Sheffield Institute for Nucleic Acids

Professor Jane A. Grasby

Research Interests

Our laboratory is interested in the interactions and reactions of nucleic acids with a particular interest in enzymes that catalyse phosphoryl transfer reactions in nucleic acids. Most recently the target of our studies has been structure-specific nucleases that recognise aberrant structures in DNA and hydrolyse them to reinstate the genome.

One of our favourite enzymes is flap endonucleases (FENs).  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 in eukaryotes 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.

We are working out the molecular mechanism of FENs and related family members, understanding how they recognise DNA substrates and specifically hydrolyse them often using nucleic acid chemistry to help us. With Smythe we are learning how FEN activity is controlled during the cell cycle. Finally, as FENs are overexpressed in certain types of cancer, we are also investigating how to inhibit these enzymes. We also collaborate with Williams on understanding how alkylation of DNA is dealt with in the cell.


Publications

  • Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, McWhirter C, Siöberg CL, Martinez Molina D, Abbott WM, Jones CD, Nissink JW, Durant ST, Grasby JA (2016) Cellularly Active N-Hydroxyurea FEN1 Inhibitors Block Substrate Entry to the Active Site. Nature Chemical Biology. 12, 815-821.
Professor Jane A. Grasby
Professor of Biological Chemistry
Department of Chemistry
+(0) 114 222 9478
j.a.grasby@sheffield.ac.uk