个人简介

B.Sc., University of Wisconsin ?C Stevens Point, 2000 Ph.D., University of Minnesota, 2005 American Cancer Society Postdoctoral Fellow, The Scripps Research Institute, 2007-2010

研究领域

BIOLOGICAL & PHYSICAL CHEMISTRY

The primary focus of our research is to utilize a multidisciplinary approach incorporating structural biology, biophysics, biochemistry, molecular biology and cellular biology to investigate mechanistic questions in the area of transcriptional regulation. We are particularly interested in applying these methodologies to discern structure-function relationships for specialized transcription factors that recognize epigenetically modified methyl-CpG DNA sequences. In eukaryotes, DNA methylation in the context of CpG dinucleotides is an essential epigenetic modification required for genomic stability, regulation of chromatin structure and long-term transcriptional silencing of genes. Aberrant alterations in genomic DNA methylation patterns, leading to inappropriate gene silencing, have been associated with cancer promotion and progression. These findings have prompted an interest in discerning the regulatory mechanisms of DNA methylation in gene transcription by investigating the factors that are involved in modification, recognition, and translation of the methylation signal. Methyl-CpG binding proteins directly read and interpret the methylation signal, making them ideal reporters for the methylation status in the cancerous state. Initial areas of research interest include: 1) identification and characterization of specific methyl-CpG binding protein DNA targets utilizing a parallel in vitro biophysical and in cell genomic approach to delineate the molecular mechanisms by which these proteins recognize DNA and regulate transcription in cancer; 2) structural investigations of these DNA interactions to ascertain differential modes of recognition between various methyl-CpG binding proteins; and 3) structural and biophysical characterizations of protein/protein interactions to begin evaluating how interpretation of the methylation signal triggers chromatin remodeling. Structural evaluation of methyl-CpG binding proteins with their interaction partners is critical for gaining mechanistic insight into the complex roles of these proteins in cancer epigenetics. Further, as important interpreters of methylation status in the cancerous state, methyl-CpG binding protein binding activities can be exploited for identifying cancer-specific methylated genes that may have diagnostic value. Thus, this combined research approach may provide the means for identifying epigenetic-based biomarkers as well as establish the basis for advancing therapeutic design directed toward key methyl-CpG binding protein regulatory networks/pathways.

近期论文

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Buck-Koehntop, B. A.; Defossez, P.-A. On how Mammalian Transcription Factors Recognize Methylated DNA. Epigenetics2013, 8, 131-137. Buck-Koehntop, B. A.; Stanfield, R. L.; Ekiert, D. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wilson, I. A.; Wright, P. E. Molecular Basis for Recognition of Methylated and Specific DNA Sequences by the Zinc Finger Protein Kaiso. Proc. Nat. Acad. Sci.2012, 109, 15229-15234. Buck-Koehntop, B. A.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Kaiso uses all Three Zinc Fingers and Adjacent Sequence Motifs for High Affinity Binding to Sequence-specific and Methyl-CpG DNA Targets. FEBS Lett.2012, 586, 734-739. Porcelli, F.; Triggiani, D.; Buck-Koehntop, B. A.; Masterson, L. R.; Veglia, G. Pseudoenzymatic Dealkylation of Alkyltins by Biological Dithiols. J. Biol. Inorg. Chem.2009, 14, 1219-1225. Buck-Koehntop, B. A.; Lee, B. M.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Embryonic Neural Inducing Factor Churchill is not a DNA-binding Zinc Finger Protein: Solution Structure Reveals a Solvent-exposed beta-Sheet and Zinc Binuclear Cluster. J. Mol. Biol.2007, 371, 1274-1289. Buck-Koehntop, B. A.; Porcelli, F.; Lewin, J. L.; Cramer, C. J.; Veglia, G. Biological Chemistry of Organotin Compounds: Interactions and Dealkylation by Dithiols. J. Organomet. Chem. 2006, 691, 1748-1755. Porcelli, F.; Buck-Koehntop, B. A.; Thennarasu, S.; Ramamoorthy, A.; Veglia, G. Structures of the Dimeric and Monomeric Variants of Magainin Antimicrobial Peptides (MSI-78 and MSI-594) in Micelles and Bilayers, Determined by NMR Spectroscopy. Biochemistry2006, 45, 5793-5799. Billingsley, M. L.; Yun, J.; Reese, B. E.; Davidson, C. E.; Buck-Koehntop, B. A.; Veglia, G. Functional and Structural Properties of Stannin: Roles in Cellular Growth, Selective Toxicity, and Mitochondrial Responses to Injury. J. Cell. Biochem. 2006, 98, 243-250. Buffy, J. J.; Buck-Koehntop, B. A.; Porcelli, F.; Traaseth, N. J.; Thomas, D. D.; Veglia, G. Defining the Intramembrane Binding Mechanism of Sarcolipin to Calcium ATPase Using Solution NMR Spectroscopy. J. Mol. Biol. 2006, 358, 420-429. Buck-Koehntop, B. A.; Mascioni, A.; Buffy, J. J.; Veglia, G. Structure, Dynamics, and Membrane Topology of Stannin: A Mediator of Neuronal Cell Apoptosis Induced by Trimethyltin Chloride. J. Mol. Biol. 2005, 354, 652-665. Porcelli, F.; Buck, B.; Lee, D. K.; Hallock, K. J.; Ramamoorthy, A.; Veglia, G. Structure and Orientation of Pardaxin Determined by NMR Experiments in Model Membranes. J. Biol. Chem. 2004, 279, 45815-45823. Buck, B. A.; Mascioni, A.; Cramer, C. J.; Veglia, G. Interactions of Alkyltin Salts with Biological Dithiols: Dealkylation and Induction of a Regular b-Turn Structure. J. Am. Chem. Soc. 2004, 126, 14400-14410. Buck, B.; Mascioni, A.; Que, L. Jr.; Veglia, G. Dealkylation of Organotin Compounds by Biological Dithiols: Toward the Chemistry of Organotin Toxicity. J. Am. Chem. Soc. 2003, 125, 13316-13317. Buck, B.; Zamoon, J.; Desilva, T. M.; Karim, C.; Kirby, T. L.; Thomas, D.; Veglia, G. Overexpression, Purification and Characterization of Recombinant Ca-ATPase Regulators for High Resolution Solution and Solid-State NMR Studies. Protein Exp. Purif. 2003, 30, 253-261.