Mutagenesis and DNA repair
We have determined the molecular basis of the mutagenic effect of a number of chemical lesions in DNA, including two of the most important DNA lesions, O(6)-methyl guanine (View paper) and 8-oxoguanine (View paper). This was the first time that the structural basis of a mutation caused by chemical damage to DNA had been defined at the molecular level and was pioneering. Our studies highlighted the fact that mispaired bases form distinct structures and cause minimal distortion to the overall conformation of the DNA duplex. Therefore enzymatic recognition of modified base pairs in living systems must depend upon subtle differences at the molecular level. To confirm this we investigated the origin of the recognition of mismatched and mutagenic bases by DNA repair enzymes. An example of this is my collaboration with Prof. Laurence Pearl to elucidate the structural basis of specific base-excision repair by uracil-DNA glycosylase (UDGase) (View paper) and MUG (View paper). UDGase is of interest as a target for antiviral therapy. These essential enzymes reverse the damage that is caused to DNA by oxidation of cytosine bases. Remarkably they are able to recognize the absence of a single methyl group to initiate excision repair. More than 10 years after this work there is a resurgence of interest in DNA repair and its implications for cancer and ageing.