Research in this laboratory is concerned with the biochemistry of radiation-induced DNA damage, its repair and the mechanisms by which it is translated into biologic effects such as cell lethality, mutation, recombination and neoplastic transformation. In particular we are interested in the relationship of DNA repair to certain human genetic disorders that display cellular hypersensitivity to UV and a predisposition to cancer. Experiments are also being conducted with the simple eukaryote Saccharomyces cerevisiae to elucidate the molecular mechanisms by which specific DNA lesions are repaired and the genetic consequences associated with the induction and repair of these DNA lesions. Recent efforts have been largely concerned with the induction, repair and biologic significance of closely opposed pyrimidine dimers. It is expected that the bifilar nature of these lesions will require different repair mechanisms and may have greater biologic impact than isolated dimers. Sensitive enzymatic assays, developed in this laboratory, have facilitated the detection and quantification of closely opposed dimers and have been used to partially characterize the cellular functions necessary for the initiation of their repair. Future studies will focus on later steps in the repair of closely opposed dimers and in particular on the role of double-strand breaks as intermediates in this process. These studies will include detailed investigations into the effects of DNA sequence on the induction of closely opposed dimers and into the role of closely opposed dimers in the induction of genetic recombination. Throughout results with isolated and closely opposed dimers will be compared to determine the relative importance of bifilar and unifilar DNA alterations.
