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    Danica Galonic Fujimori, PhD

    TitleAssociate Professor
    SchoolUCSF School of Medicine
    DepartmentCellular Molecular Pharmacology
    Address600 16th St
    San Francisco CA 94158
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      Collapse Biography 
      Collapse Awards and Honors
      University of California, Berkeley 2015Sackler Sabbatical Exchange Program
      University of California, San Francisco2015Chauncey D. Leake Lectureship in Cellular and Molecular Pharmacology
      University of California, San Francisco2014UCSF Haile T. Debas Academy of Medical Educators Excellence in Teaching Award
      Kinship Foundation2011Searle Scholar Award
      National Science Foundation2011NSF Career Award
      March of Dimes2011Basil O'Connor Starter Scholar Research Award
      V Foundation2010V Foundation Scholar Award
      Hellman Family Foundation2010Hellman Family Early-Career Faculty Award
      Sidney Kimmel Foundation for Cancer Research2009Kimmel Scholar Award
      National Institutes of Health2007NIH Pathway to Independence Award
      Damon Runyon Cancer Research Foundation 2005Postdoctoral Fellowship

      Collapse Overview 
      Collapse Overview
      Our group investigates mechanisms, regulation, and biological functions of methyl group addition to proteins and RNA. Methylation, a common post-transcriptional and post-translational modification, has a profound effect on the regulation of fundamental biological processes such as gene expression, cellular localization, and RNA structure and function. Deregulation of methylation is associated with a wide range of diseases. The enzymatic regulation of methyl group addition and removal provides an opportunity for therapeutic intervention. We seek to understand the molecular mechanisms that control methylation, and develop chemical probes to interrogate the pathophysiological function of enzymes that regulate this modification. Specifically, our research focuses on the following areas:

      Regulation and Small Molecule Inhibition of Jumonji Histone Demethylases
      Jumonji histone demethylases, a family of epigenetic “erasers”, catalyze the removal of methyl marks from lysine residues in proteins. Jumonji demethylases are complex proteins that, in addition to the catalytic domain, often contain one or more chromatin “reader” domains. The reader modules commonly interact with chromatin, and this interaction can be modulated by chromatin modifications. We investigate the functional cross-talk between chromatin recognition and demethylation in the jumonji family to understand how chromatin context impacts methyl mark removal, and consequently transcription. Furthermore, we are interested in understanding how additional regulatory inputs, such as metabolism and cellular signaling cascades, influence chromatin methylation and transcriptional regulation. In addition, our lab is actively involved in the development of small molecule inhibitors of the jumonji demethylases that can be used as cellular probes of their function. We use both rational design and high-throughput screening to identify starting scaffolds, and further optimize these scaffolds through iterative cycles of chemical synthesis and testing their potency and selectivity. Our goal is to use these molecules to inhibit aberrant demethylation caused by misregulation of demethylases in disease models.

      Mechanisms and Cellular Roles of RNA Methylation
      Methylation of RNA is the abundant post-transcriptional modification identified in various types of RNAs. Despite its prevalence, the functional role of methylation is poorly understood. We are interested in elucidating the mechanisms responsible for RNA methylation, and understanding the role this modification plays in controlling the cellular function of RNA. We are particularly interested in 2-methyl and 8-methyladenosine modifications, catalyzed by related enzymes that utilize an unusual mechanism to achieve methylation. Incorporation of 2-methyladenosine into RNA has been implicated in the regulation of translational fidelity, although the mechanisms by which this is achieved are yet to be elucidated. In contrast, 8-methyladenosine formation is responsible for resistance to five chemically distinct classes of antibiotics that target the peptidyltransferase center of the bacterial ribosome, including linezolid. We investigate catalytic mechanisms, substrate recognition, and evolution of function in enzymes that carry out these methylations. Our goal is to determine the impact of methylation on the cellular function of substrate RNA.

      Collapse Interests
      Histone Demethylases, Chromatin, Epigenetics, Cancer, Radical SAM Enzymes, Antibiotics Resistance

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      Collapse In The News
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      Collapse Global Health
      Collapse Featured Publications

      Collapse Bibliographic 
      Collapse Publications
      Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
      List All   |   Timeline
      1. Pack LR, Yamamoto KR, Fujimori DG. Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C). J Biol Chem. 2016 Mar 18; 291(12):6060-70. PMID: 26747609.
        View in: PubMed
      2. Korczynska M, Le DD, Younger N, Gregori-Puigjané E, Tumber A, Krojer T, Velupillai S, Gileadi C, Nowak RP, Iwasa E, Pollock SB, Ortiz Torres I, Oppermann U, Shoichet BK, Fujimori DG. Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors. J Med Chem. 2016 Feb 25; 59(4):1580-98. PMID: 26699912.
        View in: PubMed
      3. Torres IO, Fujimori DG. Functional coupling between writers, erasers and readers of histone and DNA methylation. Curr Opin Struct Biol. 2015 Dec; 35:68-75. PMID: 26496625.
        View in: PubMed
      4. Lu J, Trnka MJ, Roh SH, Robinson PJ, Shiau C, Fujimori DG, Chiu W, Burlingame AL, Guan S. Improved Peak Detection and Deconvolution of Native Electrospray Mass Spectra from Large Protein Complexes. J Am Soc Mass Spectrom. 2015 Dec; 26(12):2141-51. PMID: 26323614.
        View in: PubMed
      5. Stojkovic V, Fujimori DG. Radical SAM-Mediated Methylation of Ribosomal RNA. Methods Enzymol. 2015; 560:355-76. PMID: 26253978; PMCID: PMC4530497.
      6. Torres IO, Kuchenbecker KM, Nnadi CI, Fletterick RJ, Kelly MJ, Fujimori DG. Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism. Nat Commun. 2015; 6:6204. PMID: 25686748.
        View in: PubMed
      7. Dumesic PA, Homer CM, Moresco JJ, Pack LR, Shanle EK, Coyle SM, Strahl BD, Fujimori DG, Yates JR, Madhani HD. Product binding enforces the genomic specificity of a yeast polycomb repressive complex. Cell. 2015 Jan 15; 160(1-2):204-18. PMID: 25533783; PMCID: PMC4303595 [Available on 01/15/16].
      8. Fujimori DG. Radical SAM-mediated methylation reactions. Curr Opin Chem Biol. 2013 Aug; 17(4):597-604. PMID: 23835516; PMCID: PMC3799849.
      9. Shiau C, Trnka MJ, Bozicevic A, Ortiz Torres I, Al-Sady B, Burlingame AL, Narlikar GJ, Fujimori DG. Reconstitution of nucleosome demethylation and catalytic properties of a Jumonji histone demethylase. Chem Biol. 2013 Apr 18; 20(4):494-9. PMID: 23601638; PMCID: PMC3704229.
      10. Le DD, Cortesi AT, Myers SA, Burlingame AL, Fujimori DG. Site-specific and regiospecific installation of methylarginine analogues into recombinant histones and insights into effector protein binding. J Am Chem Soc. 2013 Feb 27; 135(8):2879-82. PMID: 23398247; PMCID: PMC4260808.
      11. McCusker KP, Medzihradszky KF, Shiver AL, Nichols RJ, Yan F, Maltby DA, Gross CA, Fujimori DG. . . Covalent Intermediate in the Catalytic Mechanism of the Radical S-Adenosyl-l-methionine Methyl Synthase RlmN Trapped by Mutagenesis. J Am Chem Soc. 2012; 134(43):18074-81.
      12. McCusker KP, Medzihradszky KF, Shiver AL, Nichols RJ, Yan F, Maltby DA, Gross CA, Fujimori DG. Covalent intermediate in the catalytic mechanism of the radical S-adenosyl-L-methionine methyl synthase RlmN trapped by mutagenesis. J Am Chem Soc. 2012 Oct 31; 134(43):18074-81. PMID: 23088750; PMCID: PMC3499099.
      13. Le DD, Fujimori DG. Protein and nucleic acid methylating enzymes: mechanisms and regulation. Curr Opin Chem Biol. 2012 Dec; 16(5-6):507-15. PMID: 23085277; PMCID: PMC3545634.
      14. McCusker KP, Fujimori DG. The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance. ACS Chem Biol. 2012 Jan 20; 7(1):64-72. PMID: 22208312; PMCID: PMC3499096.
      15. Yan F, Fujimori DG. RNA methylation by radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift. Proc Natl Acad Sci U S A. 2011 Mar 8; 108(10):3930-4. PMID: 21368151; PMCID: PMC3054002.
      16. Fujimori DG. A novel enzymatic rearrangement. Chem Biol. 2010 Dec 22; 17(12):1269-70. PMID: 21168760.
        View in: PubMed
      17. Yan F, LaMarre JM, Röhrich R, Wiesner J, Jomaa H, Mankin AS, Fujimori DG. RlmN and Cfr are radical SAM enzymes involved in methylation of ribosomal RNA. J Am Chem Soc. 2010 Mar 24; 132(11):3953-64. PMID: 20184321; PMCID: PMC2859901.
      18. Wong C, Fujimori DG, Walsh CT, Drennan CL. Structural analysis of an open active site conformation of nonheme iron halogenase CytC3. J Am Chem Soc. 2009 Apr 8; 131(13):4872-9. PMID: 19281171; PMCID: PMC2663892.
      19. Fujimori DG. Hypoxia sensing goes gauche. Nat Chem Biol. 2009 Apr; 5(4):202-3. PMID: 19295524.
        View in: PubMed
      20. Neumann CS, Fujimori DG, Walsh CT. Halogenation strategies in natural product biosynthesis. Chem Biol. 2008 Feb; 15(2):99-109. PMID: 18291314.
        View in: PubMed
      21. Neidig ML, Brown CD, Light KM, Fujimori DG, Nolan EM, Price JC, Barr EW, Bollinger JM, Krebs C, Walsh CT, Solomon EI. CD and MCD of CytC3 and taurine dioxygenase: role of the facial triad in alpha-KG-dependent oxygenases. J Am Chem Soc. 2007 Nov 21; 129(46):14224-31. PMID: 17967013; PMCID: PMC2525739.
      22. Fujimori DG, Barr EW, Matthews ML, Koch GM, Yonce JR, Walsh CT, Bollinger JM, Krebs C, Riggs-Gelasco PJ. Spectroscopic evidence for a high-spin Br-Fe(IV)-oxo intermediate in the alpha-ketoglutarate-dependent halogenase CytC3 from Streptomyces. J Am Chem Soc. 2007 Nov 7; 129(44):13408-9. PMID: 17939667.
        View in: PubMed
      23. Fujimori DG, Hrvatin S, Neumann CS, Strieker M, Marahiel MA, Walsh CT. Cloning and characterization of the biosynthetic gene cluster for kutznerides. Proc Natl Acad Sci U S A. 2007 Oct 16; 104(42):16498-503. PMID: 17940045; PMCID: PMC2034236.
      24. Fujimori DG, Walsh CT. What's new in enzymatic halogenations. Curr Opin Chem Biol. 2007 Oct; 11(5):553-60. PMID: 17881282; PMCID: PMC2151916.
      25. Krebs C, Galonic Fujimori D, Walsh CT, Bollinger JM. Non-heme Fe(IV)-oxo intermediates. Acc Chem Res. 2007 Jul; 40(7):484-92. PMID: 17542550; PMCID: PMC3870002.
      26. Galonic DP, Gin DY. Chemical glycosylation in the synthesis of glycoconjugate antitumour vaccines. Nature. 2007 Apr 26; 446(7139):1000-7. PMID: 17460660; PMCID: PMC2631661.
      27. Kelly WL, Boyne MT, Yeh E, Vosburg DA, Galonic DP, Kelleher NL, Walsh CT. Characterization of the aminocarboxycyclopropane-forming enzyme CmaC. Biochemistry. 2007 Jan 16; 46(2):359-68. PMID: 17209546.
        View in: PubMed
      28. Galonic DP, Barr EW, Walsh CT, Bollinger JM, Krebs C. Two interconverting Fe(IV) intermediates in aliphatic chlorination by the halogenase CytC3. Nat Chem Biol. 2007 Feb; 3(2):113-6. PMID: 17220900.
        View in: PubMed
      29. Ueki M, Galonic DP, Vaillancourt FH, Garneau-Tsodikova S, Yeh E, Vosburg DA, Schroeder FC, Osada H, Walsh CT. Enzymatic generation of the antimetabolite gamma,gamma-dichloroaminobutyrate by NRPS and mononuclear iron halogenase action in a streptomycete. Chem Biol. 2006 Nov; 13(11):1183-91. PMID: 17114000.
        View in: PubMed
      30. Galonic DP, Vaillancourt FH, Walsh CT. Halogenation of unactivated carbon centers in natural product biosynthesis: trichlorination of leucine during barbamide biosynthesis. J Am Chem Soc. 2006 Mar 29; 128(12):3900-1. PMID: 16551084.
        View in: PubMed
      31. Galonic DP, Ide ND, van der Donk WA, Gin DY. Aziridine-2-carboxylic acid-containing peptides: application to solution- and solid-phase convergent site-selective peptide modification. J Am Chem Soc. 2005 May 25; 127(20):7359-69. PMID: 15898784.
        View in: PubMed
      32. Galonic DP, van der Donk WA, Gin DY. Site-selective conjugation of thiols with aziridine-2-carboxylic acid-containing peptides. J Am Chem Soc. 2004 Oct 13; 126(40):12712-3. PMID: 15469231.
        View in: PubMed
      33. Galonic DP, Van Der Donk WA, Gin DY. Oligosaccharide-peptide ligation of glycosyl thiolates with dehydropeptides: synthesis of S-linked mucin-related glycopeptide conjugates. Chemistry. 2003 Dec 15; 9(24):5997-6006. PMID: 14679512.
        View in: PubMed
      34. Gieselman MD, Zhu Y, Zhou H, Galonic D, van der Donk WA. Selenocysteine derivatives for chemoselective ligations. Chembiochem. 2002 Aug 2; 3(8):709-16. PMID: 12203969.
        View in: PubMed
      35. Lalic G, Galonic D, Matovic R, Saicic RN. . J Serb Chem Soc. Model Study of Epothilone Synthesis: An Alternative Synthetic Approach to the C1-C7 fragment. 2002; 67:221-7.
      36. Lalic G, Petrovski Z, Galonic DP, Matovic R, Saicic RN. . Tetrahedron. Alkylation of Carbonyl Compounds in the TiCl4-promoted Reaction of Trimethylsilyl Enol Ethers with Epoxides. 2001; 57:583-591.
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