个人简介

B.S. University of California at Davis (1984) M.S. University of Chicago (1989) Ph.D. University of Chicago (1989) Postdoctoral Fellow, Harvard University (1989-1994)

研究领域

Biological/Chemical Biology

The laboratory uses a broad range of molecular, biochemical and biophysical research tools centered around X-ray crystal structure determination to understand the mechanism of chromatin recognition and assembly and post-translational histone and protein modification in the regulation of gene expression; and kinase signaling pathways. The laboratory is particularly interested in gene regulatory proteins and their upstream signaling kinases that are aberrantly regulated in cancer and age-related metabolic disorders such as type II diabetes and obesity, and the use of high-throughput small molecule screening and structure-based design strategies towards the development of protein-specific small-molecule probes to be used to further interrogate protein function and for development into therapeutic agents. Chromatin recognition and assembly and histone modification in gene regulation. DNA within the eukaryotic nucleus is compacted into chromatin containing histone proteins and its appropriate regulation orchestrates all DNA-templated reactions such as DNA transcription, replication, repair, mitosis, and apoptosis. Among the many proteins that regulate chromatin, the proteins that recognize DNA, assemble chromatin, called histone chaperones, and that modify the histones through the addition or removal of functional groups such as acetyl, methyl or phosphate play important roles. We are studying the DNA binding proteins p53, FoxO and the Gal4 family; the histone chaperones HIRA, Asf1, Vps75 and their associated factors; and the family of histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. We are particularly interested in how DNA binding proteins navigate the recognition of their cognate DNA targets, how histone chaperones coordinate the assembly of distinct chromatin complexes correlated with different DNA regulatory processes, and how histone modification enzymes link catalysis to their substrate specific activities for their respective biological activities. More recently, we have been studying how the binding of accessory and regulatory protein subunits regulates the various activities of these proteins and in some cases we are developing small molecule protein specific inhibitors.

近期论文

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Glover SD, Jorge C, Liang L, Valentine KG, Hammarström L, Tommos C (2014) Photochemical tyrosine oxidation in the structurally well-defined α3Y protein: Proton-coupled electron transfer and a long-lived tyrosine radical. J Am Chem Soc 136(40):13941-14320. PMID: 25121576 Moorman VR, Valentine KG, Bédard S, Kasinath V, Dogan J, Love FM, Wand AJ (2014) Dynamic and thermodynamic response of the Ras protein Cdc42Hs upon association with the effector domain of PAK3. Journal of Molecular Biology 426:3520–3538. PMID: 25109462 DeNizio, JE, Elsässer SJ, Black BE (2014) DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues. Nucleic Acids Research 42(7):4318-4331. PMID: 24493739 Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R, Yusuf R, Côté D, Vinogradov SA, David T. Scadden DT, Lin CP (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature PubMed PMID: 24590072 Valentine KG, Mathies G, Bédard S, Nucci NV, Dodevski I, Stetz MA, Can TV, Griffin RG, Wand AJ (2014) Reverse micelles as a platform for dynamic nuclear polarization in solution NMR of proteins. J Am Chem Soc 136(7):2800-2807. PubMed PMID: 24456213 Jackrel ME, DeSantis ME, Martinez BA, Castellano LM, Stewart RM, Caldwell KA, Caldwell GA, Shorter J (2014) Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156(1&2):170-182. PubMed PMID: 24439375 D'Arcy S, Martin KW, Panchenko T, Chen X, Bergeron S, Stargell LA, Black BE, Luger K. (2013) Chaperone Nap1 shields histone surfaces used in a nucleosome and can put H2A-H2B in an unconventional tetrameric form. Mol Cell 51(5):662-677. PubMed PMID: 23973327 Hasson D, Panchenko T, Salimian KJ, Salman MU, Sekulic N, Alonso A, Warburton PE, Black BE (2013) The octamer is the major form of CENP-A nucleosomes at human centromeres. Nat Struct Mol Biol. 20(6):687-695. PubMed PMID: 23644596 Farid TA, Kodali G, Solomon LA, Lichtenstein BR, Sheehan MM, Fry BA, Bialas C, Ennist NM, Siedlecki JA, Zhao Z, Stetz MA, Valentine KG, Anderson JL, Wand AJ, Discher BM, Moser CC, Dutton PL (2013) Elementary tetrahelical protein design for diverse oxidoreductase functions. Nat Chem Biol. doi: 10.1038/nchembio.1362. PubMed PMID: 24121554 Younis I, Dittmar K, Wang W, Foley SW, Berg MG, Hu KY, Wei Z, Wan L, Dreyfuss G (2013) Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA. Elife. 2:e00780. doi: 10.7554/eLife.00780. PubMed PMID: 23908766 Kan ZY, Walters BT, Mayne L, Englander SW (2013) Protein hydrogen exchange at residue resolution by proteolytic fragmentation mass spectrometry analysis. Proc Natl Acad Sci USA 110(41):16438-16443. PubMed PMID: 24019478 Hu W, Walters BT, Kan ZY, Mayne L, Rosen LE, Marqusee S, Englander SW (2013) Stepwise protein folding at near amino acid resolution by hydrogen exchange and mass spectrometry. Proc Natl Acad Sci USA 110(19):7684-7689. PubMed PMID: 2360327 Cho I, Tsai PF, Lake RJ, Basheer A, Fan HY (2013) ATP-dependent chromatin remodeling by Cockayne syndrome protein B and NAP1-like histone chaperones is required for efficient transcription-coupled DNA repair. PLoS Genet 9(4):e1003407. doi: 10.1371/journal.pgen.1003407. PubMed PMID: 23637612 Sridharan R, Gonzales-Cope M, Chronis C, Bonora G, McKee R, Huang C, Patel S, Lopez D, Mishra N, Pellegrini M, Carey M, Garcia BA, Plath K (2013) Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1γ in reprogramming to pluripotency. Nat Cell Biol 15(7):872-882. PubMed PMID: 23748610 Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340(6134):857-861. PubMed PMID: 23539183 Wang CI, Alekseyenko AA, LeRoy G, Elia AE, Gorchakov AA, Britton LM, Elledge SJ, Kharchenko PV, Garcia BA, Kuroda MI (2013) Chromatin proteins captured by ChIP-mass spectrometry are linked to dosage compensation in Drosophila. Nat Struct Mol Biol. 20(2):202-209. PubMed PMID: 23295261 Leroy G, Dimaggio PA, Chan EY, Zee BM, Blanco MA, Bryant B, Flaniken IZ, Liu S, Kang Y, Trojer P, Garcia BA (2013) A quantitative atlas of histone modification signatures from human cancer cells. Epigenetics & Chromatin 6(1):20. PubMed PMID: 23826629 Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS, Li X, Gueroussov S, Albu M, Zheng H, Yang A, Na H, Irimia M, Matzat LH, Dale RK, Smith SA, Yarosh CA, Kelly SM, Nabet B, Mecenas D, Li W, Laishram RS, Qiao M, Lipshitz HD, Piano F, Corbett AH, Carstens RP, Frey BJ, Anderson RA, Lynch KW, Penalva LO, Lei EP, Fraser AG, Blencowe BJ, Morris QD, Hughes TR. (2013) A compendium of RNA-binding motifs for decoding gene regulation. Nature 499(7457):172-177. PubMed PMID: 23846655 Prentki M, Matschinsky FM, Madiraju SR (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18(2):162-185. PubMed PMID: 23791483