cox, L.S. (2013), A fluorescence-based exonuclease assay to characterize DmWRNexo, orthologue of human progeroid WRN exonuclease, and its application to other nucleases, Journal of Visualized Experiments, (82), e50722.
Mason, P.A., Boubriak, I., Robbins, T., Lasala, R., Saunders, R., Cox, L.S. (2013), The Drosophila orthologue of progeroid human WRN exonuclease, DmWRNexo, cleaves replication substrates but is inhibited by uracil or abasic sites: Analysis of DmWRNexo activity in vitro, Age, 35 (3), pp. 793-806.
Kenessary, A., Zhumadilov, Z., Nurgozhin, T., Kipling, D., Yeoman, M., Cox, L., Ostler, E., Faragher, R. (2013), Biomarkers, interventions and healthy ageing, New Biotechnology, 30 (4), pp. 373-377.
Mason, P.A., Cox, L.S. (2012), The role of DNA exonucleases in protecting genome stability and their impact on ageing, Age, 34 (6), pp. 1317-1340.
Cox, L.S., Boubriak, I. (2012), DNA Instability in premature aging (Book Chapter), DNA Damage Repair, Repair Mechanisms and Aging, pp. 1-34.
Bird, J.L.E., Jennert-Burston, K.C.B., Bachler, M.A., Mason, P.A., Lowe, J.E., Heo, S.-J., Campisi, J., Faragher, R.G.A., Cox, L.S. (2012), Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease, Biogerontology, 13 (1), pp. 49-62.
Cox, LS. (2009) Editor: Molecular Themes in DNA Replication. Research monograph, Royal Society of Chemistry. Published 30th September 2009. ISBN: 978-0-85404-164-0
Cox, LS. And Kearsey S. (2009) Ring structures and six-fold symmetry in DNA replication. In Molecular Themes in DNA Replication, Research monograph, Royal Society of Chemistry. Published 30th September 2009. ISBN: 978-0-85404-164-0
Budd, ME, Cox, LS and Campbell, JL. (2009) Coordination of nucleases and helicases during DNA replication and double-strand break repair. In Molecular Themes in DNA Replication, Research monograph, Royal Society of Chemistry. Published 30th September 2009. ISBN: 978-0-85404-164-0
Video of our research on WRN in flies: