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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 Experimental illumination of a fitness landscape.
Academic Article Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease.
Academic Article Solubility-promoting function of Hsp90 contributes to client maturation and robust cell growth.
Academic Article Fitness analyses of all possible point mutations for regions of genes in yeast.
Academic Article Latent effects of Hsp90 mutants revealed at reduced expression levels.
Academic Article Flexible linkers leash the substrate binding domain of SspB to a peptide module that stabilizes delivery complexes with the AAA+ ClpXP protease.
Academic Article Altered tethering of the SspB adaptor to the ClpXP protease causes changes in substrate delivery.
Academic Article Mutations in the hydrophobic core of ubiquitin differentially affect its recognition by receptor proteins.
Academic Article Analyses of the effects of all ubiquitin point mutants on yeast growth rate.
Academic Article Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro.
Concept Mutation
Concept Point Mutation
Concept Mutation, Missense
Academic Article Influenza virus drug resistance: a time-sampled population genetics perspective.
Academic Article Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain.
Academic Article Shifting fitness landscapes in response to altered environments.
Academic Article Alanine scan of core positions in ubiquitin reveals links between dynamics, stability, and function.
Academic Article A bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in challenging environments.
Academic Article Systematic exploration of ubiquitin sequence, E1 activation efficiency, and experimental fitness in yeast.
Academic Article Viewing protein fitness landscapes through a next-gen lens.
Academic Article Mechanistic Asymmetry in Hsp90 Dimers.
Academic Article A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance.
Academic Article Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function.
Academic Article Quantifying and understanding the fitness effects of protein mutations: Laboratory versus nature.
Academic Article Editorial.
Academic Article An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy.
Academic Article The Combined Effect of Oseltamivir and Favipiravir on Influenza A Virus Evolution.
Academic Article CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.
Academic Article Synonymous Mutations at the Beginning of the Influenza A Virus Hemagglutinin Gene Impact Experimental Fitness.
Academic Article Mutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem Antibody.
Academic Article Evolutionary mechanisms studied through protein fitness landscapes.
Academic Article Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution.
Academic Article Quantifying and understanding the fitness effects of protein mutations: Laboratory versus nature.
Academic Article Correction to Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.
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 Comprehensive fitness maps of Hsp90 show widespread environmental dependence.
Academic Article The Adaptive Potential of the Middle Domain of Yeast Hsp90.
Concept Silent Mutation
Concept Mutation Rate
Academic Article Identification of a Permissive Secondary Mutation That Restores the Enzymatic Activity of Oseltamivir Resistance Mutation H275Y.
Academic Article Mutational fitness landscape and drug resistance.
Academic Article Systematic profiling of dominant ubiquitin variants reveals key functional nodes contributing to evolutionary selection.
Academic Article Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation.
Academic Article Contributions of Hyperactive Mutations in Mpro from SARS-CoV-2 to Drug Resistance.
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