Sheffield Institute for Nucleic Acids

Dr David M. Williams

Research Interests

We have over 20 years experience in nucleic acid chemistry and biochemistry. Our interests include the chemical synthesis of base-modified nucleosides, nucleotides and nucleic acids for understanding the mechanisms of DNA base damage and how specific proteins recognise and repair this damage. Over the last 10 years we have focused on DNA containing O6-alkylguanine adducts. Our research is both collaborative and multidisciplinary.

Highlights include developing methodology for the chemical synthesis of O6-alkylguanine-containing oligodeoxyribonucleotides, the first biochemical and structural characteristion of “alkyltransferase-like” (ATL) proteins, that bind, but do not de-alkylate O6-alkG adducts in DNA, details about the cellular role of ATL proteins in enlisting Nucleotide Excision Repair details of how these proteins distinguish O6-alkG adducts from guanine in DNA.

Collaborations within the Sheffield Centre for Nucleic Acid & Genome Biology

Our current collaborations within the group are with Prof. Jane Grasby, and recently with Prof Sherif El-Khamisy in which we are engaged in the chemical synthesis of modified oligodeoxyribonucletides for studying the substrate properties of human DNA nucleic acid processing enzymes FEN-1 and Topoisomerase I. We are also collaborating with Dr Mark Dickman to use MS-based techniques to quantify levels of O6-alkylguanines in DNA.


Publications

  • Zhang, F, Tsunoda, M, Suzuki, K, Kikuchi, Y, Wilkinson, O, Millington, CL, Margison, GP, Williams, DM, Czarina Morishita, E and Takénaka, A, Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations. Nucleic Acids Res. 2013, 41, 5524-5532.
  • Senthong, P, Millington, CL, Wilkinson, OJ, Marriott, AS, Watson, AJ, Reamtong, O, Eyers, CE, Williams, DM, Margison, GP and Povey, AC, The nitrosated bile acid DNA lesion O6-carboxymethylguanine is a substrate for the human DNA repair protein O6-methylguanine-DNA methyltransferase. Nucleic Acids Res. 2013, 41, 3047–3055.
  • 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 and Williams, DM, Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-π interactions. Natl. Acad. Sci. U.S.A., 2012, 109, 18755-18760.
  • Patel, N, Atack, JM, Finger, LD, Exell, JC, Thompson, P, Tsutakawa, S, Tainer, JA, Williams, DM and Grasby, JA, Flap endonucleases pass 5′-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5′-ends. Nucleic Acids Res, 2012, 40, 4507-4519.
  • Latypov, VF, Tubbs, JL, Watson, AJ, Marriott, AS, McGown, G, Thorncroft, M, Wilkinson, OJ, Senthong, P, Butt, A, Arvai, AS, Millington, CL, Povey, AC, Williams, DM, Santibanez-Koref, MF. Tainer, JA and Margison, GP, Atl1 Regulates Choice between Global Genome and Transcription-Coupled Repair of O6-Alkylguanines. Cell 2012, 47, 50-60.
  • Tubbs JL, Latypov, V, Kanugula, S, Butt, A, Melikishvili, M, Kraehenbuehl, R, Fleck O, Marriott A, Watson AJ, Verbeek B, McGown, G, Thorncroft, M, Santibanez-Koref, MF, Millington C, Arvai, S, Kroeger MD, Peterson LA, Williams DM, Fried, MG, Margison, GP, Pegg, AE and Tainer, JA, Flipping of alkylated DNA damage bridges base and nucleotide excision repair. Nature, 2009, 459, 808-813.
  • Pearson, S, Wharton, S, Watson, A, Begum, G, Butt, A, Glynn, N, Williams, DM, Shibata, T, Santibáñez-Koref, M and Margison, GP, A novel DNA damage recognition protein in pombe. Nucleic Acids Res. 2006, 34, 2347–2354.
  • Shibata, T, Glynn, N, McMurry, TBH, McElhinney, RS, Margison, GP and Williams, DM, Novel synthesis of O6-alkylguanine containing oligodeoxyribonucleotides as substrates for the human DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT). Nucleic Acids Res., 2006, 34, 1884-1891.
Dr David M. Williams
Reader in Chemical Biology
Department of Chemistry
+44 (0)114 222 9502
d.m.williams@sheffield.ac.uk