Dr Lynne Cox

George Moody Fellow and Tutor in Biochemistry

Dr Lynne Cox, MA (MA, PhD Camb).

University Lecturer
Fellow of Oriel College
Department of Biochemistry
Phone +44 (0)1865 275721
Fax +44 (0)1865 275721
E-mail lynne.cox@bioch.ox.ac.uk
Department Web page

Teaching:

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.

Research:

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.

Recent Research Publications:

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

Cox LS. Live fast, die young: new lessons in mammalian longevity. Rejuvenation Res. 2009 Aug;12(4):283-8. PubMed PMID: 19725776.

Cox LS, Mattison JA. Increasing longevity through caloric restriction or rapamycin feeding in mammals: common mechanisms for common outcomes? Aging Cell. 2009 Sep;8(5):607-13. Epub 2009 Aug 12. PubMed PMID: 19678809.

Cox, LS. Cell senescence: the future of ageing? Biogerontology. 2009 Jun;10(3):229-33. Epub 2008 Dec 30. PubMed PMID: 19115080.

Boubriak I, Mason PA, Clancy DJ, Dockray J, Saunders RD, Cox LS. DmWRNexo is a 3'-5' exonuclease: phenotypic and biochemical characterization of mutants of the Drosophila orthologue of human WRN exonuclease. Biogerontology. 2009 Jun;10(3):267-77. DOI: 10.1007/s10522-008-9181-3

 Cox, LS (2008). Hypothesis: causes of Type 2 Diabetes in Progeroid Werner Syndrome. Open Longevity Science 2: 100-103 (4) doi: 10.2174/1876326X00802010100

Saunders RD, Boubriak I, Clancy DJ, Cox LS. (2008) Identification and characterization of a Drosophila ortholog of WRN exonuclease that is required to maintain genome integrity. Aging Cell. 2008 Jun;7(3):418-25. Epub 2008 Mar 11. PMID: 18346216

Cox LS, Clancy DJ, Boubriak I, Saunders RD. (2007) Modeling Werner Syndrome in Drosophila melanogaster: hyper-recombination in flies lacking WRN-like exonuclease. Ann N Y Acad Sci. 2007 Nov;1119:274-88. PMID: 18056975

Cox LS, Faragher RG. (2007) From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing. Cell Mol Life Sci. 2007 Oct;64(19-20):2620-41. Review. PMID: 17660942

Rodriguez-Lopez AM, Whitby MC, Borer CM, Bachler MA, Cox LS. Correction of
proliferation and drug sensitivity defects in the progeroid Werner's Syndrome by
Holliday junction resolution. Rejuvenation Res. 2007 Mar;10(1):27-40. PubMed
PMID: 17378750.

Video of our research on WRN in flies:
http://www.youtube.com/watch?gl=GB&hl=en-GB&v=IGQwz2Wv9FU