The goals of this program are to elucidate basic molecular mechanisms which relate to the macromolecular behavior of DNA, its repair, recombination, and mutagenesis. This proposal incorporates seven senior investigators and their research groups into a program focussed on biochemical and molecular approaches to study of basic problems in macromolecular DNA metabolism. Studies are proposed using both procaryotic and eucaryotic systems, using model systems as well as clinically relevant approaches. In this continuation application, renewal of the five projects is proposed along with addition of two new projects. The research work proposed in this Program-Project involves biochemical and genetic experiments to study recombination, DNA repair and mutagenesis in both procaryotes and eucaryotes. Projects 3, 4 and 6 (Low, Liskay and Radding) involve study of mechanisms of recombination. In Projects 1 and 2 (Brash and Rupp) details of excision repair pathway will be studied in eucaryotic cells (Brash) and in the UVRABC system in E. coli (Rupp). Brash (Project 1) will investigate the role of oncogenes in processes of DNA repair and mutagenesis. Summers (Project 5) proposes to study the mechanisms by which DNA damage can induce new gene expression or modify pre-existing cellular activities. Hutchinson (Project 8) plans to synthesize and systematize existing data in molecular radiobiology and to develop general principles of structure-function relationships for specific types of DNA damage. It is clear that several of the projects will overlap at the conceptual level: the work of Radding, Liskay and Low all require heuristic models of genetic recombination. Enzymological and biochemical methods and approaches will be shared by Rupp, Radding, and Summers. Pathways of excision repair and molecular models will guide the approaches of both Rupp and Brash, while the work proposed by Hutchinson will draw upon, and potentially contribute to, all the components of the Program.
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