SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R C E L L B I O L O G Y P R O G R A M that is activated in response to defects in DNA replication initiation. The laboratory currently is continuing efforts to identify proteins that are involved in the early steps of DNA synthesis and how these proteins may be involved in the activation of a checkpoint pathway that prevents premature entry into mitosis. SELECTED PUBLICATIONS 2003 Wiley, DJ, Marcus, S, D’Urso, G, and Verde, F. Control of cell polarity in fission yeast by association of Orb6p kinase with the highly conserved protein methyltransferase Skb1p. Journal of Biological Chemistry 278:25256-63, 2003. Feng, W, Rodriguez-Menocal, L, Tolun, G, and D’Urso, G. Schizosacchromyces pombe Dpb2 binds to origin DNA early in S phase and is required for chromosomal DNA replication. Molecular Biology of the Cell 14:3427-36, 2003. Burhans, WC, Weinberger, J, Marchetti, MA, Ramachandran, L, D’Urso, G, and Huberman, J. Apoptosis-like yeast cell death in response to DNA damage and replication defects. Mutation Research 532:227-43, 2003. HIGHLIGHTS/DISCOVERIES • Pol ε is required for initiation of DNA replication. These results were particularly important because Pol ε had earlier been shown to be nonessential for SV40 viral DNA replication, an extensively used model system of eukaryotic DNA replication. • Loss of the catalytic domains of this enzyme had no effect on cell viability in yeast. • These findings and observations led to an understanding of the role of Pol ε in DNA replication, and suggested that Pol ε provides multiple functions in promoting DNA replication. Recent data from this laboratory suggest that at least one of these functions is to facilitate assembly of the DNA replication initiation complex. TERACE M. FLETCHER, PH.D. Assistant Professor of Biochemistry and Molecular Biology DESCRIPTION OF RESEARCH Dr. Fletcher’s research interests focus on chromatin structure and steroid hormone regulation of transcription, telomere chromatin structure and genomic stability, telomerase biochemistry, and mechanisms of inhibition. The eukaryotic genome is organized into complex DNA-protein macromolecular assemblies known as chromatin. Chromatin has both an architectural and regulatory function in the nucleus. Dr. Fletcher’s laboratory efforts are concentrated in two processes influenced by chromatin structure: telomere maintenance and transcription. Telomere Chromatin Structure Telomeres, specialized nucleoprotein complexes at the end of chromosomes, have a crucial role in genomic stability. Disruption of telomere structure induces cell growth arrest or death. Cancer cells, unlike most normal somatic cells, maintain stable telomeres through the activation of the telomere-specific DNA polymerase, telomerase. Dr. Fletcher is particularly interested in the structural features of telomere higher-order assemblies and the mechanisms by which different telomere configurations are formed. Possible influences on telomere structure are telomerase activity, telomere length, association of telomere binding and DNA repair proteins, and DNA structure. To structurally and biochemically characterize telomere chromatin, Dr. Fletcher’s laboratory is reconstituting model telomeres in vitro. They use these model telomeres to determine recruitment of telomere binding and DNA repair proteins under certain conditions. They also are interested in the effects of telomere structure on functions such as telomerase activity and chromosome end protection. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 73
T U M O R C E L L B I O L O G Y P R O G R A M Finally, researchers in her laboratory are investigating the biochemical and hydrodynamic properties of telomere higher-order structures. One hydrodynamic method they will focus on is a unique agarose gel electrophoresis technique. This technique allows the investigator to analyze surface electrical charge density and solution structure of large macromolecular DNA/protein assemblies from either purified components or in complex mixtures. Dr. Fletcher and her colleagues are applying this technique to study the structure of native telomeres isolated from nuclei. Chromatin Structure and Transcription It is well established that the same promoter sequence in different chromatin contexts has diverse responses to cellular signals. The biochemical mechanisms by which nucleosomes, the fundamental units of chromatin, exert their influence are under intense investigation. The role of chromatin higher-order structures in transcriptional activation, however, is still largely unexplored. A goal of Dr. Fletcher’s research is to simultaneously analyze the structural characteristics of chromatin and transcriptional activation under various reaction conditions. Specifically, her laboratory is interested in the reciprocal relationship between transcription factors and their chromatin targets. Research efforts include reconstituting promoters and coding regions into chromatin in vitro and analyzing protein binding, chromatin remodeling, and transcriptional activation. Dr. Fletcher and her colleagues also are characterizing the solution structure of these chromatin fibers, both reconstituted in vitro and isolated from cells. SELECTED PUBLICATIONS 2002 Fletcher, TM, Xiao, N, Mautino, G, Baumann, CT, Wolford, R, Warren, BS, and Hager, GL. ATP-dependent mobilization of the glucocorticoid receptor during chromatin remodeling. Molecular and Cellular Biology 22:3255-63, 2002. Lu, H, Pise-Masison, CA, Fletcher, TM, Schiltz, RL, Nagaich, AK, Radonovich, M, Hager, G, Cole, PA, and Brady, JN. Acetylation of nucleosomal histones by p300 facilitates transcription from tax-responsive human T-cell leukemia virus type 1 chromatin template. Molecular and Cellular Biology 22:4450-62, 2002. Keeton, EK, Fletcher, TM, Baumann, CT, Hager, GL, and Smith, CL. Glucocorticoid receptor domain requirements for chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter in different nucleoprotein contexts. Journal of Biological Chemistry 277:28247-55, 2002. 2003 Georgel, PT, Fletcher, TM, Hager, GL, and Hansen, JC. Formation of higher-order secondary and tertiary chromatin structures by genomic mouse mammary tumor virus promoters. Genes & Development 17:1617-29, 2003. Fletcher, TM. Telomere higher-order structure and genomic instability. IUBMB Life 55:443-49, 2003. HIGHLIGHTS/DISCOVERIES • Obtained patent for methods and compositions for modulation and inhibition of telomerase. 74 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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G L O S S A R Y IFN—interferon IL
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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