UCLA Neuroscience Program Ph.D. Admissions Neuroscience Faculty UCLA and Beyond  



Steven Clarke
Biochemistry of Aging and Posttranslational Modifications of Proteins

Work Email Address:  clarke@mbi.ucla.edu
Home Page: http://www.biochemistry.ucla.edu/biochem/Faculty/SClarke/

Laboratory Address:
Boyer Hall 628, 637 & 638
Office Address:
Boyer Hall 640
Phone Numbers:
(310) 825-3137 & 825-8121 Laboratory
Phone Numbers:
(310) 825-8754 Office

Selected 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.
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.
Petrossian Laurie K, Clarke Laurie K Multiple motif scanning to identify methyltransferases from the yeast proteome.. Molecular & cellular proteomics : MCP. 2009; 284(17): .
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.
Lipson Rebecca S, Clarke Steven G S-adenosylmethionine-dependent protein methylation in mammalian cytosol via tyrphostin modification by catechol-O-methyltransferase.. J. Biol. Chem.. 2007; 282(42): 31094-102.
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.
Zou Yan, Webb Kristofor, Perna Avi D, Zhang Qingchun, Clarke Steven, Wang Yinsheng A mass spectrometric study on the in vitro methylation of HMGA1a and HMGA1b proteins by PRMTs: methylation specificity, the effect of binding to AT-rich duplex DNA, and the effect of C-terminal phosphorylation.. Biochemistry. 2007; 46(26): 7896-906.
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.
Vinci Chris R, Clarke Steven G Recognition of age-damaged (R,S)-adenosyl-L-methionine by two methyltransferases in the yeast Saccharomyces cerevisiae.. J. Biol. Chem.. 2007; 282(12): 8604-12.
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.
Farrar Christine, Houser Carolyn R, Clarke Steven Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice.. Aging cell. 2005; 4(1): 1-12.
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.
Clarke Steven Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair.. Ageing research reviews. 2003; 2(3): 263-85.
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.
Research Interest:

My laboratory studies the biochemistry of the aging process. We want to understand the role of spontaneous reactions that result in covalent alterations to proteins and the role of enzymatic reactions that can reverse at least some types of the damage. We have focused on the degradation of aspartic acid and asparagine residues and the subsequent metabolism of their racemized and isomerized derivatives. The alteration of these residues can represent a significant fraction of the irreversible damage to proteins and would be expected to contribute to the limitation of their useful lifetime and that of the organism as a whole. We are presently determining the biological role of protein methyltransferases that specifically modify proteins containing altered aspartyl residues. These enzymes can initiate the conversion of D-aspartyl residues to the L-configuration as well as the conversion of isopeptide linkages to normal peptide bonds. Such "repair" reactions may greatly increase the useful lifetime of cellular proteins. We are presently examining these reactions in humans, mice, nematodes, plants, and bacteria. In each case, we are taking advantage of the particular features of each system - the medical relevance in humans, the usefulness of transgenic mice gene knockouts, the ease of working with the relatively small genomes of Arabidopsis, Caenorhabditis elegans, and Escherichia coli. We have also been interested in understanding the role of protein carboxyl methyltransferases that may be involved in modulating the function of other regulatory proteins. In 1993 we discovered that protein phosphatase 2A, the major dephosphorylating enzyme involved in both metabolism and cell cycle control, was itself methylated at its C-terminal leucine residue. Using the yeast Saccharomyces cerevisiae as an experimental system, we are taking both biochemical and genetic approaches to rationalize this methylation reaction. Finally, again using yeast as a model system, we are searching for novel methyltransferases that may regulate as yet unknown pathways.