DNA-Drug Interaction

Since Watson and Crick’s discovery of the function of DNA based on Rosalind Franklin’s and Maurice Wilkin’s X-ray diffraction patterns, tremendous scientific curiosity has been aroused by the molecule of life. A-DNA and B-DNA are different conformations of the DNA molecule (Figure 1), which is stabilised by hydrogen interactions between base pairs, stacking interactions between neighbouring bases and long-range intra- and inter-backbone forces. We are interested in applying Fourier transform infrared (FTIR) spectroscopy to understand DNA conformation in relation to hydration and its potential role in clinical diagnostics.(1) We are particularly interested in the method of hydration as a way to interpret DNA conformational change in response to anticancer drug interactions and have had a long standing collaboration with Professor Glen Deacon (School of Chemistry) testing a range of novel Pt(II) and Pt(IV) compounds on DNA in cells and tissues.(2,3)  We are also interested in exploring the advantages of investigating B-DNA in the hydrated state, as opposed to A-DNA in the dehydrated state and have published a number of papers highlighting applications of the technology for (1) improved quantification of DNA in cells(4); (2) improved discrimination and reproducibility of FTIR spectra recorded of cells progressing through the cell cycle(5); (3) discovered insights into the biological significance of A-DNA as evidenced by an interesting study on bacteria, which can survive desiccation and at the same time undergo the B–A–B transition.(6) We have also investigated the effects of UV radiation on DNA(7) and proton irradiation of cells(8) using tip enhanced Raman spectroscopy (TERS) and more recently applied TERS to investigate the drug Pt103 binding to plasmid DNA.

Fig 1. A-DNA and B-DNA conformations.

Fig 2. AFM image of plasmid DNA inoculated with a Pt103 along with recorded TERS spectra.

1.B. R. Wood, The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues. Chemical Society reviews 45, 1980-1998 (2016); published online EpubApr 7 (10.1039/c5cs00511f).
2.E. Lipiec, J. Czapla, J. Szlachetko, Y. Kayser, W. Kwiatek, B. Wood, G. B. Deacon, J. Sá, Novel in situ methodology to observe the interactions of chemotherapeutical Pt drugs with DNA under physiological conditions. Dalton Transactions 43, 13839-13844 (2014).
3.J. Sa, J. Czapla-Masztafiak, E. Lipiec, Y. Kayser, W. Kwiatek, B. Wood, G. B. Deacon, G. Berger, F. Dufrasne, D. L. Fernandes, J. Szlachetko, The use of Resonant X-ray Emission Spectroscopy (RXES) for the electronic analysis of metal complexes and their interactions with biomolecules. Drug discovery today. Technologies 16, 1-6 (2015); published online EpubSep (10.1016/j.ddtec.2015.07.001).
4.D. R. Whelan, K. R. Bambery, L. Puskar, D. McNaughton, B. R. Wood, Quantification of DNA in simple eukaryotic cells using Fourier transform infrared spectroscopy. Journal of biophotonics 6, 775-784 (2013).
5.D. R. Whelan, K. R. Bambery, L. Puskar, D. McNaughton, B. R. Wood, Synchrotron Fourier transform infrared (FTIR) analysis of single living cells progressing through the cell cycle. Analyst 138, 3891-3899 (2013).
6.D. R. Whelan, K. R. Bambery, D. McNaughton, L. Puskar, B. R. Wood, Monitoring the Conformation and Concentration of DNA in Live Cells using Fourier Transform Infrared Spectroscopy. Biophysical Journal 106, 206a (2014).
7.E. Lipiec, R. Sekine, J. Bielecki, W. M. Kwiatek, B. R. Wood, Molecular Characterization of DNA Double Strand Breaks with Tip‐Enhanced Raman Scattering. Angewandte Chemie International Edition 53, 169-172 (2014).
8.E. Lipiec, K. R. Bambery, P. Heraud, C. Hirschmugl, J. Lekki, W. M. Kwiatek, M. J. Tobin, C. Vogel, D. Whelan, B. R. Wood, Synchrotron FTIR shows evidence of DNA damage and lipid accumulation in prostate adenocarcinoma PC-3 cells following proton irradiation. Journal of Molecular Structure,  (2014).