James M. Berger, Ph.D.

Dr. Berger and his team’s current research examines replication initiation and replisome assembly. To better understand how cells regulate and initiate replication of their genomes, Berger and his colleagues are studying origin-binding proteins, helicases, primases and accessory remodeling factors from a variety of organisms within the three cellular domains of life. Work from their group is revealing important information about the mechanisms of origin processing, primer synthesis, and macromolecular assembly that occur during replisome construction. Dr. Berger’s team is also studying the nucleic acid-dependent motors, with a particular focus on a variety of DNA- and RNA-dependent motor proteins. They are working to determine how such proteins interact with nucleic acids and partner proteins, and how they use ATP to drive the architectural changes required for catalysis and physical movement.

One area of research focus is the study of DNA topoisomerases, which are well-established, clinically-validated targets of several anti-cancer agents. Dr. Berger's team has solved structures of topoisomerase targets in complex with target DNA substrates and various drugs. The goal is to understand mechanisms of drug resistance and cross-reactivity and to guide the discovery and development of new compounds with improved therapeutic potential. Dr. Berger's laboratory is also exploring whether the protein machinery responsible for initiating DNA replication can be exploited as a novel anti-cancer target. Additional research in Dr. Berger's laboratory is focused on understanding the molecular mechanisms and cellular functions of multisubunit assemblies that control the organization, preservation, and flow of genetic information. They are developing atomic-level models that explain how chemical energy is transduced into force and motion, and how dynamic assemblies control DNA replication, gene expression, chromosome superstructure, and other essential nucleic-acid transactions. The approach relies on a blend of structural, biochemical, and biophysical methods to define the architecture, function, evolution, and regulation of protein/nucleic acid complexes. X-ray crystallography and biochemistry have traditionally formed the core of his team's approach; however, they are increasingly merging these methods with other experimental tools such as small-angle X-ray scattering, single-molecule approaches, and electron microscopy. His lab has biochemically and structurally defined the range and nature of key functional intermediates and structural transitions for a variety of nucleotide-dependent “molecular machines,” including topoisomerases, helicases, condensins, and replication initiation complexes. These efforts have defined how biological systems use these factors to organize, transport, and reshape target nucleic-acid substrates at a physical level, and how their actions are controlled by both protein-protein interactions and small-molecule agents.