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Raymond C. Trievel, Ph.D.

Associate Professor, Biological Chemistry

B.S., University of Delaware
Ph.D., University of Pennsylvania
Postdoctoral Studies, National Institutes of Health

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 protein lysine methyltransferases (PKMTs), 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 PKMTs 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 PKMT 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 PKMT 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.

Awards

2000-2003 Intramural Res Training Fellowship, NIH
2003 Keystone Symposium Scholarship
2004 NIH Fellowship Award for Research Excellence
2010 Etter Early Career Award, American Crystallographic Association

Publications

Bulfer SL, Scott EM, Pillus L, Trievel RC. (2010) Structural basis for L-lysine feedback inhibition of homocitrate synthase. J Biol Chem. 2010 Jan 19 [Epub ahead of print]. PMID: 20089861

Bulfer S.L., Scott E.M., Couture J.-F., Pillus L., and Trievel R.C. (2009) Crystal structure and functional analysis of homocitrate synthase, an essential enzyme in lysine biosynthesis. J Biol Chem. 284, 35769-35780. PMID: 19776021

Takahashi Y.H., Lee J.S., Swanson S.K., Saraf A., Florens L., Washburn M.P., Trievel R.C., and Shilatifard A. (2009) Regulation of H3K4 trimethylation via Cps40 (Spp1) of COMPASS is monoubiquitination independent: implication for a Phe/Tyr switch by the catalytic domain of Set1. Mol Cell Biol. 29, 3478-3486. PMID: 19398585

Raunser S., Magnani R., Huang Z., Houtz R.L., Trievel R.C., Penczek P.A., and Walz T. (2009) Rubisco in complex with Rubisco large subunit methyltransferase. Proc Natl Acad Sci USA. 106, 3160-3165. PMID: 19208805

Couture J.-F., Dirk L.M., Brunzelle J.S., Houtz R.L., and Trievel R.C. (2009) Structural origins for the product specificity of SET domain protein methyltransferases. Proc Natl Acad Sci USA. 105, 20659-64. PMID: 19088188

Couture J.-F., Collazo E., Ortiz-Tello P.A., Brunzelle J.S., and Trievel R.C. (2007) Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nat Struct Mol Biol. 14, 689-695. PMID: 17589523

Couture J.-F., Collazo E., and Trievel R.C. (2006) Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 13, 140-146. PMID: 16829960

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. 281, 19280-19287. PMID: 16682405

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. PMID: 16415881

Couture J.-F., Collazo E., Brunzelle J., and Trievel R.C. (2005) Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 19, 1455-1465. PMID: 15933070

Collazo E., Couture J.-F., Bulfer S., and Trievel R.C. (2005) A coupled fluorescent assay for histone methyltransferases. Anal. Biochem. 342, 86-92. PMID: 15958184

rtrievel@umich.edu

Office: 4301C MSRB3, Box 5606
PH: (734)647-0889

PubMed: trievel+r[au]

Laboratory Members:

Postdoctoral Fellow
Paul A Del Rizzo

Department Affiliations

Chemical Biology Program
Biophysics Graduate Program
Cellular & Molecular Biology Graduate Program