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Academic Background

Dan Bolon majored in Biology at Duke University (B.S., 1997). For Dan’s graduate work, he studied computational enzyme design with Steve Mayo at the California Institute of Technology (Ph.D. in Biochemistry and Molecular Biophysics, 2002). From 2002-2005, he trained as a postdoc with Bob Sauer in the Biology Department at the Massachusetts Institute of Technology using a variety of biochemical and biophysical techniques including X-ray crystallography, fluorescence, analytical ultracentrifugation, and protein engineering to study AAA+ proteases. Dan was awarded a NIH fellowship to support his postdoctoral studies (2004-2005). Other interests include mountain biking and baseball. Dan joined the faculty in Biochemistry and Molecular Pharmacology in September, 2005.

Molecular mechanisms of adaptation in biology and diseasePhoto: Dan Bolon

The ability of biological systems to adapt to new conditions rapidly is profoundly important because natural environments are continually changing. Thus, the ability of an organism to prosper is directly related to its ability to adapt. Adaptation is particularly important in human diseases including cancer and infection by viruses or bacteria. For example, the development of cancer involves adaptive changes within the cancer cells that bypass normal growth regulation. With bacterial and viral infections the severity of the outcome depends on the adaptive potential of the host defense systems relative to the pathogen. In the Bolon lab we are broadly interested in the molecular mechanisms of adaptation because of their central role in both biology and disease.

Exploring the limits of adaptation by illuminating fitness landscapes

Over time scales that span generations, adaptation is mediated by genetic variation. For example, the application of anti-viral drugs leads to strong selective pressure for drug-resistant mutations. Similarly, the evolution of all organisms is influenced by mutations that provide selective advantages within a specific environment. In natural systems, genetic variation is generated stochastically and thus represents a random walk through fitness space. Fitness space provides fundamental limits on the process of adaptation. To explore these fundamental biological constraints, we developed an experimental approach to measure and define the observe the fitness landscape of all possible point mutations for a gene. By combining saturation mutagenesis with growth competitions monitored by deep sequencing, we measure the fitness effects of thousands of different point mutations in parallel. We term this approach EMPIRIC (Exceedingly Meticulous and Parallel Investigation of Randomized Individual Codons). We are applying this approach to study many different fast growing biological entities including yeast, bacteria, cancer cells and viruses. This approach will provide both fundamental insights into selection pressure and valuable routes to improved therapeutics (i.e., by identifying sites in drug targets that cannot be mutated without impairing the function of the host cell and hence should be refractory to the development of drug resistance).

Molecular mechanism of the Hsp90 chaperone

The ability of organisms to respond to its environment on time-scales that shorter than a generation depends upon sensing the environment. Hsp90 is an essential protein that mediates these sensing processes because it is required for the maturation of many signal transduction proteins. Because Hsp90 substrates are mutated in many different forms of cancer, Hsp90 has emerged as a promising target for drugs to treat a broad spectrum of cancer. Hsp90 is clearly involved in many different essential processes in both healthy and diseased cells. However, how Hsp90 affects these processes is poorly understood. A major goal of our research is to elucidate the molecular mechanism of Hsp90 that orchestrates the dynamic assembly of Hsp90/co-chaperone/substrate complexes and the maturation of signal transduction clients to their active conformation. To probe the physical mechanism of this dynamic protein system we utilize biophysical, biochemical and genetic approaches to dissect the conformation and protein-protein interactions of Hsp90 during substrate maturation. The goal of this work is to delineate the physical mechanism by which Hsp90 matures substrates including those involved in cancer progression.

One or more keywords matched the following items that are connected to Bolon, Daniel
Item TypeName
Academic Article Sculpting the proteome with AAA(+) proteases and disassembly machines.
Academic Article Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro.
Concept Drug Resistance, Viral
Concept RNA, Viral
Concept Antibodies, Viral
Concept Viral Plaque Assay
Concept Viral Proteins
Concept Viral Nonstructural Proteins
Concept Peptide Hydrolases
Concept Genome, Viral
Academic Article Influenza virus drug resistance: a time-sampled population genetics perspective.
Academic Article Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment.
Academic Article A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance.
Academic Article An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy.
Academic Article Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations.
Academic Article Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase.
Academic Article Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.
Academic Article Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.
Academic Article Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.
Academic Article Identification of a Permissive Secondary Mutation That Restores the Enzymatic Activity of Oseltamivir Resistance Mutation H275Y.
Academic Article Analyses of HIV proteases variants at the threshold of viability reveals relationships between processing efficiency and fitness.
Academic Article Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms.
Academic Article Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance.
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  • Proteases