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Daniel N Bolon PhD

TitleProfessor
InstitutionUniversity of Massachusetts Medical School
DepartmentBiochemistry and Molecular Pharmacology
AddressUniversity of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
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    Other Positions
    InstitutionUMMS - School of Medicine
    DepartmentBiochemistry and Molecular Pharmacology

    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


    Collapse Biography 
    Collapse education and training
    Duke University, Durham, NC, United StatesBSBiology
    California Institute of Technology, Pasadena, CA, United StatesPHDBiochemistry & Molecular Bio

    Collapse Overview 
    Collapse overview

    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.



    Collapse 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.




    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    List All   |   Timeline
    1. Van Oosten-Hawle P, Bolon DN, LaPointe P. The diverse roles of Hsp90 and where to find them. Nat Struct Mol Biol. 2017 Jan 05; 24(1):1-4. PMID: 28054566.
      View in: PubMed
    2. Prachanronarong KL, Özen A, Thayer KM, Yilmaz LS, Zeldovich KB, Bolon DN, Kowalik TF, Jensen JD, Finberg RW, Wang JP, Kurt-Yilmaz N, Schiffer CA. Molecular Basis for Differential Patterns of Drug Resistance in Influenza N1 and N2 Neuraminidase. J Chem Theory Comput. 2016 Dec 13; 12(12):6098-6108. PMID: 27951676.
      View in: PubMed
    3. Duenas-Decamp M, Jiang L, Bolon D, Clapham PR. Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations. PLoS Pathog. 2016 Nov; 12(11):e1005988. PMID: 27820858.
      View in: PubMed
    4. Bank C, Renzette N, Liu P, Matuszewski S, Shim H, Foll M, Bolon DN, Zeldovich KB, Kowalik TF, Finberg RW, Wang JP, Jensen JD. An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy. Evolution. 2016 Nov; 70(11):2470-2484. PMID: 27566611.
      View in: PubMed
    5. Bolon DN, Baker D, Tawfik DS. Editorial. Protein Sci. 2016 Jul; 25(7):1164-7. PMID: 27214768.
      View in: PubMed
    6. Mavor D, Barlow K, Thompson S, Barad BA, Bonny AR, Cario CL, Gaskins G, Liu Z, Deming L, Axen SD, Caceres E, Chen W, Cuesta A, Gate RE, Green EM, Hulce KR, Ji W, Kenner LR, Mensa B, Morinishi LS, Moss SM, Mravic M, Muir RK, Niekamp S, Nnadi CI, Palovcak E, Poss EM, Ross TD, Salcedo EC, See SK, Subramaniam M, Wong AW, Li J, Thorn KS, Conchúir SÓ, Roscoe BP, Chow ED, DeRisi JL, Kortemme T, Bolon DN, Fraser JS. Determination of ubiquitin fitness landscapes under different chemical stresses in a classroom setting. Elife. 2016 Apr 25; 5. PMID: 27111525.
      View in: PubMed
    7. Mishra P, Flynn JM, Starr TN, Bolon DN. Systematic Mutant Analyses Elucidate General and Client-Specific Aspects of Hsp90 Function. Cell Rep. 2016 Apr 19; 15(3):588-98. PMID: 27068472.
      View in: PubMed
    8. Boucher JI, Bolon DN, Tawfik DS. Quantifying and understanding the fitness effects of protein mutations: Laboratory versus nature. Protein Sci. 2016 Jul; 25(7):1219-26. PMID: 27010590.
      View in: PubMed
    9. Jiang L, Liu P, Bank C, Renzette N, Prachanronarong K, Yilmaz LS, Caffrey DR, Zeldovich KB, Schiffer CA, Kowalik TF, Jensen JD, Finberg RW, Wang JP, Bolon DN. A Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance. J Mol Biol. 2016 Feb 13; 428(3):538-53. PMID: 26656922.
      View in: PubMed
    10. Flynn JM, Mishra P, Bolon DN. Mechanistic Asymmetry in Hsp90 Dimers. J Mol Biol. 2015 Sep 11; 427(18):2904-11. PMID: 25843003.
      View in: PubMed
    11. Zeldovich KB, Liu P, Renzette N, Foll M, Pham ST, Venev SV, Gallagher GR, Bolon DN, Kurt-Jones EA, Jensen JD, Caffrey DR, Schiffer CA, Kowalik TF, Wang JP, Finberg RW. Positive Selection Drives Preferred Segment Combinations during Influenza Virus Reassortment. Mol Biol Evol. 2015 Jun; 32(6):1519-32. PMID: 25713211.
      View in: PubMed
    12. Bank C, Hietpas RT, Jensen JD, Bolon DN. A systematic survey of an intragenic epistatic landscape. Mol Biol Evol. 2015 Jan; 32(1):229-38. PMID: 25371431.
      View in: PubMed
    13. Boucher JI, Cote P, Flynn J, Jiang L, Laban A, Mishra P, Roscoe BP, Bolon DN. Viewing protein fitness landscapes through a next-gen lens. Genetics. 2014 Oct; 198(2):461-71. PMID: 25316787.
      View in: PubMed
    14. Roscoe BP, Bolon DN. Systematic exploration of ubiquitin sequence, E1 activation efficiency, and experimental fitness in yeast. J Mol Biol. 2014 Jul 29; 426(15):2854-70. PMID: 24862281.
      View in: PubMed
    15. Foll M, Poh YP, Renzette N, Ferrer-Admetlla A, Bank C, Shim H, Malaspinas AS, Ewing G, Liu P, Wegmann D, Caffrey DR, Zeldovich KB, Bolon DN, Wang JP, Kowalik TF, Schiffer CA, Finberg RW, Jensen JD. Influenza virus drug resistance: a time-sampled population genetics perspective. PLoS Genet. 2014 Feb; 10(2):e1004185. PMID: 24586206.
      View in: PubMed
    16. Mishra P, Bolon DN. Designed Hsp90 heterodimers reveal an asymmetric ATPase-driven mechanism in vivo. Mol Cell. 2014 Jan 23; 53(2):344-50. PMID: 24462207.
      View in: PubMed
    17. Bank C, Hietpas RT, Wong A, Bolon DN, Jensen JD. A bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: uncovering the potential for adaptive walks in challenging environments. Genetics. 2014 Mar; 196(3):841-52. PMID: 24398421.
      View in: PubMed
    18. Lee SY, Pullen L, Virgil DJ, Castañeda CA, Abeykoon D, Bolon DN, Fushman D. Alanine scan of core positions in ubiquitin reveals links between dynamics, stability, and function. J Mol Biol. 2014 Apr 3; 426(7):1377-89. PMID: 24361330.
      View in: PubMed
    19. Renzette N, Caffrey DR, Zeldovich KB, Liu P, Gallagher GR, Aiello D, Porter AJ, Kurt-Jones EA, Bolon DN, Poh YP, Jensen JD, Schiffer CA, Kowalik TF, Finberg RW, Wang JP. Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro. J Virol. 2014 Jan; 88(1):272-81. PMID: 24155392.
      View in: PubMed
    20. Wagenaar TR, Ma L, Roscoe B, Park SM, Bolon DN, Green MR. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 2014 Jan; 27(1):124-33. PMID: 24112705.
      View in: PubMed
    21. Hietpas RT, Bank C, Jensen JD, Bolon DN. Shifting fitness landscapes in response to altered environments. Evolution. 2013 Dec; 67(12):3512-22. PMID: 24299404.
      View in: PubMed
    22. 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. PMID: 23867252.
      View in: PubMed
    23. 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. PMID: 23825969.
      View in: PubMed
    24. 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. PMID: 23376099.
      View in: PubMed
    25. Hietpas R, Roscoe B, Jiang L, Bolon DN. Fitness analyses of all possible point mutations for regions of genes in yeast. Nat Protoc. 2012 Jun 21; 7(7):1382-96. PMID: 22722372.
      View in: PubMed
    26. 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. PMID: 22660624.
      View in: PubMed
    27. 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. PMID: 22295904.
      View in: PubMed
    28. Bolon DN. Bound for observation. J Mol Biol. 2012 Jan 6; 415(1):1-2. PMID: 22094315.
      View in: PubMed
    29. Hietpas RT, Jensen JD, Bolon DN. Experimental illumination of a fitness landscape. Proc Natl Acad Sci U S A. 2011 May 10; 108(19):7896-901. PMID: 21464309.
      View in: PubMed
    30. 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. PMID: 21278257.
      View in: PubMed
    31. Wayne N, Mishra P, Bolon DN. Hsp90 and client protein maturation. Methods Mol Biol. 2011; 787:33-44. PMID: 21898225.
      View in: PubMed
    32. Wayne N, Bolon DN. Charge-rich regions modulate the anti-aggregation activity of Hsp90. J Mol Biol. 2010 Sep 3; 401(5):931-9. PMID: 20615417.
      View in: PubMed
    33. 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. PMID: 19906642.
      View in: PubMed
    34. Munson M, Bolon DN. Watching proteins in motion. Genome Biol. 2009; 10(10):316. PMID: 19863776.
      View in: PubMed
    35. 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. PMID: 18054791.
      View in: PubMed
    36. 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. PMID: 17908693.
      View in: PubMed
    37. 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. PMID: 17317664.
      View in: PubMed
    38. 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. PMID: 16129838.
      View in: PubMed
    39. 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. PMID: 15989952.
      View in: PubMed
    40. 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. PMID: 15525508.
      View in: PubMed
    41. 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. PMID: 15454077.
      View in: PubMed
    42. 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. PMID: 14967151.
      View in: PubMed
    43. 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. PMID: 14536075.
      View in: PubMed
    44. 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. PMID: 12767838.
      View in: PubMed
    45. Bolon DN, Voigt CA, Mayo SL. De novo design of biocatalysts. Curr Opin Chem Biol. 2002 Apr; 6(2):125-9. PMID: 12038994.
      View in: PubMed
    46. Bolon DN, Mayo SL. Enzyme-like proteins by computational design. Proc Natl Acad Sci U S A. 2001 Dec 4; 98(25):14274-9. PMID: 11724958.
      View in: PubMed
    47. Bolon DN, Mayo SL. Polar residues in the protein core of Escherichia coli thioredoxin are important for fold specificity. Biochemistry. 2001 Aug 28; 40(34):10047-53. PMID: 11513583.
      View in: PubMed
    48. Ambrosino DM, Bolon D, Collard H, Van Etten R, Kanchana MV, Finberg RW. Effect of Haemophilus influenzae polysaccharide outer membrane protein complex conjugate vaccine on macrophages. J Immunol. 1992 Dec 15; 149(12):3978-83. PMID: 1460286.
      View in: PubMed
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