Grasby, Jane A., Professor

Professor Jane A. Grasby (she/her)

School of Mathematical and Physical Sciences

School Director of One University

Professor of Biological Chemistry

j.a.grasby@sheffield.ac.uk
+44 114 222 9478

Dainton Building

Full contact details

Professor Jane A. Grasby
School of Mathematical and Physical Sciences
Dainton Building
13 Brook Hill
91ֱ��
S3 7HF

Profile

Professor Grasby obtained her BSc in Chemistry from the University of Birmingham in 1988. After obtaining her PhD in Biochemistry 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 91ֱ��, where she was promoted to Senior Lecturer in 1999, Reader in 2002 and a Personal Chair in 2013. Prof. Grasby has acted as Chair of the Faculty of Science Equality Diversity Committee.

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, shown below human FEN1 (hFEN1) with DNA substrate) 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. FEN1 is the prototypical member of a superfamily of structure-specific 5’-nucleases whose differing activities span all the major DNA metabolic pathways.

Each of the 5’-nucleases acts on a different substrates. Recently, we have been trying to understand both common features of 5’-nucleases and the specialised mechanisms they use to carry out their extraordinary feats of molecular recognition. We have a learnt that the single stranded DNA flap is threaded through a hole in the protein known as the helical arch.

This threading mechanism allows the enzyme to act on discontinuous flap DNAs that have free 5’-ends, but importantly not at single-strand double-strand junctions in DNA that are continuous. The DNA becomes threaded through the arch while this region of the protein is disordered. Forming the helical structure delivers key amino acid residues to the active site to catalyse phosphodiester hydrolysis.

Publications

Journal articles

Morton SB, Finger LD, van der Sluijs R, Mulcrone WD, Hodskinson M, Millington CL, Vanhinsbergh C, Patel KJ, Dickman MJ, Knipscheer P , Grasby JA et al (2023) . Journal of the American Chemical Society, 145(2), 953-959.
Algasaier SI, Finger LD, Bennet IA & Grasby JA (2018) . Biochemistry, 57(50), 6838-6847.
Thompson MJ, Gotham V, Ciani B & Grasby JA (2018) . Nucleic Acids Research, 46(15), 7858-7872.
Bennet I, Finger LD, Baxter NJ, Ambrose B, Hounslow A, Thompson MJ, Exell JC, Shahari NNBM, Craggs TD, Waltho JP & Grasby JA (2018) . Nucleic Acids Research, 46(11), 5618-5633.
Tsutakawa SE, Thompson MJ, Arvai AS, Neil AJ, Shaw SJ, Algasaier SI, Kim JC, Finger LD, Jardine E, Gotham VJB , Sarker AH et al (2017) . Nature Communications.
Shaw SJ, Finger LD & Grasby JA (2017) . Biochemistry, 56(29), 3704-3707.
Tsutakawa SE, Thompson MJ, Arvai AS, Neil AJ, Shaw SJ, Algasaier SI, Kim JC, Finger LD, Jardine E, Gotham VJB , Sarker AH et al (2017) . Nature Communications, 8.
Exell JC, Thompson MJ, Finger LD, Shaw SJ, Debreczeni J, Ward TA, McWhirter C, Siöberg CLB, Martinez Molina D, Abbott WM , Jones CD et al (2016) . Nature Chemical Biology, 12, 815-821.
Algasaier SI, Exell JC, Bennet IA, Thompson MJ, Gotham VJB, Shaw SJ, Craggs TD, Finger LD & Grasby JA (2016) . Journal of Biological Chemistry, 291(15), 8258-8268.
Kime L, Clarke JE, Romero A D, Grasby JA & McDowall KJ (2014) . Nucleic Acids Res, 42(7), 4577-4589.
Patel N, Exell JC, Jardine E, Ombler B, Finger LD, Ciani B & Grasby JA (2013) . J. Biol. Chem., 288, 34239-34248.
Finger LD, Patel N, Beddows A, Ma L, Exell JC, Jardine E, Jones AC & Grasby JA (2013) . Nucleic Acids Res, 41(21), 9839-9847.
Finger LD, Atack JM, Tsutakawa S, Classen S, Tainer J, Grasby J & Shen B (2012) , 301-326.
Wilkinson OJ, Latypov V, Tubbs JL, Millington CL, Morita R, Blackburn H, Marriott A, McGown G, Thorncroft M, Watson AJ , Connolly BA et al (2012) . Proc Natl Acad Sci U S A, 109(46), 18755-18760.
Abdu K, Aiertza MK, Wilkinson OJ, Grasby JA, Senthong P, Povey AC, Margison GP & Williams DM (2012) . Chem Commun (Camb), 48(91), 11214-11216.
Beddows A, Patel N, Finger LD, Atack JM, Williams DM & Grasby JA (2012) . Chem Commun (Camb), 48(71), 8895-8897.
Patel N, Atack JM, Finger LD, Exell JC, Thompson P, Tsutakawa S, Tainer JA, Williams DM & Grasby JA (2012) . Nucleic Acids Res, 40(10), 4507-4519.
Grasby JA, Finger LD, Tsutakawa SE, Atack JM & Tainer JA (2012) . Trends in Biochemical Sciences, 37(2), 74-84.
Grasby JA, Finger LD, Tsutakawa SE, Atack JM & Tainer JA (2012) . Trends Biochem Sci, 37(2), 74-84.
Tomlinson CG, Syson K, Sengerová B, Atack JM, Sayers JR, Swanson L, Tainer JA, Williams NH & Grasby JA (2011) . J Biol Chem, 286(35), 30878-30887.
Tsutakawa SE, Classen S, Chapados BR, Arvai AS, Finger LD, Guenther G, Tomlinson CG, Thompson P, Sarker AH, Shen B , Cooper PK et al (2011) . Cell, 145(2), 198-211.
Sengerová B, Tomlinson C, Atack JM, Williams R, Sayers JR, Williams NH & Grasby JA (2010) . Biochemistry, 49(37), 8085-8093.
Tomlinson CG, Atack JM, Chapados B, Tainer JA & Grasby JA (2010) . Biochem Soc Trans, 38(2), 433-437.
Finger LD, Blanchard MS, Theimer CA, Sengerová B, Singh P, Chavez V, Liu F, Grasby JA & Shen B (2009) . J Biol Chem, 284(33), 22184-22194.
Syson K, Tomlinson C, Chapados BR, Sayers JR, Tainer JA, Williams NH & Grasby JA (2008) . J Biol Chem, 283(42), 28741-28746.
Williams R, Sengerová B, Osborne S, Syson K, Ault S, Kilgour A, Chapados BR, Tainer JA, Sayers JR & Grasby JA (2007) . J Mol Biol, 371(1), 34-48.
Bastock JA, Webb M & Grasby JA (2007) . J Mol Biol, 368(2), 421-433.
Marsh AJ, Williams DM & Grasby JA (2004) . Org Biomol Chem, 2(14), 2103-2112.
Kovacheva YS, Tzokov SB, Murray IA & Grasby JA (2004) . Nucleic Acids Res, 32(21), 6240-6250.
Sidorov AV, Grasby JA & Williams DM (2004) . Nucleic Acids Res, 32(4), 1591-1601.
Redko Y, Tock MR, Adams CJ, Kaberdin VR, Grasby JA & McDowall KJ (2003) . J Biol Chem, 278(45), 44001-44008.
Tock MR, Frary E, Sayers JR & Grasby JA (2003) . EMBO J, 22(5), 995-1004.
Tzokov SB, Murray IA & Grasby JA (2002) . J Mol Biol, 324(2), 215-226.
Dickman MJ, Ingleston SM, Sedelnikova SE, Rafferty JB, Lloyd RG, Grasby JA & Hornby DP (2002) . Eur J Biochem, 269(22), 5492-5501.
Patel D, Tock MR, Frary E, Feng M, Pickering TJ, Grasby JA & Sayers JR (2002) . J Mol Biol, 320(5), 1025-1035.
Dervan JJ, Feng M, Patel D, Grasby JA, Artymiuk PJ, Ceska TA & Sayers JR (2002) . Proc Natl Acad Sci U S A, 99(13), 8542-8547.
Ingleston SM, Dickman MJ, Grasby JA, Hornby DP, Sharples GJ & Lloyd RG (2002) . Eur J Biochem, 269(5), 1525-1533.
Dickman MJ, Conroy MJ, Grasby JA & Hornby DP (2002) . RNA, 8(2), 247-251.
Gourlain T, Sidorov A, Mignet N, Thorpe SJ, Lee SE, Grasby JA & Williams DM (2001) . Nucleic Acids Res, 29(9), 1898-1905.
Lee SE, Sidorov A, Gourlain T, Mignet N, Thorpe SJ, Brazier JA, Dickman MJ, Hornby DP, Grasby JA & Williams DM (2001) . Nucleic Acids Res, 29(7), 1565-1573.
Patel D, Garforth SJ, Pickering TJ, Grasby JA & Sayers JR (2001) . Biochemical Society Transactions, 29(1), A30-A30.
Lee SE, Vyle JS, Williams DM & Grasby JA (2000) Novel syntheses of (Z)-alkene and alkane base-modified nucleosides. TETRAHEDRON LETT, 41(2), 267-270.
Pickering TJ, Garforth S, Sayers JR & Grasby JA (1999) . J Biol Chem, 274(25), 17711-17717.
Young KJ, Vyle JS, Pickering TJ, Cohen MA, Holmes SC, Merkel O & Grasby JA (1999) . J Mol Biol, 288(5), 853-866.
Pickering TJ, Garforth SJ, Thorpe SJ, Sayers JR & Grasby JA (1999) . Nucleic Acids Res, 27(3), 730-735.
Holmes SC, Pearson ND & Grasby JA (1999) Synthesis and incorporation of a novel nucleoside phosphoramidite linker into oligonucleotides. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 2, 119-123.
Lee SE, Mignet N, Vyle JS, Whetton L, Grasby JA & Williams DM (1999) The synthesis of modified 5-(aminoalkyl)- and 5-(aminoalkenyl)uridine 5 '-triphosphates. CHEMISTRY OF NUCLEIC ACID COMPONENTS, 2, 35-38.
Vyle JS, Williams NH & Grasby JA (1998) A novel solid support for synthesis of 2 ',3 '-cyclic phosphate terminated oligonucleotides. TETRAHEDRON LETT, 39(43), 7975-7978.
Vyle JS, Young KJ & Grasby JA (1998) Incorporation of methylated pyrimidine analogues into RNA. TETRAHEDRON LETT, 39(28), 5093-5096.
Young KJ, Gill F & Grasby JA (1997) . Nucleic Acids Res, 25(19), 3760-3766.
Thorogood H, Grasby JA & Connolly BA (1996) . J Biol Chem, 271(15), 8855-8862.
Young KJ, Gill F & Grasby JA (1996) Mechanistic studies of the hairpin ribozyme. COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, 61, S268-S270.
Vyle JS, Young KJ, Jones S & Grasby JA (1996) Synthesis of uridine analogues to probe the functional group requirements of the hairpin ribozyme. COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, 61, S280-S282.
Grasby JA, Mersmann K, Singh M & Gait MJ (1995) . Biochemistry, 34(12), 4068-4076.
GRASBY JA, SINGH M, KARN J & GAIT MJ (1995) SYNTHESIS AND APPLICATIONS OF OLIGORIBONUCLEOTIDES CONTAINING N-4-METHYLCYTIDINE. NUCLEOSIDES & NUCLEOTIDES, 14(3-5), 1129-1132.
GAIT MJ, GRASBY JA, KARN J, MERSMANN K & PRITCHARD GE (1995) SYNTHETIC RIBONUCLEOTIDE ANALOGS FOR RNA STRUCTURE-FUNCTION STUDIES. NUCLEOSIDES & NUCLEOTIDES, 14(3-5), 1133-1144.
GRASBY JA, PRITCHARD CE & GAIT MJ (1994) APPLICATIONS OF SYNTHETIC OLIGORIBONUCLEOTIDE ANALOGS IN STUDIES OF RNA STRUCTURE AND FUNCTION. P INDIAN AS-CHEM SCI, 106(5), 1003-1022.
Pritchard CE, Grasby JA, Hamy F, Zacharek AM, Singh M, Karn J & Gait MJ (1994) . Nucleic Acids Res, 22(13), 2592-2600.
Grasby JA & Gait MJ (1994) . Biochimie, 76(12), 1223-1234.
Grasby JA, Jonathan P, Butler G & Gait MJ (1993) . Nucleic Acids Res, 21(19), 4444-4450.
Grasby JA, Pritchard CE, Mersmann K, Seela F & Gait MJ (1993) . Collection of Czechoslovak Chemical Communications, 58(s1), 154-157.
SEELA F, MERSMANN K, GRASBY JA & GAIT MJ (1993) 7-DEAZAADENOSINE - OLIGORIBONUCLEOTIDE BUILDING-BLOCK SYNTHESIS AND AUTOCATALYTIC HYDROLYSIS OF BASE-MODIFIED HAMMERHEAD RIBOZYMES. HELV CHIM ACTA, 76(5), 1809-1820.
Grasby JA & Connolly BA (1992) . Biochemistry, 31(34), 7855-7861.
SEELA F, MERSMANN K, GRASBY JA & GAIT MJ () . ChemInform, 24(48), no-no.

Chapters

Grasby JA, Young KJ, Gill F & Vyle JS (1996) The hairpin ribozyme In Meunier B (Ed.) (pp. 295-306).
Grasby JA & Williams DM () , Organophosphorus Chemistry (pp. 161-230). Royal Society of Chemistry
Grasby JA & Williams DM () , Organophosphorus Chemistry (pp. 170-236). Royal Society of Chemistry
Grasby JA & Williams DM () , Organophosphorus Chemistry (pp. 177-263). Royal Society of Chemistry
Grasby JA & Williams DM () , Organophosphorus Chemistry (pp. 196-264). Royal Society of Chemistry

Conference proceedings papers

Finger LD, Bennet IA, Hounslow A, Exell JC, Baxter NJ, Waltho JP & Grasby JA (2015) The Catalytic Cycle of hFEN1 Requires Protein and DNA Conformational Changes, but Are They Rate-Limiting?. PROTEIN SCIENCE, Vol. 24 (pp 147-147)
Tsutakawa S, Arvai A, Sarker A, Querol-Audi J, Finger D, Nogales E, Ivanov I, Cooper P, Grasby J & Tainer J (2014) . Biophysical Journal, Vol. 106(2) (pp 230a-230a)
Osborne SD & Grasby JA (2005) Investigations into substrate analogues for Fen-1. Chemistry of Nucleic Acid Components, Vol. 7 (pp 347-350)
Kovacheva YS, Tzokov SB, Murray IA & Grasby JA (2002) Kinetic studies of the Neurospora vs ribozyme. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 352-355)
Tzokov SB, Macdonald IK, Murray IA & Grasby JA (2002) Investigating catalytic RNA molecules. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 231-240)
Marsh AJ, Price C & Grasby JA (2002) Synthesis of polyamine-uridine conjugates by derivatisation at the 5-position. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 5 (pp 241-244)
Pickering TJ, Garforth SJ, Sayers JR & Grasby JA (1999) Mechanistic studies of a 5 ' nuclease from T5 bacteriophage. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 2 (pp 161-167)
McDonald IK, Holmes SC, Young KJ, Vyle JS, Pickering TJ & Grasby JA (1999) Functional group mutagenesis of the hairpin ribozyme. CHEMISTRY OF NUCLEIC ACID COMPONENTS, Vol. 2 (pp 306-309)

Website content

Grasby JA Home Page.

Teaching interests: Organic Chemistry; Biological Chemistry

Teaching activities

Undergraduate and postgraduate taught modules

Carbonyl Compounds and Carboxylic Acids (Level 1)
This lecture course introduces methods for the synthesis of carboxylic acid derivatives and discusses their reactions.
Chemistry in a Sustainable Future (Level 1)
Introduction to Chemical Biology & Medicinal Chemistry (Level 3)
This course introduces the basic principles of chemical biology and medicinal chemistry
Skills for Success (Level 3; course 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.

Support Teaching:

Tutorials: Level 1 General Chemistry.
Level 3 Literature Review

Laboratory Teaching:

Level 4 Research Project