Research in my laboratory is focused on understanding the molecular mechanisms and cellular functions of multisubunit assemblies that control the organization, preservation, and flow of genetic information. We are particularly interested in 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 group’s approach relies on a blend of structural, biochemical, and biophysical methods to define the architecture, function, evolution, and regulation of biological complexes. X-ray crystallography and traditional biochemistry have traditionally formed the core of our methodology; however, we are increasingly merging these tools with single-molecule, chemical biological, electron microscopic, and proteomic approaches.
Ongoing project areas:
Replication initiation mechanisms. In all cells, the onset of DNA replication is controlled by dedicated ATPases that assist with origin recognition, helicase loading, and at times the melting of parental template DNA strands. How these ‘initiator’ factors coordinately assemble with appropriate nucleic acid substrates and each other to promote replisome assembly is not understood at a molecular level. Our work has helped resolve both recent and long-standing problems, from how certain mutations implicated in primordial dwarfism disorders impact the assembly of the eukaryotic Origin Recognition Complex (ORC) to how bacterial DnaA recognizes and melts replication origins.
Molecular control of DNA superstructure. The appropriate organization and management of chromosomal strands depends on the action of enzymes that modulate DNA supercoiling, looping, and topology. How these factors productively disentangle strands and control DNA twist and writhe is a long-standing issue in the field. We have helped establish how type IIA topoisomerases bind and cleave duplex DNA and how ATP binding and hydrolysis coordinate the passage of a second DNA segment through this break. We have also helped to define the evolution of different type II topoisomerase families, connecting one branch of this group to meiotic recombination processes.
Ring ATPase assembly and mechanism. Numerous essential cellular processes, ranging from DNA replication and chromatin modeling to vesicle trafficking and proteolytic degradation, rely on oligomeric, ring-shaped ATPases for proper function. How a common class of ATPase folds can actively support such a broad number of systems and functions is a poorly understood. We have helped define the structural basis of distinct ring-opening and ring-assembly mechanisms that permit the loading of hexameric helicases and onto target nucleic acid substrates, and we have showed how accessory factors assist in controlling ring-ATPase function and mechanism.
Applied and Translational Research. We have an established track record in developing innovative solutions to technical problems and in addressing practical issues, such as defining small molecule inhibitor mechanisms. In particular, we have an interest in understanding how nucleic acid-dependent motors can be disrupted by agents with known or anticipated therapeutic potential. These efforts are being taken in new directions within the Cancer Chemical and Structural Biology Program, which I presently co-direct with Dr. Jun O. Liu on behalf of Hopkins Sydney Kimmel Comprehensive Cancer Center.
Blower TR, Williamson BH, Kerns RJ, Berger JM. Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2016 PMID: 26792525.
Arias-Palomo E, Berger JM. An Atypical AAA+ ATPase Assembly Controls Efficient Transposition through DNA Remodeling and Transposase Recruitment. Cell. 2015 PMID: 26276634.
Bleichert F, Botchan MR, Berger JM. Crystal structure of the eukaryotic origin recognition complex. Nature. 2015 PMID: 25762138.
Costa A, Renault L, Swuec P, Petojevic T, Pesavento JJ, Ilves I, MacLellan-Gibson K, Fleck RA, Botchan MR, Berger JM. DNA binding polarity, dimerization, and ATPase ring remodeling in the CMG helicase of the eukaryotic replisome. Elife. 2014 PMID: 25117490.
Vos SM, Lyubimov AY, Hershey DM, Schoeffler AJ, Sengupta S, Nagaraja V, Berger JM. Direct control of type IIA topoisomerase activity by a chromosomally encoded regulatory protein. Genes Dev. 2014 PMID: 24990966.