Fox, Keith R - University of Southampton - Discipline of Biological Sciences

个人简介

Career history 2000-present: Professor of Biochemistry. University of Southampton, UK. 2012-2013: Acting Head of Biological Sciences 1994-2000: Reader, Division of Biochemistry & Molecular Biology, School of Biological Sciences, University of Southampton. 1992-1994: Senior Lecturer, Department of Physiology & Pharmacology, University of Southampton. 1989-1994: Lister Institute Research Fellow. 1987-1991: Lecturer, Department of Physiology & Pharmacology, University of Southampton. 1982-1986: Research Fellow, Emmanuel College, Cambridge. 1980-1986: Research Associate, Department of Pharmacology, University of Cambridge. Academic qualifications PhD (Pharmacology). University of Cambridge, UK. MPhil (Pharmacology). University of Cambridge, UK. MA Natural Sciences (Biochemistry). University of Cambridge, UK.

研究领域

My research concerns the sequence specific recognition of DNA by small molecules, oligonucleotides and proteins, and the formation of unusual DNA structures (triplexes and quadruplexes). Compounds that bind to DNA in a sequence specific fashion have potential for artificially controlling gene expression and may be used as anticancer or antiviral agents. Several DNA binding antibiotics are currently used in cancer chemotherapy, and we are seeking to understand the molecular mechanisms by which they bind to DNA with a view to designing new agents with improved selectivity. In all our studies we make extensive use of the footprinting technique, using both natural and synthetic DNA fragments, and have developed this assay as a powerful tool for measuring the specificity, stability and kinetics of ligand-DNA interactions. This has been used to determine the sequence selectivity of several DNA-binding small molecules. For the past 15 years my work has focussed on triple helix formation as a means for targeting specific DNA sequences. Together with Professor Tom Brown (Chemistry) I have developed several nucleotide analogues, which are designed to form stable triplexes under physiological conditions. Using a combination of these we demonstrated the first example of four base-pair recognition of a DNA sequence by a triplex-forming oligonucleotide at pH 7. In order to facilitate our studies on the stability of triplexes, quadruplexes and small-molecule-DNA complexes we developed a high throughput fluorescence assay for determining DNA melting profiles. DNA quadruplexes can be formed by G-rich DNA sequences, and these may play a role in telomere structure or controlling gene expression. We have studied their biophysical properties studies, examining their stability, structure, and competition with DNA duplexes. Together with Professor Tom Brown (now in Chemistry, Oxford) we have developed a novel fluorescence assay for measuring the stability of DNA duplexes, triplexes and quadruplexes [Darby et al. (2002) High throughput measurement of duplex, triplex and quadruplex melting curves using molecular beacons and the LightCycler. Nucleic Acids Res. 29, e39]. This uses synthetic oligonucleotides to which are attached a fluorophore (fluorescein) and a quencher (methyl red). These are positioned so that these groups are close together in a folded DNA structure, such as a quadruplex or duplex, thereby quenching the fluorescence. On increasing the temperature the DNA melts, separating these fluorescence groups and there is a large increase in fluorescence. These experiments are performed on the Roche LightCycler, allowing us to examine 32 samples in parallel, using only small volumes (20 µL) of dilute oligonucleotides (0.25 µM).

近期论文

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Stabilisation of self-assembled DNA crystals by triplex-directed photo-cross-linking - Abdallah, Hatem O., Ohayon, Yoel P., Chandrasekaran, Arun Richard, Sha, Ruojie, Fox, Keith R., Brown, Tom, Rusling, David A., Mao, Chengde and Seeman, Nadrian C. Published:2016Publication:Chemical CommunicationsVolume:52, (51)Page Range:8014-8017doi:10.1039/c6cc03695c Breakthrough articles: putting science first - Corey, D.R., Wise, J.A., Fox, K.R. and Stoddard, B.L. Published:2014Publication:Nucleic Acids ResearchVolume:42, (18)Page Range:11273-11274doi:10.1093/nar/gku853 A mutant of uracil DNA glycosylase that distinguishes between cytosine and 5-methylcytosine - Kimber, Scott T., Brown, Tom and Fox, Keith R. Published:2014Publication:PLoS ONEVolume:9, (4)Page Range:e95394doi:10.1371/journal.pone.0095394 Functionalizing designer DNA crystals with a triple-helical veneer - Rusling, David A., Chandrasekaran, Arun Richard, Ohayon, Yoel P., Brown, Tom, Fox, Keith R., Sha, Ruojie, Mao, Chengde and Seeman, Nadrian C. Published:2014Publication:Angewandte Chemie International EditionVolume:53, (15)Page Range:3979-3982doi:10.1002/anie.201309914 Sequence-specific recognition of DNA nanostructures - Rusling, David A. and Fox, Keith R. Published:2014Publication:MethodsPage Range:1-11doi:10.1016/j.ymeth.2014.02.028 Thioester bonds of Thiocoraline can be replaced with NMe-Amide bridges without affecting its DNA-binding properties - Zamudio-Vázquez, Rubí, Albericio, Fernando, Tulla-Puche, Judit and Fox, Keith R. Published:2014Publication:ACS Medicinal Chemistry LettersVolume:5, (1)Page Range:45-50doi:10.1021/ml400323x A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells - Miranda, Elena, Nordgren, Ida, Male, Abigail, Lawrence, Charlotte, Hoakwie, Franciane, Cuda, F., Court, William, Fox, Keith R., Townsend, Paul, Packham, Graham K., Eccles, Suzanne A. and Tavassoli, Ali Published:2013Publication:Journal of the American Chemical SocietyVolume:135, (28)Page Range:10418-10425doi:10.1021/ja402993uPMID:23796364