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Steven Clarke, Ph.D.

Website:

Steven Clarke's Home Page.

Work Email Address:

clarke@mbi.ucla.edu

Laboratory Address:

Boyer Hall 628, 637 & 638

Office Address:

Boyer Hall 640

Lab Number:

(310) 825-3137 & 825-8121

Work Phone Number:

(310) 825-8754
Professor
Biochemistry
Director
Molecular Biology Institute
Member
Biochemistry & Molecular Biology (BMB) Graduate Program

A Short Biography:

Professor Clarke received his B.A. degree from Pomona College in 1970 and his Ph.D. degree from Harvard University in 1976. After a two-year postdoctoral appointment as a Miller Fellow at the University of California at Berkeley, he joined the UCLA faculty in 1978.

Professor Clarke accepts graduate students through the Biochemistry and Molecular Biology (BMB) Graduate Program and the UCLA ACCESS Ph.D. Program.

Awards and Honors:

Alfred P. Sloan Research Fellowship in Chemistry Alfred P. Sloan Research Fellowship in Chemistry ; American Chemical Society American Chemical Society/Ralph F. Hirschmann Award in Peptide Chemistry ; Harvard NSF Predoctoral Fellow ; Miller Research Fellow, UC Berkeley Miller Research Fellow, UC Berkeley ; NIH MERIT Award Pomona College Wilson Prize in Chemistry ; Princeton University Visiting Fellow, Princeton University ; UCLA Academic Senate Distinguished Teaching Award, including the Eby Award for the Art of Teaching UCLA Academic Senate Distinguished Teaching Award, including the Eby Award for the Art of Teaching ; Joseph F. Foster Memorial Lecturer, Purdue University

Research Interest:

Dr. Clarke has established the paradigm that biological aging is no less than war waged between chemistry and biology. Chemistry represents the spontaneous reactions that degrade biomolecules and biology represents the response of the organism to limit the chemical damage. His laboratory discovered and has characterized a novel pathway that has demonstrated that macromolecular repair is not just for DNA, but for proteins as well! These studies have not only given us a new window to view protein "life" but also suggest that the biological aging process may be closely linked to how well one can keep polypeptides free of spontaneous damage. He has gone on to show that the enzymatic recognition of damage is not limited to DNA and proteins but is a more general response of cells to molecular damage, particularly of crucial metabolites such as cis -aconitate and S -adenosylmethionine. His laboratory has also been in the forefront of identifying new types of methyltransferases that are involved in cellular signaling reactions. His laboratory has discovered enzymes that modify signaling proteins by methylation reactions at C-terminal isoprenylated cysteine residues and leucine residues, as well the first member of the family of protein arginine methyltransferases involved in multiple cellular processes including DNA repair, gene expression, protein translocation, and signaling.


Detailed Biography:

Steven Clarke has been on the faculty of the UCLA Department of Chemistry and Biochemistry since 1978. He is currently a Professor of Biochemistry and Director of the UCLA Molecular Biology Institute. He was born in Los Angeles and attended public schools in Altadena and Pasadena, California. He did his undergraduate work at Pomona College in Claremont, majoring in Chemistry and Zoology. During this time, he did undergraduate research at the UCLA Brain Research Institute with Dr. James E. Skinner and Professor Donald Lindsley on neural mechanisms of attention. He was also an NIH fellow in the laboratory of Dr. Peter Mitchell at Glynn Research Laboratories in Bodmin, England studying mitochondrial amino acid transport. He obtained his PhD in Biochemistry and Molecular Biology at Harvard University working as an NSF Fellow with Professor Guido Guidotti on membrane protein-detergent interactions and the identification of the major rat liver mitochondrial polypeptides as enzymes of the urea cycle. He returned to California to do postdoctoral work as a Miller Fellow at the University of California, Berkeley, with Professor Dan Koshland, identifying membrane receptors for bacterial chemotaxis. His research at UCLA has focused on roles of novel protein methyltransferases in aging and biological regulation highlighted by discoveries of the protein L-isoaspartyl repair methyltransferase, the isoprenylcysteine protein methyltransferase, and the protein phosphatase 2A methyltransferase. He has been a visiting scholar at Princeton University (1986-87) and at the University of Washington (2004-2005).

Publications:

Petrossian, T. C., and Clarke, S. G.   Bioinformatic Identification of Novel Methyltransferases. Epigenomics, 2009; 1: 163-175.
Khare Shilpi, Gomez Tara, Linster Carole L, Clarke Steven G   Defective responses to oxidative stress in protein l-isoaspartyl repair-deficient Caenorhabditis elegans. Mechanisms of ageing and development, 2009; 130(10): 670-80.
Petrossian Laurie K, Clarke Laurie K   Multiple motif scanning to identify methyltransferases from the yeast proteome. Molecular & cellular proteomics : MCP, 2009; 284(17): .
Fisk John C, Sayegh Joyce, Zurita-Lopez Cecilia, Menon Sarita, Presnyak Vladimir, Clarke Steven G, Read Laurie K   A type III protein arginine methyltransferase from the protozoan parasite Trypanosoma brucei. The Journal of biological chemistry, 2009; 284(17): 11590-600.
Bedford Mark T, Clarke Steven G   Protein arginine methylation in mammals: who, what, and why. Molecular cell, 2009; 33(1): 1-13.
Webb Kristofor J, Laganowsky Arthur, Whitelegge Julian P, Clarke Steven G   Identification of two SET domain proteins required for methylation of lysine residues in yeast ribosomal protein Rpl42ab. The Journal of biological chemistry, 2008; 283(51): 35561-8.
Gomez Tara A, Banfield Kelley L, Clarke Steven G   The protein L-isoaspartyl-O-methyltransferase functions in the Caenorhabditis elegans stress response. Mechanisms of ageing and development, 2008; 129(12): 752-8.
Linster Carole L, Clarke Steven G   L-Ascorbate biosynthesis in higher plants: the role of VTC2. Trends in plant science, 2008; 13(11): 567-73.
Sayegh Joyce, Clarke Steven G   Hsl7 is a substrate-specific type II protein arginine methyltransferase in yeast. Biochem. Biophys. Res. Commun., 2008; 372(4): 811-5.
Banfield Kelley L, Gomez Tara A, Lee Wendy, Clarke Steven, Larsen Pamela L   Protein-repair and hormone-signaling pathways specify dauer and adult longevity and dauer development in Caenorhabditis elegans. The journals of gerontology. Series A, Biological sciences and medical sciences, 2008; 63(8): 798-808.
Linster Carole L, Adler Lital N, Webb Kristofor, Christensen Kathryn C, Brenner Charles, Clarke Steven G   A second GDP-L-galactose phosphorylase in arabidopsis en route to vitamin C. Covalent intermediate and substrate requirements for the conserved reaction. J. Biol. Chem., 2008; 283(27): 18483-92.
Alfaro Joshua F, Gillies Laura A, Sun He G, Dai Shujia, Zang Tianzhu, Klaene Joshua J, Kim Byung Ju, Lowenson Jonathan D, Clarke Steven G, Karger Barry L, Zhou Zhaohui Sunny   Chemo-enzymatic detection of protein isoaspartate using protein isoaspartate methyltransferase and hydrazine trapping. Anal. Chem., 2008; 80(10): 3882-9.
Dumlao Darren S, Hertz Nicholas, Clarke Steven   Secreted 3-isopropylmalate methyl ester signals invasive growth during amino acid starvation in Saccharomyces cerevisiae. Biochemistry, 2008; 47(2): 698-709.
Sayegh Joyce, Webb Kristofor, Cheng Donghang, Bedford Mark T, Clarke Steven G   Regulation of protein arginine methyltransferase 8 (PRMT8) activity by its N-terminal domain. J. Biol. Chem., 2007; 282(50): 36444-53.
Pasternack Deborah A, Sayegh Joyce, Clarke Steven, Read Laurie K   Evolutionarily divergent type II protein arginine methyltransferase in Trypanosoma brucei. Eukaryotic Cell, 2007; 6(9): 1665-81.
Clarke Steven Gerard   HIV protease inhibitors and nuclear lamin processing: getting the right bells and whistles. Proc. Natl. Acad. Sci. U.S.A., 2007; 104(35): 13857-8.
Gomez Tara A, Clarke Steven G   Autophagy and insulin/TOR signaling in Caenorhabditis elegans pcm-1 protein repair mutants. Autophagy, 2007; 3(4): 357-9.
McBride Anne E, Zurita-Lopez Cecilia, Regis Anthony, Blum Emily, Conboy Ana, Elf Shannon, Clarke Steven   Protein arginine methylation in Candida albicans: role in nuclear transport. Eukaryotic Cell, 2007; 6(7): 1119-29.
Chen Hui, Xia Meng, Lin Mark, Yang Heping, Kuhlenkamp John, Li Tony, Sodir Nicole M, Chen Yong-Heng, Josef-Lenz Heinz, Laird Peter W, Clarke Steven, Mato Jos���� M, Lu Shelly C   Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells. Gastroenterology, 2007; 133(1): 207-18.
Linster Carole L, Gomez Tara A, Christensen Kathryn C, Adler Lital N, Young Brian D, Brenner Charles, Clarke Steven G   Arabidopsis VTC2 encodes a GDP-L-galactose phosphorylase, the last unknown enzyme in the Smirnoff-Wheeler pathway to ascorbic acid in plants. J. Biol. Chem., 2007; 282(26): 18879-85.
Porras-Yakushi Tanya R, Whitelegge Julian P, Clarke Steven   Yeast ribosomal/cytochrome c SET domain methyltransferase subfamily: identification of Rpl23ab methylation sites and recognition motifs. J. Biol. Chem., 2007; 282(17): 12368-76.
Gomez Tara A, Banfield Kelley L, Trogler Dorothy M, Clarke Steven G   The L-isoaspartyl-O-methyltransferase in Caenorhabditis elegans larval longevity and autophagy. Developmental biology, 2007; 303(2): 493-500.
Porras-Yakushi Tanya R, Whitelegge Julian P, Clarke Steven   A novel SET domain methyltransferase in yeast: Rkm2-dependent trimethylation of ribosomal protein L12ab at lysine 10. The Journal of biological chemistry, 2006; 281(47): 35835-45.
Vigneswara Vasanthy, Lowenson Jonathan D, Powell Claire D, Thakur Matthew, Bailey Kevin, Clarke Steven, Ray David E, Carter Wayne G   Proteomic identification of novel substrates of a protein isoaspartyl methyltransferase repair enzyme. The Journal of biological chemistry, 2006; 281(43): 32619-29.
Miranda Tina Branscombe, Sayegh Joyce, Frankel Adam, Katz Jonathan E, Miranda Mark, Clarke Steven   Yeast Hsl7 (histone synthetic lethal 7) catalyses the in vitro formation of omega-N(G)-monomethylarginine in calf thymus histone H2A. The Biochemical journal, 2006; 395(3): 563-70.
Farrar Christine E, Huang Christine S, Clarke Steven G, Houser Carolyn R   Increased cell proliferation and granule cell number in the dentate gyrus of protein repair-deficient mice. The Journal of comparative neurology, 2005; 493(4): 524-37.
Porras-Yakushi Tanya R, Whitelegge Julian P, Miranda Tina Branscombe, Clarke Steven   A novel SET domain methyltransferase modifies ribosomal protein Rpl23ab in yeast. The Journal of biological chemistry, 2005; 280(41): 34590-8.
Miranda Tina Branscombe, Webb Kristofor J, Edberg Dale D, Reeves Raymond, Clarke Steven   Protein arginine methyltransferase 6 specifically methylates the nonhistone chromatin protein HMGA1a. Biochemical and biophysical research communications, 2005; 336(3): 831-5.
Farrar Christine E, Clarke Steven   Diet-dependent survival of protein repair-deficient mice. The Journal of nutritional biochemistry, 2005; 16(9): 554-61.
Lee Jaeho, Sayegh Joyce, Daniel Jeremy, Clarke Steven, Bedford Mark T   PRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family. The Journal of biological chemistry, 2005; 280(38): 32890-6.
Kalhor Hamid R, Penjwini Mahmud, Clarke Steven   A novel methyltransferase required for the formation of the hypermodified nucleoside wybutosine in eucaryotic tRNA. Biochemical and biophysical research communications, 2005; 334(2): 433-40.
Miranda Tina Branscombe, Lowenson Jonathan D, Clarke Steven   A new type of protein methylation activated by tyrphostin A25 and vanadate. FEBS letters, 2004; 577(1-2): 181-6.
Singh Vinita, Miranda Tina Branscombe, Jiang Wei, Frankel Adam, Roemer Martha E, Robb Victoria A, Gutmann David H, Herschman Harvey R, Clarke Steven, Newsham Irene F   DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo. Oncogene, 2004; 23(47): 7761-71.
Wang Yanming, Wysocka Joanna, Sayegh Joyce, Lee Young-Ho, Perlin Julie R, Leonelli Lauriebeth, Sonbuchner Lakshmi S, McDonald Charles H, Cook Richard G, Dou Yali, Roeder Robert G, Clarke Steven, Stallcup Michael R, Allis C David, Coonrod Scott A   Human PAD4 regulates histone arginine methylation levels via demethylimination. Science (New York, N.Y.), 2004; 306(5694): 279-83.
Miranda Tina Branscombe, Khusial Permanan, Cook Jeffry R, Lee Jin-Hyung, Gunderson Samuel I, Pestka Sidney, Zieve Gary W, Clarke Steven   Spliceosome Sm proteins D1, D3, and B/B' are asymmetrically dimethylated at arginine residues in the nucleus. Biochemical and biophysical research communications, 2004; 323(2): 382-7.
Xu Qilong, Belcastro Marisa P, Villa Sarah T, Dinkins Randy D, Clarke Steven G, Downie A Bruce   A second protein L-isoaspartyl methyltransferase gene in Arabidopsis produces two transcripts whose products are sequestered in the nucleus. Plant physiology, 2004; 136(1): 2652-64.
Vitali Ryan, Clarke Steven   Improved rotorod performance and hyperactivity in mice deficient in a protein repair methyltransferase. Behavioural brain research, 2004; 153(1): 129-41.
Katz Jonathan E, Dumlao Darren S, Wasserman Jacob I, Lansdown Michael G, Jung Michael E, Faull Kym F, Clarke Steven   3-Isopropylmalate is the major endogenous substrate of the Saccharomyces cerevisiae trans-aconitate methyltransferase. Biochemistry, 2004; 43(20): 5976-86.
Miranda Tina Branscombe, Miranda Mark, Frankel Adam, Clarke Steven   PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. The Journal of biological chemistry, 2004; 279(22): 22902-7.
Katz Jonathan E, Dumlao Darren S, Clarke Steven, Hau Jörg   A new technique (COMSPARI) to facilitate the identification of minor compounds in complex mixtures by GC/MS and LC/MS: tools for the visualization of matched datasets. Journal of the American Society for Mass Spectrometry, 2004; 15(4): 580-4.
Boulanger Marie-Chloé, Miranda Tina Branscombe, Clarke Steven, Di Fruscio Marco, Suter Beat, Lasko Paul, Richard Stéphane   Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4. The Biochemical journal, 2004; 379(Pt 2): 283-9.
Clarke Steven, Tamanoi Fuyuhiko   Fighting cancer by disrupting C-terminal methylation of signaling proteins. The Journal of clinical investigation, 2004; 113(4): 513-5.
Kalhor Hamid R, Clarke Steven   Novel methyltransferase for modified uridine residues at the wobble position of tRNA. Molecular and cellular biology, 2003; 23(24): 9283-92.
Katz Jonathan E, Dlakić Mensur, Clarke Steven   Automated identification of putative methyltransferases from genomic open reading frames. Molecular & cellular proteomics : MCP, 2003; 2(8): 525-40.
Mura Cameron, Katz Jonathan E, Clarke Steven G, Eisenberg David   Structure and function of an archaeal homolog of survival protein E (SurEalpha): an acid phosphatase with purine nucleotide specificity. Journal of molecular biology, 2003; 326(5): 1559-75.
Farrar Christine, Clarke Steven   Altered levels of S-adenosylmethionine and S-adenosylhomocysteine in the brains of L-isoaspartyl (D-Aspartyl) O-methyltransferase-deficient mice. The Journal of biological chemistry, 2002; 277(31): 27856-63.
Clarke Steven D, Gasperikova Daniela, Nelson Carolanne, Lapillonne Alexandre, Heird William C   Fatty acid regulation of gene expression: a genomic explanation for the benefits of the mediterranean diet. Annals of the New York Academy of Sciences, 2002; 967(31): 283-98.
Clarke Steven   The methylator meets the terminator. Proceedings of the National Academy of Sciences of the United States of America, 2002; 99(3): 1104-6.
Frankel Adam, Yadav Neelu, Lee Jaeho, Branscombe Tina L, Clarke Steven, Bedford Mark T   The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. The Journal of biological chemistry, 2002; 277(5): 3537-43.
Thapar Nitika, Griffith Scott C, Yeates Todd O, Clarke Steven   Protein repair methyltransferase from the hyperthermophilic archaeon Pyrococcus furiosus. Unusual methyl-accepting affinity for D-aspartyl and N-succinyl-containing peptides. The Journal of biological chemistry, 2002; 277(2): 1058-65.
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