DNA Repair and Mutagenesis

Previous and current research
Instability of DNA under in vivo conditions can be the consequence of exposure to environmental mutagens and cytotoxic compounds, but a major cause is the susceptibility of DNA to endogenous events such as spontaneous hydrolysis, oxidation, and interaction with reactive metabolites. DNA damage caused by endogenous compounds is largely corrected by the base excision-repair process, initiated by DNA glycosylases that excise altered bases. Using purified human enzymes, the base excision-repair process has been reconstituted with DNA and chromatin substrates.

Ongoing studies with gene 'knock-out' mice that are lacking various repair enzymes demonstrate the importance of DNA endogenous events in malfunctioning cells. Protein-protein interactions between enzymes active in base excision-repair and other cellular factors are being defined, in attempts to clarify the regulation and possible induction of cellular defence processes. Cellular repair mechanisms are biochemically characterised, especially with regard to alkylating agents, which are endogenous and wide-spread environmental mutagens, as well as being used as anti-cancer drugs. A novel form of DNA repair that involves direct reversion of alkylation lesions by oxidative demethylation of alkylated bases, catalysed by the AlkB enzyme and other DNA dioxygenases, was discovered recently by our group. Several putative demethylation enzymes are encoded by the human genome, and their precise substrates and physiological functions are investigated.