James Berger

James Berger

Professor of Biochemistry, Biophysics and Structural Biology*
*And Member, Physical Biosciences Division, Lawrence Berkeley National Laboratory; Member, Biophysics Graduate Program; Member, Chemistry and Biology Graduate Program.

Lab Homepage: http://biophysics.med.jhmi.edu/berger/

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Research Interests

My laboratory’s research is focused on understanding how multi-subunit assemblies use ATP for overcoming topological challenges within the chromosome and controlling the flow of genetic information.  We are particularly interested in developing mechanistic models that explain how macromolecular machines transduce chemical energy into force and motion, and in determining how cells exploit these complexes and their activities for regulating the initiation of DNA replication, chromosome superstructure, and other essential nucleic acid transactions.  Our principal approaches rely on a variety of structural, biochemical, and biophysical methods to define the architecture, function, evolution, and regulation of biological complexes.  We also have extensive interests in mechanistic enzymology and the study of small-molecule inhibitors of therapeutic potential, the development of chemical approaches to trapping weak protein/protein and protein/nucleic acid interactions, and in using microfluidics for biochemical investigations of protein dynamics and structure.

 

Current Projects

Replication initiation and replisome assembly. The initiation of DNA replication relies on a large and multi-faceted complement of proteins that coordinately recognize origin sequences, unwind the origin DNA, and assemble the replisome.  Initially, phylogenetic analyses suggested that replication factors fell into two general classes, bacterial and eukaryotic/archaeal; however, structural and biochemical data have since indicated that nearly all of initiation proteins share fundamental architectural and functional features.  To better understand how cells regulate and initiate replication of their genomes, we 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 our group is revealing important information about the mechanisms of origin processing, primer synthesis, and macromolecular assembly that occur during replisome construction (Fig. 1).  We are now biochemically and structurally dissecting the reaction cycles of these initiation proteins, both individually and complexed with various targets, to better understand their molecular and cellular function.

 

 Nucleic acid-dependent motors. The length and double-helical properties of DNA present the cell with topological and information processing challenges.  For example, transcription and replication require melting of duplex DNA to read out the coded nucleotide sequence, while chromosomal tangles and knots can arise during replication, recombination, and DNA compaction.  To resolve these problems, cells use a host of molecular motor proteins, including type II DNA topoisomerases (Fig. 2), helicase/translocases, and chromosome-condensation assemblies to modulate and reorganize DNA or RNA superstructure.  Many of these proteins utilize ATP, but direct it toward different purposes, such as transporting one DNA duplex through a transient break in another, or moving along a DNA or RNA chain while concomitantally unwinding paired nucleic-acid strands. Despite such significant functional differences, each of these proteins nonetheless uses ATP binding and hydrolysis to trigger cascades of conformational changes that result in motion and force generation. We are currently studying DNA- and RNA-dependent motor proteins from bacterial, archaeal, and eukaryotic organisms. Using structural and solution-based analyses of different conformational and substrate-bound states, combined with directed biochemical and enzymological studies, we are determining 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.  We also are exploring how small-molecule inhibitors with validated clinical utility block enzyme function to elicit therapeutic effects.

 

 

Selected Publications

Mott ML, Erzberger JP, Coons MM, and Berger JM, “Structural Synergy and Molecular Crosstalk between Bacterial Helicase Loaders and Replication Initiators,” Cell, 135:623-34, 2008.

Schoeffler AJ and Berger JM. “DNA topoisomerases: harnessing and constraining energy to govern chromosome topology.”  Quart. Rev. Biophys. 41:41-101, 2008.

Corn JE, Pelton JG, and Berger JM. “Identification of a DNA primase template tracking site redefines the geometry of primer synthesis,” Nature Struct. Mol. Biol., 15:163-169, 2008.

Dong KC and Berger JM, “Structural basis for Gate-DNA recognition and bending by type IIA topoisomerases,” Nature, 450:1201-1205, 2007.

Dueber EC, Corn JE, Bell SD, and Berger JM, “Replication origin recognition and deformation by a heterodimeric archaeal Cdc6/Orc1 complex”, Science, 317:1210-1213, 2007.

Corbett KD and Berger JM, “Holoenzyme assembly and ATP-mediated conformational dynamics of topoisomerase VI” Nature Struct. Mol. Biol, 14:611-619, 2007.

Erzberger JP, Mott ML, and Berger JM, ”Structural basis for ATP-dependent DnaA assembly and replication-origin remodeling,” Nat Struct Mol Biol, 13:676-83, 2006.

Hansen, C.L., Classen, D.S., Berger, J.M., and Quake, S.R., “A Microfluidic Device for Kinetic Optimization of Protein Crystallization and In Situ Structure Determination”, J. Am. Chem. Soc., 128:3142-3143, 2006.

Corn, J.E., Pease, P.J., Hura, G.L., and Berger, J.M., “Crosstalk between primase subunits can act to regulate primer synthesis in trans”, Mol. Cell, 20:391-401, 2005.

Skordalakes, E., Andrew P. Brogan, Boon Saeng Park, Harold Kohn, and Berger, J.M., “Structural mechanism of inhibition of the Rho transcription termination factor by the antibiotic biocyclomycin,” Structure, 13:99-109, 2005.

Classen, D.S., Olland, S. and Berger, J.M., “Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic, ICRF-187,” Proc. Nat. Acad. Sci. USA, 100:10629-10634, 2003.

Skordalakes, E. and Berger, J.M., “Structure of the Rho transcription terminator: mechanism of mRNA recognition and helicase loading,” Cell (Cover), 114: 135-146, 2003.

Last Updated 2009-10-11