Grasby, Jane A - University of Sheffield

个人简介

Professor Grasby obtained her BSc in Chemistry from the University of Birmingham in 1988. After obtaining her PhD in Chemistry from the University of Southampton in 1992, she became a Research Fellow at the Laboratory of Molecular Biology in Cambridge. In 1994 she was appointed to a Lectureship at the University of Sheffield, where she was promoted to Senior Lecturer in 1999, Reader in 2002 and a personal chair in 2013. Prof. Grasby is Chair of the Faculty of Science Equality Diversity Committee and was recently seconded to work 2 days a week on an EPSRC funded project entitled "Developing Women Research Leaders."

研究领域

The interactions and reactions of nucleic acids are fundamental to life. Our research has seeks to understand these processes using a range of techniques including chemical synthesis of modified nucleic acids, molecular biology, enzymology, biophysics (fluorescence, CD and NMR spectroscopies) and X-ray crystallography. We are particularly interested in the catalysis of reactions of nucleic acids (RNA and DNA) and most recently in the question of how structure, but not sequence, specific nucleases achieve specificity in nucleic acid hydrolysis. Flap endonucleases (FENs illustrated in (a) below) have been the focus of much of our recent work. FENs are a vital component of the lagging strand DNA replication apparatus in all organisms and also play role in DNA repair in eukaryotes. FENs remove 5’-single-stranded protrusions to double-stranded DNA known as flaps, formed as a result of DNA polymerase strand displacement synthesis. In humans FENs have to carry out approximately 50 million phosphate diester hydrolyses to allow replication of a single cell. FENs are the prototypical members of a superfamily of structure-specific 5’-nucleases whose differing activities span all major DNA metabolic pathways. Although 5’-nucleases act on different substrates, their reactions have a common feature. All 5’-nucleases catalyse hydrolysis one nucleotide into double stranded DNA. A recent highlight of our work was to discover the origins of this specificity to be a double nucleotide unpairing mechanism, that allows only the target phosphate diester to contact catalytic metal ions (illustrated in (b) below). Currently we are trying to understand the features of FENs and other family members that are required for unpairing DNA, how conformational dynamics of the protein are related to this and whether unpairing of duplex ends is a general feature of the mechanisms of other DNA replicative, repair and recombination nucleases.

近期论文

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Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, McWhirter C, Siöberg CLB, Martinez Molina D, Abbott WM, Jones CD, Nissink WM, Durant ST & Grasby JA (2016) Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site. Nature Chemical Biology, 12, 815-821. View this article in WRRO Algasaier SI, Exell JC, Bennet IA, Thompson MJ, Gotham VJB, Shaw SJ, Craggs TD, Finger LD & Grasby JA (2016) DNA and Protein Requirements for Substrate Conformational Changes Necessary for Human Flap Endonuclease-1-catalyzed Reaction. Journal of Biological Chemistry, 291(15), 8258-8268. View this article in WRRO Kime L, Clarke JE, Romero A D, Grasby JA & McDowall KJ (2014) Adjacent single-stranded regions mediate processing of tRNA precursors by RNase E direct entry.. Nucleic Acids Res, 42(7), 4577-4589. Patel N, Exell JC, Jardine E, Ombler B, Finger LD, Ciani B & Grasby JA (2013) Proline Scanning Mutagenesis Reveals a Role for the Flap Endonuclease-1 Helical Cap in Substrate Unpairing. J. Biol. Chem.. View this article in WRRO Finger LD, Patel N, Beddows A, Ma L, Exell JC, Jardine E, Jones AC & Grasby JA (2013) Observation of unpaired substrate DNA in the flap endonuclease-1 active site.. Nucleic Acids Res, 41(21), 9839-9847. View this article in WRRO Wilkinson OJ, Latypov V, Tubbs JL, Millington CL, Morita R, Blackburn H, Marriott A, McGown G, Thorncroft M, Watson AJ, Connolly BA, Grasby JA, Masui R, Hunter CA, Tainer JA, Margison GP & Williams DM (2012) Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions.. Proc Natl Acad Sci U S A, 109(46), 18755-18760.