The University of Sheffield
Department of Chemistry

Jane GrasbyProfessor Jane A. Grasby

Professor of Biological Chemistry

Room: C71

Tel: +44-(0)114-22-29478

Fax: +44-(0)114-22-29436

email:

 


 

General Research Teaching

Biographical Sketch

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."

Research Keywords

Catalysis, protein and nucleic structure and function, nucleic acid chemistry, molecular recognition, enzymology

Teaching Keywords

Organic Chemistry; Biological Chemistry

Selected Publications:

  • Synthesis of oligodeoxyribonucleotides containing a conformationally-locked anti analogue of O-6-methyl-2 '-deoxyguanosine and their recognition by MGMT and Atl1, Kabir Abdu, Miren K. Aiertza, Oliver J. Wilkinson, Jane A. Grasby, Pattama Senthong, Andrew C. Povey, Geoffrey P. Margison and David M. Williams, Chem. Commun. 2012, 48, 11214-11216.
  • Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-pi interactions, Oliver J. Wilkinson, Vitaly Latypov, Julie L. Tubbs, Christopher L. Millington, Rihito Morita, Hannah Blackburn, Andrew Marriott, Gail McGown, Mary Thorncroft, Amanda J. Watson, Bernard A. Connolly, Jane A. Grasby, Ryoji Masui, Christopher A. Hunter, John A. Tainer, Geoffrey P. Margison and David M. Williams, Proc. Natl. Acad. Sci. USA 2012, 109, 18755-60.
  • Interstrand disulfide crosslinking of DNA bases supports a double nucleotide unpairing mechanism for flap endonucleases, Amanda Beddows, Nikesh Patel, L. David Finger, John M. Atack, David M. Williams and Jane A. Grasby, Chem. Commun. 2012, 48, 8895-8897.
  • Flap endonucleases pass 5 '-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5 '-ends, Nikesh Patel, John M. Atack, L. David Finger, Jack C. Exell, Peter Thompson, Susan Tsutakawa, John A. Tainer, David M. Williams and Jane A. Grasby, Nucleic Acids Res. 2012, 40, 4507-4519.
  • Unpairing and gating: sequence-independent substrate recognition by FEN superfamily nucleases, J. A. Grasby, L. D. Finger, S. E. Tsutakawa, J. M. Atack and J. A. Tainer, Trends Biochem. Sci 2012, 37, 74-84.
  • Neutralizing Mutations of Carboxylates That Bind Metal 2 in T5 Flap Endonuclease Result in an Enzyme That Still Requires Two Metal Ions, Christopher G. Tomlinson, Karl Syson, Blanka Sengerova, John M. Atack, Jon R. Sayers, Linda Swanson, John A. Tainer, Nicholas H. Williams and Jane A. Grasby, J. Biol. Chem. 2011, 286, 30878-30887.
  • Human Flap Endonuclease Structures, DNA Double-Base Flipping, and a Unified Understanding of the FEN1 Superfamily, S. E. Tsutakawa, S. Classen, B. R. Chapados, A. S. Arvai, L. D. Finger, G. Guenther, C. G. Tomlinson, P. Thompson, A. H. Sarker, B. H. Shen, P. K. Cooper, J. A. Grasby and J. A. Tainer, Cell 2011, 145, 198-211.
  • Substrate recognition and catalysis by flap endonucleases and related enzymes, C. G. Tomlinson, J. M. Atack, B. Chapados, J. A. Tainer and J. A. Grasby, Biochem. Soc. Trans. 2010, 38, 433-437.
  • Bronsted Analysis and Rate-Limiting Steps for the T5 Flap Endonuclease Catalyzed Hydrolysis of Exonucleolytic Substrates, B. Sengerova, C. Tomlinson, J. M. Atack, R. Williams, J. R. Sayers, N. H. Williams and J. A. Grasby, Biochemistry-Us 2010, 49, 8085-8093.
  • The 3 '-Flap Pocket of Human Flap Endonuclease 1 Is Critical for Substrate Binding and Catalysis, L. D. Finger, M. S. Blanchard, C. A. Theimer, B. Sengerova, P. Singh, V. Chavez, F. Liu, J. A. Grasby and B. H. Shen, J. Biol. Chem. 2009, 284, 22184-22194.
  • Three metal ions participate in the reaction catalyzed by T5 flap endonuclease, K. Syson, C. Tomlinson, B. R. Chapados, J. R. Sayers, J. A. Tainer, N. H. Williams and J. A. Grasby, J. Biol. Chem. 2008, 283, 28741-28746.
  • Comparison of the catalytic parameters and reaction specificities of a phage and an archaeal flap endonuclease, R. Williams, B. Sengerowa, S. Osborne, K. Syson, S. Ault, A. Kilgour, B. R. Chapados, J. A. Tainer, J. R. Sayers and J. A. Grasby, J. Mol. Biol. 2007, 371, 34-48.
  • The pH-dependence of the Escherichia coli RNase HII-catalysed reaction suggests that an active site carboxylate group participates directly in catalysis, J. A. Bastock, M. Webb and J. A. Grasby, J. Mol. Biol. 2007, 368, 421-433. 

Research Interests

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.


Research Jane Grasby

Prof. Grasby is Chair of the Faculty Equality and Diversity Committee.

Teaching Section

Organic Chemistry

Undergraduate Courses Taught

  • "Organic Chemistry 3" (Year 1)
    This segment introduces methods for the synthesis of carboxylic acid derivatives and discusses their reactions.
  • "Molecular Biology for Chemists" (Year 3)
    The course introduces the basic principles of molecular biology.
  • "Skills for Success" (Year 3; Segment Leader)
  • The Skills for Success Project aims to ensure that students identify and develop skills that will be of use to them in life, future study and employment and provide a basis from which they can undertake further training of a professional nature.

 

Tutorial & Workshop Support

  • First Year General Tutorials.
  • Second Year Organic Chemistry Tutorials.
  • Third Year Workshops.
  • Third Year Literature Review.

Laboratory Teaching

  • First Year Lab demonstrating.
  • Fourth Year Research Project.