UM Biophysics Faculty | Raymond C. Trievel

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Raymond C. Trievel

Assistant Professor of Biological Chemistry

Ph.D., University of Pennsylvania

Dept: Department of Biological Chemistry

Office Address: 4412 Medical Science Building I

Phone: 734-647-0889

Email: rtrievel@umich.edu

Post-translational modifications of proteins play pivotal roles in governing a myriad of biological functions within the cell. Gene expression, the cell cycle, intracellular signaling cascades, cytoskeletal organization, and numerous metabolic pathways are just a few examples of cellular functions that are controlled by covalent modifications. Our laboratory is interested in understanding how protein modifications within the nucleus impact transcription and other genomic processes. Histones, the major scaffolding proteins that organize genomic DNA in chromatin, are enriched in modifications such as acetylation, methylation, phosphorylation and ubiquitination. Transcription factors and other components of the transcriptional machinery are subject to similar types of covalent modifications in vivo. These modifications collectively act as molecular switches that can either activate or repress gene expression, depending on the pattern of modifications established within a given gene locus. Aberrant histone modifications have been directly linked to carcinogenesis, underscoring the fundamental importance of these pathways in governing faithful gene expression.

Our laboratory is currently investigating histone lysine methyltransferases (HKMTs), a group of enzymes that epigenetically regulate transcription, heterochromatin structure, DNA damage checkpoints, development, differentiation, and the cell cycle. Using structural and biochemical techniques, we have characterized the molecular basis of substrate recognition for several representative HKMTs in order to elucidate the mechanisms by which they catalyze site-specific lysine methylation in histones and other nuclear proteins. A thorough understanding of these specificities is critical to human health because aberrant HKMT activity has been clinically documented in a broad spectrum of cancers, including prostate, breast, lung, hepatic, and colorectal cancers. We envision that our research will enable us to develop HKMT inhibitors as novel chemotherapeutic agents and will also impact gene therapy and stem cell research due to the central importance of gene regulation to these fields.

Representative Publications

Couture, J.F., Hauk, G., Thompson, M.J., Blackburn, G.M., and Trievel, R.C. (2006) Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases. J Biol Chem., in press.

Couture, J.F., Collazo, E., Hauk, G., and Trievel R.C. (2006) Structural basis for the methylation site specificity of SET7/9. Nat Struct Mol Biol. 13, 140-146.

Couture, J.F., Collazo, E., Brunzelle, J.S., and Trievel, R.C. (2005) Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455-1465.

Collazo, E., Couture, J.F., Bulfer, S., and Trievel, R.C. (2005) A coupled flourescent assay for histone methyltransferases. Anal. Biochem. 342, 86-92.

Trievel, R.C., Flynn, E.M., Houtz, R.L., and Hurley, J.H. (2003) Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT. Nature Struct. Biol. 10, 545-552.

Trievel, R.C., Beach, B.M., Dirk, L.M., Houtz, R.L., and Hurley, J.H. (2002) Structure and catalytic mechanism of a SET domain protein methyltransferase. Cell 111, 91-103.

Trievel, R.C., Li, F.Y., and Marmorstein, R. (2000) Application of a fluorescent histone acetyltransferase assay to probe the substrate specificity of the human p300/CBP-associated factor. Anal. Biochem. 287, 319-328.

Lo, W.S., Trievel, R.C., Rojas, J.R., Duggan, L., Hsu, J.Y., Allis, C.D., Marmorstein, R., Berger, S.L. (2000) Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol. Cell 5, 917-926.

Rojas, J.R., Trievel, R.C., Zhou, J., Mo, Y., Li, X., Berger, S.L., Allis, C.D., and Marmorstein, R. (1999) Structure of Tetrahymena GCN5 bound to coenzyme A and a histone H3 peptide. Nature 401, 93-98.

Trievel, R.C., Rojas, J.R., Sterner, D.E., Venkataramani, R.N., Wang, L., Zhou, J., Allis, C.D., Berger, S.L., and Marmorstein, R. (1999) Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator. Proc. Natl. Acad. Sci. USA 96, 8931-8936.

Clements, A., Rojas, J.R., Trievel, R.C., Wang, L., Berger, S.L., and Marmorstein, R. (1999) Crystal structure of the histone acetyltransferase domain of the human PCAF transcriptional regulator bound to coenzyme A. EMBO J. 18, 3521-3532.

Tanner, K.G., Trievel, R.C., Kuo, M.H., Howard, R.M., Berger, S.L., Allis, C.D., Marmorstein, R., and Denu, J.M.. (1999) Catalytic mechanism and function of invariant glutamic acid 173 from the histone acetyltransferase GCN5 transcriptional coactivator. J. Biol. Chem. 274, 18157-18160.

Liu, L., Scolnick, D.M., Trievel, R.C., Zhang, H.B., Marmorstein, R., Halazonetis, T.D., and Berger, S.L. (1999) p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol. Cell. Biol. 19, 1202

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