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    Daniel N Bolon PhD

    TitleAssociate Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentBiochemistry and Molecular Pharmacology
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB
    Worcester MA 01605
      Other Positions
      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBiochemistry and Molecular Pharmacology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentBioinformatics and Computational Biology

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentInterdisciplinary Graduate Program

      InstitutionUMMS - Graduate School of Biomedical Sciences
      DepartmentMD/PhD Program

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBioinformatics and Integrative Biology

        Overview 
        Narrative

        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.



        Rotation Projects

        Potential Rotation Projects

        Our laboratory combines genetic and biochemical approaches to investigate the molecular underpinnings of adaptation. Potential rotation projects are available in two general (and partially overlapping) areas: exploring fitness landscapes through systematic approaches and investigating the molecular mechanism of the Hsp90 chaperone in signal transduction. Please contact the lab to discuss specific rotation projects in more detail.



        Bibliographic 
        selected publications
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        1. Beebe K, Mollapour M, Scroggins B, Prodromou C, Xu W, Tokita M, Taldone T, Pullen L, Zierer BK, Lee MJ, Trepel J, Buchner J, Bolon D, Chiosis G, Neckers L. Posttranslational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors. Oncotarget. 2013 Jul; 4(7):1065-74.
          View in: PubMed
        2. Jiang L, Mishra P, Hietpas RT, Zeldovich KB, Bolon DN. Latent effects of hsp90 mutants revealed at reduced expression levels. PLoS Genet. 2013 Jun; 9(6):e1003600.
          View in: PubMed
        3. Roscoe BP, Thayer KM, Zeldovich KB, Fushman D, Bolon DN. Analyses of the effects of all ubiquitin point mutants on yeast growth rate. J Mol Biol. 2013 Apr 26; 425(8):1363-77.
          View in: PubMed
        4. Hietpas R, Roscoe B, Jiang L, Bolon DN. Fitness analyses of all possible point mutations for regions of genes in yeast. Nat Protoc. 2012; 7(7):1382-96.
          View in: PubMed
        5. Pursell NW, Mishra P, Bolon DN. Solubility-promoting function of hsp90 contributes to client maturation and robust cell growth. Eukaryot Cell. 2012 Aug; 11(8):1033-41.
          View in: PubMed
        6. Mittal S, Cai Y, Nalam MN, Bolon DN, Schiffer CA. Hydrophobic Core Flexibility Modulates Enzyme Activity in HIV-1 Protease. J Am Chem Soc. 2012 Mar 7; 134(9):4163-8.
          View in: PubMed
        7. Bolon DN. Bound for observation. J Mol Biol. 2012 Jan 6; 415(1):1-2.
          View in: PubMed
        8. Hietpas RT, Jensen JD, Bolon DN. From the Cover: Experimental illumination of a fitness landscape. Proc Natl Acad Sci U S A. 2011 May 10; 108(19):7896-901.
          View in: PubMed
        9. Pullen L, Bolon DN. Enforced N-domain Proximity Stimulates Hsp90 ATPase Activity and Is Compatible with Function in Vivo. J Biol Chem. 2011 Apr 1; 286(13):11091-8.
          View in: PubMed
        10. Wayne N, Mishra P, Bolon DN. Hsp90 and client protein maturation. Methods Mol Biol. 2011; 787:33-44.
          View in: PubMed
        11. Wayne N, Bolon DN. Charge-rich regions modulate the anti-aggregation activity of Hsp90. J Mol Biol. 2010 Sep 3; 401(5):931-9.
          View in: PubMed
        12. Wayne N, Lai Y, Pullen L, Bolon DN. Modular control of cross-oligomerization: analysis of superstabilized Hsp90 homodimers in vivo. J Biol Chem. 2010 Jan 1; 285(1):234-41.
          View in: PubMed
        13. Munson M, Bolon DN. Watching proteins in motion. Genome Biol. 2009; 10(10):316.
          View in: PubMed
        14. Haririnia A, Verma R, Purohit N, Twarog MZ, Deshaies RJ, Bolon D, Fushman D. Mutations in the hydrophobic core of ubiquitin differentially affect its recognition by receptor proteins. J Mol Biol. 2008 Jan 25; 375(4):979-96.
          View in: PubMed
        15. Wayne N, Bolon DN. Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers. J Biol Chem. 2007 Nov 30; 282(48):35386-95.
          View in: PubMed
        16. McGinness KE, Bolon DN, Kaganovich M, Baker TA, Sauer RT. Altered tethering of the SspB adaptor to the ClpXP protease causes changes in substrate delivery. J Biol Chem. 2007 Apr 13; 282(15):11465-73.
          View in: PubMed
        17. Bolon DN, Grant RA, Baker TA, Sauer RT. Specificity versus stability in computational protein design. Proc Natl Acad Sci U S A. 2005 Sep 6; 102(36):12724-9.
          View in: PubMed
        18. Hersch GL, Burton RE, Bolon DN, Baker TA, Sauer RT. Asymmetric interactions of ATP with the AAA+ ClpX6 unfoldase: allosteric control of a protein machine. Cell. 2005 Jul 1; 121(7):1017-27.
          View in: PubMed
        19. Bolon DN, Grant RA, Baker TA, Sauer RT. Nucleotide-dependent substrate handoff from the SspB adaptor to the AAA+ ClpXP protease. Mol Cell. 2004 Nov 5; 16(3):343-50.
          View in: PubMed
        20. Sauer RT, Bolon DN, Burton BM, Burton RE, Flynn JM, Grant RA, Hersch GL, Joshi SA, Kenniston JA, Levchenko I, Neher SB, Oakes ES, Siddiqui SM, Wah DA, Baker TA. Sculpting the proteome with AAA(+) proteases and disassembly machines. Cell. 2004 Oct 1; 119(1):9-18.
          View in: PubMed
        21. Bolon DN, Wah DA, Hersch GL, Baker TA, Sauer RT. Bivalent tethering of SspB to ClpXP is required for efficient substrate delivery: a protein-design study. Mol Cell. 2004 Feb 13; 13(3):443-9.
          View in: PubMed
        22. Wah DA, Levchenko I, Rieckhof GE, Bolon DN, Baker TA, Sauer RT. Flexible linkers leash the substrate binding domain of SspB to a peptide module that stabilizes delivery complexes with the AAA+ ClpXP protease. Mol Cell. 2003 Aug; 12(2):355-63.
          View in: PubMed
        23. Bolon DN, Marcus JS, Ross SA, Mayo SL. Prudent modeling of core polar residues in computational protein design. J Mol Biol. 2003 Jun 6; 329(3):611-22.
          View in: PubMed
        24. Bolon DN, Voigt CA, Mayo SL. De novo design of biocatalysts. Curr Opin Chem Biol. 2002 Apr; 6(2):125-9.
          View in: PubMed
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