We will investigate how physiological functions are controlled by methylation reactions, focusing on the enzymes that catalyze the modification of protein arginine, lysine, and isoaspartyl residues. We are especially interested in methyltransferases that are involved in signal transduction and metabolic regulatory pathways where the presence or absence of the methyl group can modulate the function of the methyl-accepting species. These reactions are important in protecting organisms from environmental stresses and from the accumulation of spontaneous damage in aging cells. We will also develop methods to identify new types of methyltransferases that may catalyze previously unrecognized reactions in these pathways. We will determine the enzymology and functional roles of new members of the eucaryotic family of protein arginine methyltransferases (PRMTs). These enzymes alter the ability of the arginine residue to interact with RNA, DNA, and protein partners and have been shown to have roles in gene regulation, DNA repair, and intracellular signaling pathways. We will focus our work on mammalian systems, but will also use yeast and trypanosomes as model systems. We will pay special attention to the human PRMT7 protein that has been implicated in tumor formation and stem cell survival. Our overall goal is to establish the complete cast of characters of the enzymes that catalyze these modifications in nature so that their functions, especially in signaling and gene regulation in health and disease, can be fully understood. We will characterize new roles in intracellular signaling for the protein repair L-isoaspartyl/D-aspartyl methyltransferase. Here, we will utilize both mouse and worm (Caenorhabditis elegans) systems to explore the relationships between the accumulation of age-damaged proteins, their recognition by the protein repair methyltransferase, and the responses of the insulin/insulin-like signaling system to increase stress resistance and longevity. We will test several hypotheses to explain the physiological role of the linkage, including direct recognition of damaged proteins or methylated proteins by either the signaling pathway itself or a transcriptional system that upregulates one or more crucial members of the signaling pathway. We will determine the role of lysine protein methylation reactions in the translational apparatus, including ribosomal proteins and elongation factors. We will work in both yeast and mammalian cells to understand how the modifications of ribosomal proteins and eEF1A contribute to translational control and resistance to environmental toxins. Finally, we will use bioinformatic and biochemical approaches to search for and to characterize new types of methyltransferases in both yeast and humans. We are especially interested in identifying potential novel sites of methyltransferase inhibition associated with elevated plasma homocysteine levels in humans that have been linked to cardiovascular and neurological diseases.

Public Health Relevance

Our work focuses on how the modification of proteins by the addition of methyl groups can control body function, including pathways of signal transduction in metabolism and macromolecular assembly. We are also interested in how these pathways are altered in cancer and diseases associated with aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM026020-35
Application #
8413620
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Gerratana, Barbara
Project Start
1978-12-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
35
Fiscal Year
2013
Total Cost
$492,543
Indirect Cost
$163,924
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Patananan, Alexander Nikolich; Budenholzer, Lauren Michelle; Eskin, Ascia et al. (2015) Ethanol-induced differential gene expression and acetyl-CoA metabolism in a longevity model of the nematode Caenorhabditis elegans. Exp Gerontol 61:20-30
Dzialo, Maria C; Travaglini, Kyle J; Shen, Sean et al. (2014) A new type of protein lysine methyltransferase trimethylates Lys-79 of elongation factor 1A. Biochem Biophys Res Commun 455:382-9
Dzialo, Maria C; Travaglini, Kyle J; Shen, Sean et al. (2014) Translational roles of elongation factor 2 protein lysine methylation. J Biol Chem 289:30511-24
Feng, You; Hadjikyriacou, Andrea; Clarke, Steven G (2014) Substrate specificity of human protein arginine methyltransferase 7 (PRMT7): the importance of acidic residues in the double E loop. J Biol Chem 289:32604-16
Patananan, Alexander N; Capri, Joseph; Whitelegge, Julian P et al. (2014) Non-repair pathways for minimizing protein isoaspartyl damage in the yeast Saccharomyces cerevisiae. J Biol Chem 289:16936-53
Al-Hadid, Qais; Roy, Kevin; Munroe, William et al. (2014) Histidine methylation of yeast ribosomal protein Rpl3p is required for proper 60S subunit assembly. Mol Cell Biol 34:2903-16
Clarke, Steven G (2013) Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem Sci 38:243-52
MacKay, Kennen B; Tu, Yiping; Young, Stephen G et al. (2013) Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling. PLoS One 8:e65967
Nayak, Nihar R; Putnam, Andrea A; Addepalli, Balasubrahmanyam et al. (2013) An Arabidopsis ATP-dependent, DEAD-box RNA helicase loses activity upon IsoAsp formation but is restored by PROTEIN ISOASPARTYL METHYLTRANSFERASE. Plant Cell 25:2573-86
Shen-Miller, J; Lindner, Petra; Xie, Yongming et al. (2013) Thermal-stable proteins of fruit of long-living Sacred Lotus Nelumbo nucifera Gaertn var. China Antique. Trop Plant Biol 6:

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