James M. Berger, PhD

Professional Titles

• Director, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine
• Michael and Ann Hankin and Partners of Brown Advisory Professor in Scientific Innovation
• Co-Director, Cancer Chemical and Structural Biology Program, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Primary Academic Title

Professor of Biophysics and Biophysical Chemistry

Background

Centers and Institutes

• Basic Biomedical Sciences, Institute for
• Metabolism and Obesity Research, Center for
• Sidney Kimmel Comprehensive Cancer Center

Videos

• Muscling DNA Around Using Protein Nanomachines | Science: Out of the Box

• James Berger | Biological Nanomachines

Recent News Articles and Media Coverage

• Clamshell-Shaped Protein Puts the 'Jump' in 'Jumping Genes'
• Scientists Use X-ray Vision to Probe Early Stages of DNA 'Photocopying'
• James Berger on Tiny Protein Machines

Additional Academic Titles

Professor of Oncology, Professor of Pharmacology and Molecular Sciences

Research Interests

Control of DNA replication and chromosome superstructure, Small-molecule and biological regulatory mechanisms, Structural and catalytic mechanisms of nucleic-acid machines and assemblies

Lab Website

Berger Lab - Lab Website

• The Berger Lab'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. A long-term goal is to develop mechanistic models that explain in atomic level detail how macromolecular machines transduce chemical energy into force and motion, and to determine how cells exploit and control these complexes and their activities for initiating DNA replication, shaping chromosome superstructure and executing myriad other essential nucleic-acid transactions. Our principal approaches include a blend of structural (X-ray crystallography, single-particle EM, SAXS) and solution biochemical 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 and single-molecule approaches for biochemical investigations of protein dynamics.

Research Summary

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.

PubMed

http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&term=berger_jm&doptcmdl=DocSum

Selected Publications

• Bleichert F, Balasov M, Chesnokov I, Nogales E, Botchan MR, Berger JM. “A Meier-Gorlin syndrome mutation in a conserved C-terminal helix of Orc6 impedes origin recognition complex formation.” Elife. 2013 Oct 8;2:e00882. doi: 10.7554/eLife.00882.

• Mustaev A, Malik M, Zhao X, Kurepina N, Luan G, Oppegard LM, Hiasa H, Marks KR, Kerns RJ, Berger JM, Drlica K. “Fluoroquinolone-Gyrase-DNA Complexes: Two Modes of Drug Binding.” J Biol Chem. 2014 Feb 4.

• Strycharska MS, Arias-Palomo E, Lyubimov AY, Erzberger JP, O'Shea VL, Bustamante CJ, Berger JM. “Nucleotide and partner-protein control of bacterial replicative helicase structure and function.” Mol Cell. 2013 Dec 26;52(6):844-54. doi: 10.1016/j.molcel.2013.11.016.

• Toske SG, Morello DR, Berger JM, Vazquez ER. “The use of δ13C isotope ratio mass spectrometry for methamphetamine profiling: comparison of ephedrine and pseudoephedrine-based samples to P2P-based samples.” Forensic Sci Int. 2014 Jan;234:1-6. doi: 10.1016/j.forsciint.2013.10.022. Epub 2013 Oct 31.

• Vos SM, Stewart NK, Oakley MG, Berger JM. “Structural basis for the MukB-topoisomerase IV interaction and its functional implications in vivo.” EMBO J. 2013 Nov 13;32(22):2950-62. doi: 10.1038/emboj.2013.218. Epub 2013 Oct 4.

Honors

National Academy of Sciences, 1/1/13

Graduate Program Affiliations

• Pharmacology and Molecular Sciences

  Program in Molecular Biophysics (PMB)

  Biochemistry, Cellular and Molecular Biology Graduate Program (BCMB)

  Chemistry-Biology Interface Graduate Program