Danica Galonić Fujimori, PhD

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Danica Galonić Fujimori, PhD

Assistant Professor of Cellular and Molecular Pharmacology and Pharmaceutical Chemistry, UCSF

danica.fujimori@ucsf.edu

Phone: (415) 514-0147
Box 2280, UCSF
San Francisco, CA 94143-2280

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Cancer Center Membership

Associate Member » Developmental Therapeutics

Research Summary

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.

Education

University of Belgrade, Belgrade, Serbia BSc 07/2000 Chemistry
University of Illinois, Urbana, IL PhD 05/2005 Chemistry
Harvard Medical School, Boston, MA Postdoc 06/2008 Biochemistry
 

 


Professional Experience

  • 7/05-6/08
    Postdoctoral Fellow, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
  • 7/08-pres.
    Assistant Professor, Department of Cellular and Molecular Pharmacology, Department of Pharmaceutical Chemistry, University of California San Francisco

Honors & Awards

  • 2000
    Serbian Chemical Society Outstanding Undergraduate Student Award
  • 2001
    University of Illinois Teachers Rated as Excellent
  • 2003
    Procter and Gamble Predoctoral Fellowship
  • 2004
    University of Illinois Pines Predoctoral Fellowship
  • 2005
    Damon Runyon Cancer Research Foundation Postdoctoral Fellowship
  • 2007
    NIH Pathway to Independence Award
  • 2009
    Kimmel Scholar Award
  • 2010
    V Foundation Scholar Award
  • 2011
    Basil O'Connor Starter Scholar Award, March of Dimes
  • 2011
    NSF CAREER Award
  • 2011
    Searle Scholar Award
  • 2014
    UCSF Excellence in Teaching Award

Selected Publications

  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.
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  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.
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  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.
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  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.
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  5. Stojkovic V, Fujimori DG. Radical SAM-Mediated Methylation of Ribosomal RNA. Methods Enzymol. 2015; 560:355-76.
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  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.
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  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.
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  8. Fujimori DG. Radical SAM-mediated methylation reactions. Curr Opin Chem Biol. 2013 Aug; 17(4):597-604.
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  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.
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  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.
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  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.
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  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.
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  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.
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  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.
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  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.
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  16. Fujimori DG. A novel enzymatic rearrangement. Chem Biol. 2010 Dec 22; 17(12):1269-70.
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  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.
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  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.
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  19. Fujimori DG. Hypoxia sensing goes gauche. Nat Chem Biol. 2009 Apr; 5(4):202-3.
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  20. Neumann CS, Fujimori DG, Walsh CT. Halogenation strategies in natural product biosynthesis. Chem Biol. 2008 Feb; 15(2):99-109.
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