The University of Sheffield
Department of Chemistry

David WilliamsDr. David M. Williams

Senior Lecturer in Chemical Biology

Room: C79

Tel: +44-(0)114-22-29502

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

email:

 


 

General Information Research Teaching

Biographical Sketch

Dr. Williams obtained a BSc in Chemistry from the University of Liverpool in 1985, which was followed by a PhD from the same institution in 1988. From 1988, he was a Postdoctoral Research Fellow at the Max-Planck Institute for Experimental Medicine in Göttingen and from 1992-1995 at the MRC Laboratory of Molecular Biology in Cambridge. In 1995 he became a demonstrator at the University of Sheffield and in 1999 became a lecturer and in 2006 he was promoted to senior lecturer.

Research Keywords

Nucleic acid chemistry, heterocyclic chemistry, nucleotide chemistry, DNA damage, DNA repair, O6-alkylguanine-DNA alkyltransferases, alkyltransferase-like proteins

Teaching Keywords

Organic Chemistry

Selected Publications:

  • Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations, F. Zhang, M. Tsunoda, K. Suzuki,Y. Kikuchi, O. Wilkinson, C.L. Millington, G.P. Margison, D.M. Williams, E. Czarina Morishita and A. Takénaka, Nucleic Acids Res. 2013, 41, 5524-5532.
  • The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase, P. Senthong, C.L. Millington, O.J. Wilkinson, A.S. Marriott, A.J. Watson, O. Reamtong, C.E. Eyers, D.M. Williams, G.P. Margison and A.C. Povey, Nucleic Acids Res., 2013, 41, 3047–3055
  • Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation–pi interactions, O.J. Wilkinson, V. Latypov, J.L. Tubbs, C.L. Millington, R. Morita, H. Blackburn, A. Marriott, G. McGown, M. Thorncroft, A.J. Watson, B.A. Connolly, J.A. Grasby, R. Masui, C.A. Hunter, J.A. Tainer, G.P. Margison and D.M. Williams, Proc. Natl. Acad. Sci. U.S.A., 2012, 109 18755-18760
  • Synthesis of oligodeoxyribonucleotides containing a conformationally-locked anti analogue of O6-methyl-2'-deoxyguanosine and their recognition by MGMT and Atl1, K.Abdu, M.K. Aiertza, O.J. Wilkinson, J.A. Grasby, P. Senthong, A.C. Povey, G.P. Margison and D.M. Williams, Chem. Commun., 2012, 48, 11214-11216.
  • Atl1 regulates choice between global genome and transcription-coupled repair of O6-alkylguanines, V.F. Latypov, J.L. Tubbs, A.J. Watson, A.S. Marriott, G. McGown, M. Thorncroft, O.J. Wilkinson, P. Senthong, A. Butt, A.S. Arvai, C.L. Millington, A.C. Povey, D.M. Williams, M.F. Santibanez-Koref, J.A. Tainer, G.P. Margison, Mol Cell, 2012, 47, 50-60
  • Convenient and efficient syntheses of oligodeoxyribonucleotides containing O6-(carboxymethyl)guanine and O6-(4-oxo-4-(3-pyridyl)butyl)guanine, C.L. Millington, A.J. Watson, A.S. Marriott, G.P. Margison, A.C. Povey and D.M. Williams, Nucleosides Nucleotides Nucleic Acids, 2012, 31, 328-338.
  • Flap endonucleases pass 5'-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5'-ends, N. Patel, J.M. Atack, L.D. Finger, J.C. Exell, P. Thompson, S. Tsutakawa, J.A. Tainer, D.M. Williams and J.A. Grasby, Nucleic Acids Res. 2012, 40, 4507-19
  • Insights into the DNA stabilizing contributions of a bicyclic cytosine analogue: crystal structures of DNA duplexes containing 7,8-dihydropyrido [2,3-d]pyrimidin-2-one, E. C. M. Juan, S. Shimizu, X. A. Ma, T. Kurose, T. Haraguchi, F. Zhang, M. Tsunoda, A. Ohkubo, M. Sekine, T. Shibata, C. L. Millington, D. M. Williams and A. Takenaka, Nucleic Acids Res. 2010, 38, 6737-6745.
  • Flipping of alkylated DNA damage bridges base and nucleotide excision repair, J. L. Tubbs, V. Latypov, S. Kanugula, A. Butt, M. Melikishvili, R. Kraehenbuehl, O. Fleck, A. Marriott, A. J. Watson, B. Verbeek, G. McGown, M. Thorncroft, M. F. Santibanez-Koref, C. Millington, A. S. Arvai, M. D. Kroeger, L. A. Peterson, D. M. Williams, M. G. Fried, G. P. Margison, A. E. Pegg and J. A. Tainer, Nature 2009, 459, 808-813.
  • Application of the Ugi Reaction for the One-Pot Synthesis of Uracil Polyoxin C Analogues, A. Plant, P. Thompson and D. M. Williams, J. Org. Chem. 2009, 74, 4870-4873.

 

Research Interests

Our main areas of research are in the synthesis of modified nucleosides and nucleotides and their applications.

Currently we are interested in the chemical synthesis of 5'-triphosphates of base-modified, nucleoside analogues that have altered base pairing specificities. We are studying the incorporation of these analogues into DNA by polymerase enzymes in order to gain an insight into the role of base pairing during DNA replication and DNA mutagenesis.

Exposure to alkylating agents can lead to the formation of highly toxic O6-alkylguanine lesions within DNA. We have developed chemical methodology for the preparation of oligodeoxyribonucleotides containing a variety of O6-alkylguanine analogues and these are being used to study DNA recognition and repair by the human protein O6-methylguanine-DNA methyltransferase (MGMT) and the alkyltransferase-like protein Atl1.

Other areas of interest include the use SELEX for the design of nucleic acid-based ligands and catalysts containing chemically synthesised imidazolyl and amino modified nucleotides of dUTP and 7-deazadATP, studying the structural properties of nucleic acids containing modified pyrimidine and purine bases and the design and synthesis of modified oligodeoxyribonucleotides for DNA-DNA and DNA-protein cross-linking.

Teaching Section

Organic Chemistry

Courses Taught

  • Aromatic chemistry (Year 2)
    This segment reviews the concept of aromaticity and the mechanisms of reactions of aromatic systems, particularly benzene and its derivatives.
  • Introduction to organic synthesis 1 (Year 2)
    This segment revises the reactions of carbonyl compounds with nucleophiles, introduces conjugate addition reactions (electrophilic alkenes), and discusses the acid and base-catalysed reactions of carbonyl compounds at the α-carbon via enols and enolates. Methods for the synthesis of amines are also discussed.
  • Synoptic Unit: Chemical Problem Solving (Year 3)
    This unit will draw on material covered in preceding units of BSc and MChem Chemistry programmes. It provides a synoptic assessment of the application of basic chemical principles to solve a variety of chemical problems. Students will be set problems throughout the academic year and the approaches involved will be developed in a series of workshops.

Tutorial & Workshop Support

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

Laboratory Teaching

  • Second Year Laboratory Demonstrating
  • Third Year Advanced Practical Chemistry Techniques
  • Fourth Year Research Project.