Drugs that produce covalent interstrand cross-links in DNA remain important in cancer treatment. However, both inherent and clinically acquired resistance are a problem, and there is growing evidence that the efficiency of DNA cross-link elimination influences tumour response. Consequently a major goal of this laboratory is to define the DNA repair pathways acting on interstrand cross-links. We have focussed on the yeast Saccharomyces cerevisiae as a model system to understand these pathways, but more recently have begun to  translate our findings into studies of mammalian cells. We have recently characterised an interstrand cross-link pathway that relies upon the ability of specialised ‘translesion’ polymerases to copy past cross-links that have been subject to incision by the nucleotide excision repair apparatus.

Related to our studies of cross-link repair, we also have a major interest in a family of DNA repair factors that contain a metallo-β-lactamase structural domain. These factors, including yeast Pso2 and human Snm1, play an important role in the post-incision processing of cross-link repair intermediates, but the mechanistic basis of this is not well understood.

Finally, we also study the role of two closely related ATPase chromatin remodelling complexes in nucleotide excision repair. We have recently found that the yeast Ino80 and Swr complexes play a co-operative role needed for nucleotide excision repair to occur efficiently in cellular chromatin. We are now addressing whether these highly-conserved complexes play an analogous role in mammalian cells.