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    Paul D Kaufman PhD

    TitleProfessor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    364 Plantation Street, LRB-506
    Worcester MA 01605
    Phone508-856-5016
      Other Positions
      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

      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentProgram in Gene Function and Expression

        Overview 
        Narrative

        Academic Background

        Paul Kaufman received his A.B. in Biochemistry from the University of California, Berkeley and his Ph.D. in Biology from MIT. He was a postdoctoral fellow at Cold Spring Harbor Laboratory, where he was supported by the Life Sciences Research Foundation. He went on to become a Career Staff Scientist at the Lawrence Berkeley National Laboratory and Associate Adjunct Professor of Biochemistry and Molecular Biology at the University of California, Berkeley. Dr. Kaufman joined the Program in Gene Function and Expression at the University of Massachusetts Medical School as an Associate Professor in 2005 and was promoted to Full Professor in 2011.

        Current Lab Projects

        Photo: Paul D. Kaufman, Ph.D.

        We study several different classes of chromatin proteins used by human cells to regulate chromosome structure and function. We also investigate small molecule probes of pathogenesis mechanisms in the pathogenic yeast Candida albicans.

        Regulation of human nucleolar DNA interactions by chromatin proteins

        We have a long-term interest in proteins that deliver histones to DNA.  These studies include detailed analysis of the DNA-replication linked histone deposition factor termed Chromatin Assembly Factor-1 (CAF-1). CAF-1 is a three-subunit protein complex conserved throughout eukaryotes. Via its nucleosome assembly activity, CAF-1 is important for DNA replication, DNA repair, and heterochromatin formation. CAF-1 protein levels correlate with cell proliferation and cancer prognosis, making it a high priority for the medically important studies of genome stability and the maintenance of epigenetic states.

        Via mass spectrometry, we discovered multiple nucleolar proteins associated with the human CAF-1 subunit termed p150. Notably, acute depletion of p150 causes redistribution of multiple nucleolar proteins and reduces nucleolar association with several repetitive element-containing loci. The nucleolar functions of p150 are separable from its interactions with the other subunits of the CAF-1 complex, because an N-terminal fragment of p150 (p150N) that cannot interact with other CAF-1 subunits is sufficient for maintaining nucleolar chromosome and protein associations. Therefore, these data define novel functions for a separable domain of the p150 protein, regulating protein and DNA interactions at the nucleolus. (See Smith et al., Mol. Biol. Cell (2014) for details.) We are currently performing genome-scale analysis of the contributions of p150 to human chromosome interactions and functions.

         
         

        Human cells before (left panels) or after (right panels) depletion of the p150 subunit of Chromatin Assembly Factor-1. p150 depletion results in reduced localization of the proliferation marker protein Ki67 with nucleoli (green, in upper panels, showing HT1080 fibrosarcoma cells). p150 depletion also causes reduced association of alpha satellite DNA repeats from chromosome 17 (red spots, lower panels) with nucleoli (green, lower panels) in HeLa cells (lower panels, nuclear DNA stained blue with DAPI). See the article by Smith et al. MBoC (2014).

        Small molecule approaches to fungal pathogens


        We have perfomed a high-throughput screen for compounds that prevent adhesion, the first step in biofilm formation by the fungal pathogen Candida albicans. This lead to our discovery of a series of compounds that have multiple activities relevant to pathogenesis, including development of hyphal morphology and biofilm formation (Fazly et al., PNAS 110(33):13594-9 (2013)). We are using these molecules to probe pathogenic mechanisms in multiple species, with particular attention to how our lead compound, termed "filastatin", inhibits filamentation in response to multiple external stimuli. We are also exploring how these compounds can be incorporated into medical plastics and medical device coatings and how they alter biofilm formation in that context.

        User Image

        Filastatin is a small molecule inhibitor of filament formation by the fungal pathogen, Candida albicans. The chemical structure of filastatin is shown on the right. Cells were induced to form filamentous hyphae; filastatin was added to the cells shown in the rightmost photographs. The upper photographs show the cell morphology, the images on the bottom show induction of a red fluorescent protein specifically in hyphal cells. See Fazly et al., PNAS 110(33):13594-9 (2013) for details.

         



        Rotation Projects

        Rotation Projects

        1. Genome-wide analysis of chromatin protein occupancy in human cells.

        2. Genome-wide analysis of gene expression in pathogenic fungi.

        3. Biochemical and pharmacological analysis of candidate antifungal compounds.



        Rotation Projects

        1. Genome-wide analysis of nucleolar chromosome interactions in human cells.

        2.  Proteomic analysis of factors involved in chromosome interaction networks.

        3. Genome-wide analysis of gene expression in pathogenic fungi in response to small molecule inhibitors.

        4. Biochemical and pharmacological analysis of candidate antifungal compounds.





         

         

        Rotation Projects

         



         

         

        Rotation Projects

         

        1. Genome-wide analysis of nucleolar chromosome interactions in human cells.

        2.  Proteomic analysis of factors involved in chromosome interaction networks.

        3. Genome-wide analysis of gene expression in pathogenic fungi in response to small molecule inhibitors.

        4. Biochemical and pharmacological analysis of candidate antifungal compounds



         

         

         



        Post Docs

        A postdoctoral position is available to study in this laboratory.  Contact Dr. Kaufman for additional details.



        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Smith CL, Matheson TD, Trombly DJ, Sun X, Campeau E, Han X, Yates JR, Kaufman PD. A separable domain of the p150 subunit of human Chromatin Assembly Factor-1 promotes protein and chromosome associations with nucleoli. Mol Biol Cell. 2014 Jul 23.
          View in: PubMed
        2. Lopes da Rosa J, Bajaj V, Spoonamore J, Kaufman PD. A small molecule inhibitor of fungal histone acetyltransferase Rtt109. Bioorg Med Chem Lett. 2013 May 15; 23(10):2853-9.
          View in: PubMed
        3. Kaufman P. Histone chaperones and chromatin assembly. Biochim Biophys Acta. 2013 Mar-Apr; 1819(3-4):195.
          View in: PubMed
        4. Lopes da Rosa J, Kaufman PD. Chromatin-mediated Candida albicans virulence. Biochim Biophys Acta. 2013 Mar-Apr; 1819(3-4):349-55.
          View in: PubMed
        5. Lopes da Rosa J, Kaufman PD. Chromatin-mediated Candida albicans virulence. Biochim Biophys Acta. 2012 Mar; 1819(3-4):349-55.
          View in: PubMed
        6. Kaufman PD. New partners for HP1 in transcriptional gene silencing. Mol Cell. 2011 Jan 7; 41(1):1-2.
          View in: PubMed
        7. Kaufman PD. Toxicity and lifespan extension: complex outcomes of histone overexpression in budding yeast. Cell Cycle. 2010 Dec 1; 9(23):4611-2.
          View in: PubMed
        8. Kolonko EM, Albaugh BN, Lindner SE, Chen Y, Satyshur KA, Arnold KM, Kaufman PD, Keck JL, Denu JM. Catalytic activation of histone acetyltransferase Rtt109 by a histone chaperone. Proc Natl Acad Sci U S A. 2010 Nov 23; 107(47):20275-80.
          View in: PubMed
        9. Lopes da Rosa J, Holik J, Green EM, Rando OJ, Kaufman PD. Overlapping regulation of CenH3 localization and histone H3 turnover by CAF-1 and HIR proteins in Saccharomyces cerevisiae. Genetics. 2011 Jan; 187(1):9-19.
          View in: PubMed
        10. Miller A, Chen J, Takasuka TE, Jacobi JL, Kaufman PD, Irudayaraj JM, Kirchmaier AL. Proliferating cell nuclear antigen (PCNA) is required for cell cycle-regulated silent chromatin on replicated and nonreplicated genes. J Biol Chem. 2010 Nov 5; 285(45):35142-54.
          View in: PubMed
        11. Erkmann JA, Kaufman PD. A negatively charged residue in place of histone H3K56 supports chromatin assembly factor association but not genotoxic stress resistance. DNA Repair (Amst). 2009 Dec 3; 8(12):1371-9.
          View in: PubMed
        12. Campeau E, Ruhl VE, Rodier F, Smith CL, Rahmberg BL, Fuss JO, Campisi J, Yaswen P, Cooper PK, Kaufman PD. A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS One. 2009; 4(8):e6529.
          View in: PubMed
        13. Kaplan T, Liu CL, Erkmann JA, Holik J, Grunstein M, Kaufman PD, Friedman N, Rando OJ. Cell cycle- and chaperone-mediated regulation of H3K56ac incorporation in yeast. PLoS Genet. 2008 Nov; 4(11):e1000270.
          View in: PubMed
        14. Tsubota T, Berndsen CE, Erkmann JA, Smith CL, Yang L, Freitas MA, Denu JM, Kaufman PD. Histone H3-K56 acetylation is catalyzed by histone chaperone-dependent complexes. Mol Cell. 2007 Mar 9; 25(5):703-12.
          View in: PubMed
        15. Antczak AJ, Tsubota T, Kaufman PD, Berger JM. Structure of the yeast histone H3-ASF1 interaction: implications for chaperone mechanism, species-specific interactions, and epigenetics. BMC Struct Biol. 2006; 6:26.
          View in: PubMed
        16. Green EM, Antczak AJ, Bailey AO, Franco AA, Wu KJ, Yates JR, Kaufman PD. Replication-independent histone deposition by the HIR complex and Asf1. Curr Biol. 2005 Nov 22; 15(22):2044-9.
          View in: PubMed
        17. Sharp JA, Rizki G, Kaufman PD. Regulation of histone deposition proteins Asf1/Hir1 by multiple DNA damage checkpoint kinases in Saccharomyces cerevisiae. Genetics. 2005 Nov; 171(3):885-99.
          View in: PubMed
        18. Franco AA, Lam WM, Burgers PM, Kaufman PD. Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C. Genes Dev. 2005 Jun 1; 19(11):1365-75.
          View in: PubMed
        19. Sharp JA, Krawitz DC, Gardner KA, Fox CA, Kaufman PD. The budding yeast silencing protein Sir1 is a functional component of centromeric chromatin. Genes Dev. 2003 Oct 1; 17(19):2356-61.
          View in: PubMed
        20. Sutton A, Shia WJ, Band D, Kaufman PD, Osada S, Workman JL, Sternglanz R. Sas4 and Sas5 are required for the histone acetyltransferase activity of Sas2 in the SAS complex. J Biol Chem. 2003 May 9; 278(19):16887-92.
          View in: PubMed
        21. Ye X, Franco AA, Santos H, Nelson DM, Kaufman PD, Adams PD. Defective S phase chromatin assembly causes DNA damage, activation of the S phase checkpoint, and S phase arrest. Mol Cell. 2003 Feb; 11(2):341-51.
          View in: PubMed
        22. Sharp JA, Kaufman PD. Chromatin proteins are determinants of centromere function. Curr Top Microbiol Immunol. 2003; 274:23-52.
          View in: PubMed
        23. Formosa T, Ruone S, Adams MD, Olsen AE, Eriksson P, Yu Y, Rhoades AR, Kaufman PD, Stillman DJ. Defects in SPT16 or POB3 (yFACT) in Saccharomyces cerevisiae cause dependence on the Hir/Hpc pathway: polymerase passage may degrade chromatin structure. Genetics. 2002 Dec; 162(4):1557-71.
          View in: PubMed
        24. Krawitz DC, Kama T, Kaufman PD. Chromatin assembly factor I mutants defective for PCNA binding require Asf1/Hir proteins for silencing. Mol Cell Biol. 2002 Jan; 22(2):614-25.
          View in: PubMed
        25. Sharp JA, Franco AA, Osley MA, Kaufman PD. Chromatin assembly factor I and Hir proteins contribute to building functional kinetochores in S. cerevisiae. Genes Dev. 2002 Jan 1; 16(1):85-100.
          View in: PubMed
        26. Kaufman PD, Cohen JL, Osley MA. Hir proteins are required for position-dependent gene silencing in Saccharomyces cerevisiae in the absence of chromatin assembly factor I. Mol Cell Biol. 1998 Aug; 18(8):4793-806.
          View in: PubMed
        27. Kaufman PD, Kobayashi R, Stillman B. Ultraviolet radiation sensitivity and reduction of telomeric silencing in Saccharomyces cerevisiae cells lacking chromatin assembly factor-I. Genes Dev. 1997 Feb 1; 11(3):345-57.
          View in: PubMed
        28. Verreault A, Kaufman PD, Kobayashi R, Stillman B. Nucleosome assembly by a complex of CAF-1 and acetylated histones H3/H4. Cell. 1996 Oct 4; 87(1):95-104.
          View in: PubMed
        29. Kaufman PD. Nucleosome assembly: the CAF and the HAT. Curr Opin Cell Biol. 1996 Jun; 8(3):369-73.
          View in: PubMed
        30. Kaufman PD, Kobayashi R, Kessler N, Stillman B. The p150 and p60 subunits of chromatin assembly factor I: a molecular link between newly synthesized histones and DNA replication. Cell. 1995 Jun 30; 81(7):1105-14.
          View in: PubMed
        31. Kamakaka RT, Kaufman PD, Stillman B, Mitsis PG, Kadonaga JT. Simian virus 40 origin- and T-antigen-dependent DNA replication with Drosophila factors in vitro. Mol Cell Biol. 1994 Aug; 14(8):5114-22.
          View in: PubMed
        32. Kaufman PD, Botchan MR. Assembly of nucleosomes: do multiple assembly factors mean multiple mechanisms? Curr Opin Genet Dev. 1994 Apr; 4(2):229-35.
          View in: PubMed
        33. Kaufman PD, Rio DC. P element transposition in vitro proceeds by a cut-and-paste mechanism and uses GTP as a cofactor. Cell. 1992 Apr 3; 69(1):27-39.
          View in: PubMed
        34. Kaufman PD, Rio DC. Germline transformation of Drosophila melanogaster by purified P element transposase. Nucleic Acids Res. 1991 Nov 25; 19(22):6336.
          View in: PubMed
        35. Kaufman PD, Doll RF, Rio DC. Drosophila P element transposase recognizes internal P element DNA sequences. Cell. 1989 Oct 20; 59(2):359-71.
          View in: PubMed
        36. Doll RF, Kaufman PD, Misra S, Rio DC. Molecular biology of Drosophila P-element transposition. Prog Nucleic Acid Res Mol Biol. 1989; 36:47-57.
          View in: PubMed
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