Clarke, Steven G.

Biochemistry

Website

Home URL

Division

Biochemistry

Title

Faculty
Distinguished Professor

Specialties

Aging and Development
Biochemistry
Chemical Biology
Metabolism
Systems Biology and Biological Regulation

clarke@mbi.ucla.edu

Office

Boyer Hall 640

Office Phone

(310) 825-8754

Lab

Boyer Hall 628, 637, & 638

Office Lab

(310) 825-3137

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).

Professor Steven Clarke’s 2009 UCLA Faculty Research Lecture on Nov. 3rd
“Aging & Rejuvenation: Chemistry and Biology at Work” UCTV, Webcast, YouTube

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

Research Interests

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.

Representative Publications

Below is the list of selected and most recent publications. For the full list, please visit here.

Clarke, S. G. and Eisenberg, D. S. (2024) “Paul Delos Boyer: A Biographical Memoir” Biographical Memoirs, National Academy of Sciences. Online publication available at: https://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/boyer-paul.pdf.
Holtz, A. G., Lowe, T. L., Aoki, Y., Kubota, Y., Hoffman, R. M., and Clarke, S. G. (2023) “Asymmetric and Symmetric Protein Arginine Methylation in Methionine-Addicted Human Cancer Cells” PLoS ONE 18, e0296291. DOI: 10.1371/journal.pone.0296291.
Yang, M.-L., Lam, T. T., Kanyo, J., Kang, I., Zhou, S. Z., Clarke, S. G. and Mamula, M. J. (2023) “Natural isoaspartyl modification of ZAP70 alters T cell responses in lupus” Autoimmunity 1, 2282945. DOI: 10.1080/08916934.2023.2282945.
Feoli, A., Iannelli, G., Cipriano, A., Milite, C., Shen, L., Wang, Z., Hadjikryiacou, A., Lowe, T. L., Safaeipour, C., Viviano, M., Sarno, G., Morretta, E., Monti, M., Yang, Y., Clarke, S. G., Cosconati, S., Castellano, S., and Sbardella, G. (2023) “Identification of a Protein Arginine Methyltransferase 7 (PRMT7)/Protein Arginine Methyltransferase 9 (PRMT9) Inhibitor” J. Med. Chem. 66, 13665-13683. DOI: 10.1021/acs.jmedchem.3c01030. Selected for cover illlustrative art.
Bondoc, T. J., Lowe, T. L., Clarke, S. G. (2023) “The exquisite specificity of human protein arginine methyltransferase 7 (PRMT7) toward Arg-X-Arg sites” PLoS ONE 18, e0285812. DOI: 10.1371/journal.pone.0285812.
Yang, M. L., Connolly, S. E., Gee, R. J., Lam, T. T., Kanyo, J., Peng, J., Guyer, P., Syed, F., Tse, H. M., Clarke, S. G., Clarke, C. F., James, E. A., Speake, C., Evans-Molina, C., Arvan, P., Herold, K. C., Wen, L., Mamula, M. J. (2022) “Carbonyl Posttranslational Modification Associated With Early-Onset Type 1 Diabetes Autoimmunity” Diabetes 71, 1979-1993. DOI: 10.2337/db21-0989.
Lowe, T. L. and Clarke, S. G. (2022) “Human protein arginine methyltransferases (PRMTs) can be optimally active under nonphysiological conditions” J. Biol. Chem. 298, 102290. DOI: 10.1016/j.jbc.2022.102290.
Warmack, R. A., Pang, E. Z., Peluso, E., Lowenson, J. D., Ong, J. Y., Torres, J. Z., Clarke, S. G. (2022) “Human Protein-L-isoaspartate O-Methyltransferase Domain-Containing Protein 1 (PCMTD1) Associates with Cullin-RING Ligase Proteins” Biochemistry 61, 879-894. DOI: 10.1021/acs.biochem.2c00130.
Yamamoto, J., Inubushi, S., Han, Q., Tashiro, Y., Sugisawa, N., Hamada, K., Aoki, Y., Miyake, K., Matsuyama, R., Bouvet. M., Clarke, S. G., Endo, I., Hoffman, R. M. (2022) “Linkage of methionine addiction, histone lysine hypermethylation, and malignancy” iScience 25, 104162. DOI: 10.1016/j.isci.2022.104162.
Clarke, S. G. “Guido Guidotti (1933 – 2021) Remembering a biochemist’s biochemist.” ASBMB Today, Mar. 2022, pp.9-12.
Yamamoto, J., Aoki, Y., Inubushi, S., Han, Q., Hamada, K., Tashiro, Y., Miyake, K., Matsuyama, R., Bouvet, M., Clarke, S. G., Endo, I., and Hoffman, R. M. (2022) “Extent and Instability of Trimethylation of Histone H3 Lysine Increases with Degree of Malignancy and Methionine Addiction” Cancer Genom. Proteom. 19, 12-18. DOI: 10.21873/cgp.20299.
Gladyshev, V. N., Kritchevsky, S. B., Clarke, S. G., Cuervo, A. M., Fiehn, O., de Magalhaes, J. P., Mau, T., Maes, M., Moritz, R., Niedernhofer, L. J., Van Schaftingen, E., Tranah, G. J., Walsh, K., Yura, Y., Zhang, B., and Cummings, S. R. (2021) “Molecular Damage in Aging” Nat. Aging 1, 1096-1106. DOI: 10.1038/s43587-021-00150-3.
Ayer, A., Fazakerley D. J., Suarna, C., Maghzal, G. J., Sheipouri, D., Lee, K. J., Bradley, M. C., Fernández-del-Rio, L., Tumanov, S., Kong, S. M. Y., van der Veen, J. N., Yang, A., Ho, J. W. K., Clarke, S. G., James, D. E., Dawes. I. W., Vance, D. E., Clarke, C. F., Jacobs, R. L., and Stocker, R. (2021) “Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q” Redox Biol. 46, 102127. DOI: 10.1016/j.redox.2021.102127.
Soliman, R., Cordero-Maldonado, M. L., Martins, T. G., Moein, M., Conrotte, J.-F., Warmack, R.A., Skupin, A., Crawford, A. D., Clarke, S.G., and Linster, C.L. (2021) “L-Isoaspartyl methyltransferase deficiency in zebrafish leads to 1 impaired calcium signaling in the brain” Front. Genet. 11, 612343. DOI: 10.3389/fgene.2020.612343.
Histidine Methylation of Yeast Ribosomal Protein Rpl3p is Required for Proper 60S Subunit Assembly Al-Hadid,Q., Roy, K., Munroe, W., Dzialo, M.C., Chanfreau, G.F., and Clarke, S.G. (2014) Molecular and Cellular Biology,Aug;34(15):2903-16.
Non-Repair Pathways for Minimizing Protein Isoaspartyl Damage in the Yeast Saccharomyces cerevisiae Patananan, A.N., Capri, J., Whitelegge, J.P., and Clarke, S.G. (2014) Journal of Biological Chemistry,Jun 13;289(24):16936-53.
A novel small molecule methyltransferase is important for virulence in Candida albican Lissina E, Weiss D, Young B, Rella A, Cheung-Ong K, Del Poeta M, Clarke SG, Giaever G, Nislow C. (2013) ACS Chem Biol. 2013 Dec 20;8(12):2785-93.
Mammalian protein arginine methyltransferase 7 (PRMT7) specifically targets RXR sites in lysine-and arginine-rich regions Feng Y, Maity R, Whitelegge JP, Hadjikyriacou A, Li Z, Zurita-Lopez C,Al-Hadid Q, Clark AT, Bedford MT, Masson JY, Clarke SG. (2013) J Biol Chem. 2013 Dec 27;288(52):37010-25.
Thermal-Stable Proteins of Fruit of Long-Lived Sacred Lotus Nelumbo nucifera Gaertn var China Antique Shen-Miller, J., Linder, P., Xie, Y., Villa, S., Wooding, K., Clarke, S.G., Loo, R.R.O, and Loo, J.A. (2013) Tropical Plant Biology, 6, 69-84.
Brain Proteomics Supports the Role of Glutamate Metabolism and Suggests Other Metabolic Alterations in Protein L-Isoaspartyl Methyltransferase (PIMT)-Knockout Mice Yang,H., Lowenson, J.D., Clarke, S., and Zubarev, R.A. (2013) J. Proteome Research, 12, 4566-4576.
An Arabidopsis ATP-Dependent, DEAD-Box RNA Helicase Loses Activity Upon IsoAsp Formation but Is Restored by Protein Isoaspartyl Methyltransferase Nayak, N.R., Putnam, A.A., Addepalli, B., Lowenson, J.D., Chen, T., Jankowsky, E., Perry, S.E., Dinkins, R.D., Limbach, P.A., Clarke, S.G., and Downie, A.B. (2013) Plant Cell, 25, 2573-2586.
Circumventing Embryonic Lethality with Lcmt1 Deficiency: Generation of Hypomorphic Lcmt1 Mice with Reduced Protein Phosphatase 2A Methyltransferase Expression and Defects in Insulin Signaling MacKay, K. B., Tu., Y., Young, S. G., and Clarke, S. G. (2013) PLos One, 8,1-11.
A Novel Automethylation Reaction in the Aspergillus nidulans LaeA Protein Generates S-Methylmethionine Patananan,A. N., Palmer, J. M., Garvey, G. S., Keller, N. P., and Clarke, S. G. (2013) J. Biol. Chem. 288, 20, 14032-14045.
Protein Methylation at the Surface and Buried Deep: Thinking Outside the Histone Box Clarke, S. G. (2013) Trends in Biochemical Sciences, May 2013, 38, 5, 243-252.
Integrated Proteomic Analysis of Major Isoaspartyl-Containing Proteins in the Urine of Wild Type and Protein L-Isoaspartate O-Methyltransferase-Deficient Mice Dai, S., Ni, W., Patananan, A. N., Clarke, S. G., Karger, B. L., and Zhou, Z. S. (2013) Analytical Chemistry 2013, 85, 2423-2430.
Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs Dhar, S., Vemulapalli, V., Patananan, A. N., Huang, G. L., Di Lorenzo, A., Richard, S., Comb, M. J., Guo, A., Clarke, S. G., and Bedford, M. T. (2013) Scientific Reports, 3:3011, 1-6.
Lupus Autoimmunity Altered by Cellular Methylation Metabolism Yang,M-L., Gee, A. J. P., Gee, R. J., Zurita-Lopez, C. I., Khare, S.,Clarke, S. G., and Mamula, M. J. (2013) Autoimmunity, 46(1), 21-31.
Isoaspartyl Dipeptidase (IadA) Patananan,A. N., and Clarke, S. G. (2013) In Handbook of Proteolytic Enzymes, Vol. 1, Ed. Rawlings, N. D., and Salvesen, G. S., Oxford: Academic Press, 1654-1663.
Systems and Trans-System Level Analysis Identifies Conserved Iron Defciency Responses in the Plant Lineage Urzica, E. I., Casero, D., Yamasaki, H., Hsieh, S., Adler, L. N., Karpowicz, S. J., Blaby-Haas, C. E., Clarke, S. G., Loo, J. A., Pellegrini, M.,and Merchant, S. M. (2012) The Plant Cell 24, 3921-3948.
Wortmannin Reduces Insulin Signaling and Death in Seizure-Prone Pcmt1-/- Mice MacKay, K., Lowenson, J. D., and Clarke, S. G. (2012) PLOS One, 7, 1-14.
Identification of Methylated Proteins in the Yeast Small Ribosomal Subunit: A Role for SPOUT Methyltransferases in Protein Arginine Methylation Young,B. D., Weiss, D. I., Zurita-Lopez, C. I., Webb, K. J., Clarke, S., G., and McBride, A. E. (2012) Biochemistry 51, 5091-5104.
Impact of Oxidative Stress on Ascorbate Biosynthesis in Chlamydomonas via Regulation of the VTC2 Gene Encoding a GDP-L-galactose Phosphorylase Urzica,E. I., Adler, L. N., Page, M. D., Linster, C., Arbing, M. A., Casero, D., Pellegrini, M., Merchant, S. S., and Clarke, S. G. (2012) J. Biol. Chem. 287, 17, 14234-14245.
Human Protein Arginine Methyltransferase 7 (PRMT7) Is a Type III Enzyme Forming ω -NG-Monomethylated Arginine Residues Zurita-Lopez, C. I., Sandberg, T., Kelly, R., and Clarke, S.G. (2012) J. Biol. Chem. 287, 11, 7859-7870.
Caenorhabditis elegans Battling Starvation Stress: Low Levels of Ethanol Prolong Lifespan in L1 Larvae Castro,P. V., Khare, S., Young, B. D., and Clarke, S. G. (2012) PLos One, 7, 1-12.
A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis Lissina,E., Young, B., Urbanus, M. L., Guan, X. L., Lowenson, J., Hoon, S., Baryshnikova, A., Riezman, I., Michaut, M., Riezman, H., Cowen, Leah E., Wenk, M., Clarke, S. G., Giaever, G., and Nislow, C. (2011) PLoS Genetics, 7, 1-16.
A Novel GDP-D-glucose Phosphorylase Involved in Quality Control of the Nucleoside Diphosphate Sugar Pool in Caenorhabditis elegans and Mammals Adler, L. N., Gomez, T. A., Clarke, S. G., and Linster, C. L. (2011) J. Biol. Chem. 286, 24, 21511–21523.
The Interplay between Protein L-Isoaspartyl Methyltransferase Activity and Insulin-Like Signaling to Extend Lifespan in Caenorhabditis elegans Khare,S., Linster, C. L., and Clarke, S. G. (2011) PLos One, 6, 1-12.
The Ribosomal L1 Protuberance in Yeast Is Methylated on a Lysine Residue Catalyzed by a Seven-β-strand Methyltransferase Webb.,K. J., Al-Hadid, Q., Zurita-Lopez, C. I., Young, B. D., Lipson, R.S., and Clarke, S. G. (2011) J. Biol.Chem. 286, 21, 18405–18413.
Mechanistic Studies on Transcriptional Coactivator Protein Arginine Methyltransferase 1 Rust,H. L., Zurita-Lopez. C. I., Clarke, S. G., Thompson, P.R. (2011) Biochemistry 50, 3332–3345.
Y. R. (2011) Protein-arginine Methyltransferase 1 (PRMT1) Methylates Ash2L, a Shared Component of Mammalian Histone H3K4 Methyltransferase Complexes Butler, J. S., Zurita-Lopez, C. I., Clarke, S. G., Bedford, M. T., Dent, S. J. Biol.Chem. 286, 14, 12234–12244.
Petrossian,T. C., and Clarke, S. G. (2011) Uncovering the Human Methyltransferasome Molecular & Cellular Proteomics 10.1, 1-12.

Steven Clarke Research Lab » Watch Steven Clarke on Youtube :: Aging and Rejuvenation: Chemistry and Biochemistry at Work »

Clarke, Steven G.

Biography

Research Interests

Honors & Awards

Representative Publications