The activities of the group are centred on the following areas.

The development and exploitation of methods to study drug-DNA interactions, and their repair, at the genome, gene, sub-gene and single nucleotide level in naked DNA and intact cells (both in vitro and in clinical samples).

To use the information derived from experiments in biological systems to assist in the design and evaluation of novel DNA interacting drugs, in particular, DNA interstrand cross-linking agents, and DNA sequence specific agents as potential modulators of gene expression.

To define the major repair pathways for drug-DNA adducts and to explore the relationship between different types of drug-induced DNA damage, the efficiency of repair of these lesions, and biological response.

To determine the molecular basis of inherent sensitivity of some tumour types to DNA damaging agents and the molecular basis of clinical acquired resistance to DNA damaging drugs in order to develop strategies to overcome or circumvent this resistance.

Fig1. Single cell gel electrophoresis (comet) assay images of irradiated human lymphocytes either before (left) or after (right) treatment with a DNA cross-linking drug.

Fig2. DNase 1 footprinting showing the sequence selective interaction of a DNA minor groove binding agent.

Fig3. Cellular staining of EGFR showing relocation from the cytoplasm (left) to the nucleus (right) following DNA damage.

Fig4. Molecular model showing 2:1 binding of sequence selective non-covalent DNA binding agents (blue) in the minor groove of DNA.

Spanswick, V.J., Craddock, C., Sekhar, M., Mahendra, P., Shankaranarayana, P., Hughes, R.G., Hochhauser, D., Hartley, J.A.: Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma. Blood, 100, 224-229, 2002. (pubmed)

O’Hare, C.C., Mack, D., Tandon, M., Sharma, S.K., Lown, J.W., Kopka, M.L., Dickerson, R.E., and Hartley, J.A.: DNA sequence recognition in the minor groove by crosslinked polyamides: the effect of N-terminal head group and linker length on binding affinity and specificity. Proc. Natl. Acad. Sci. USA, 99, 72-77, 2002. (pubmed)

De Silva, I.U., McHugh, P.J., Clingen, P.H., and Hartley, J.A.: Defects in interstrand crosslink uncoupling do not account for the extreme sensitivity of ERCC1 and XPF cells to cisplatin. Nucleic Acids Res., 30, 3848-3856, 2002. (pubmed)

Kiakos, K., Howard, T.T., Lee, M., Hartley, J.A., and McHugh, P.J.: Saccharomyces cerevisiae RAD5 influences the excision repair of DNA minor groove adducts. J.Biol. Chem., 227, 44576-44581, 2002. (pubmed)

Hartley, J.A., Spanswick V.J., Brooks N., Clingen P.H., McHugh P.J., Hochhauser D., Pedley R.B., Kelland L.R., Alley M.C., Schultz R, Hollingshead M.G., Schweikart K.M., Tomaszewski J., Sausville E.A., Gregson S.J., Howard P.W. and Thurston D.E.: SJG-136 (NSC 694501) a novel rationally designed DNA minor groove interstrand crosslinking agent with potent and broad spectrum antitumor activity. Part 1: Cellular pharmacology, in vitro and initial in vivo antitumor activity. Cancer Research, 64, 6693-6699, 2004. (pubmed)

Friedmann, B.J., Caplin, M., Hartley, J.A., and Hochhauser, D: Modulation of DNA repair in vitro following treatment with chemotherapeutic agents by the epidermal growth factor receptor inhibitor gifitinib (ZD1839). Clinical Cancer Res., 10, 6476-6486, 2004. (pubmed)

Barber, L.J., Ward, T.A., Hartley, J.A., McHugh, P.J.: DNA interstrand cross-link repair in the yeast cell cycle: overlapping roles for PSO2/SNM1 with MutS factors and EXO1 during S-phase. Mol. Cell Biol., 25, 2297-2309, 2005. (pubmed)

Clingen, P.H., De Silva, I.U., McHugh, P.J., Ghadessy, F.J., Tilby, M.J., Thurston, D.E., and Hartley, J.A.: The XPF-ERCC1 endonuclease and homologous recombination contribute to the repair of minor groove DNA interstrand crosslinks in mammalian cells produced by the pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136. Nucleic Acids Res., 33, 3283-3291, 2005. (pubmed)

Friedmann, B.J., Caplin, M., Savic, B., Shah, T., Lord, C.J., Ashworth, A., Hartley, J.A., and Hochhauser, D: Interaction of the epidermal growth factor receptor and the DNA-dependent protein kinase pathway following gefitinib treatment. Molecular Cancer Therapeutics, 5, 209-218, 2006. (pubmed)

Hochhauser, D., Kotecha, M., O’Hare, C., Morris, P.J., Hartley, J.M., Taherbhai, Z., Harris, D., Mantovani, R., Lee, M., and Hartley, J.A.: Modulation of topoisomerase IIa expression by a DNA sequence-specific polyamide. Molecular Cancer Therapeutics, 6, 346-354, 2007. (pubmed)