Macromolecular assemblies and mechanisms of DNA replication and repair. (360G-Wellcome-084279_Z_07_Z)

The ability to repair injuries to the DNA that arise from exposure to genotoxic agents or during nucleic acid metabolism is critical for cellular life. Equally vital is the faithful replication of the genetic information encoded in the DNA in preparation for mitosis. Cells have evolved complex molecular systems in order to repair and replicate our DNA, and failure to maintain the integrity of DNA is a major contributing factor in human disease. The goal of this proposal is to define atomic struc ture and mechanism of action of macromolecular assemblies responsible for the closely associated processes of DNA recombination and replication. Thus, we are interested in determining the structural basis of strand transfer between homologous DNA molecules, which lies at the heart of DNA recombination, as well as the regulatory interactions that alter the structural state of the nucleoprotein filament, the central molecular species of recombination. In DNA replication, we seek to determine the s tructural basis for the crucial step of initiation of nucleic acid synthesis by the pol a/primase complex, the macromolecular assembly responsible for starting DNA replication in eukaryotic cells.