Asymmetric Arginine Dimethylation Determines Life Span in C. elegans by Regulating Forkhead Transcription Factor DAF-16

Takahashi, Yuta; Daitoku, Hiroaki; Hirota, Kaoru; Tamiya, Hiroko; Yokoyama, Atsuko; Kako, Koichiro; Nagashima, Yusuke; Nakamura, Ayumi; Shimada, Takashi; Watanabe, Satoshi; Yamagata, Kunio; Yasuda, Kayo; Ishii, Naoaki; Fukamizu, Akiyoshi

doi:10.1016/j.cmet.2011.03.017

Cited by 73 publications

(53 citation statements)

References 41 publications

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“…This list contains genes known to have positive influence on longevity, such as SIRT6 (Kanfi et al., 2012), PRMT1 (Takahashi et al., 2011), or PCK1 (Hakimi et al., 2007). Remarkably, however, the positive effect of these genes on longevity in the studied models is seen particularly upon overexpression of these genes.…”

Section: Resultsmentioning

confidence: 99%

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

et al. 2018

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SummaryAnimals show a large variability of lifespan, ranging from short‐lived as Caenorhabditis elegans to immortal as Hydra. A fascinating case is flatworms, in which reversal of aging by regeneration is proposed, yet conclusive evidence for this rejuvenation‐by‐regeneration hypothesis is lacking. We tested this hypothesis by inducing regeneration in the sexual free‐living flatworm Macrostomum lignano. We studied survival, fertility, morphology, and gene expression as a function of age. Here, we report that after regeneration, genes expressed in the germline are upregulated at all ages, but no signs of rejuvenation are observed. Instead, the animal appears to be substantially longer lived than previously appreciated, and genes expressed in stem cells are upregulated with age, while germline genes are downregulated. Remarkably, several genes with known beneficial effects on lifespan when overexpressed in mice and C. elegans are naturally upregulated with age in M. lignano, suggesting that molecular mechanism for offsetting negative consequences of aging has evolved in this animal. We therefore propose that M. lignano represents a novel powerful model for molecular studies of aging attenuation, and the identified aging gene expression patterns provide a valuable resource for further exploration of anti‐aging strategies.

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Section: Resultsmentioning

confidence: 99%

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

et al. 2018

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“…This decrease in Arg levels and a concomitant increase in dimethylarginine under rapamycin treatment is an indication of methylation of proteinaceous Arg. Arg dimethylation acts as an antiaging modification in Caenorhabditis elegans and increased its life span (Takahashi et al, 2011). Decreased levels of the polyamine precursors, Arg and Orn, were noted alongside increased levels of the biogenic amines, agmatine and putrescine, and the product of their catabolism, 5-methylthioadenosine (see Supplemental Figure 3D online).…”

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confidence: 99%

Target of Rapamycin Signaling Regulates Metabolism, Growth, and Life Span in Arabidopsis

et al. 2012

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Target of Rapamycin (TOR) is a major nutrition and energy sensor that regulates growth and life span in yeast and animals. In plants, growth and life span are intertwined not only with nutrient acquisition from the soil and nutrition generation via photosynthesis but also with their unique modes of development and differentiation. How TOR functions in these processes has not yet been determined. To gain further insights, rapamycin-sensitive transgenic Arabidopsis thaliana lines (BP12) expressing yeast FK506 Binding Protein12 were developed. Inhibition of TOR in BP12 plants by rapamycin resulted in slower overall root, leaf, and shoot growth and development leading to poor nutrient uptake and light energy utilization. Experimental limitation of nutrient availability and light energy supply in wild-type Arabidopsis produced phenotypes observed with TOR knockdown plants, indicating a link between TOR signaling and nutrition/light energy status. Genetic and physiological studies together with RNA sequencing and metabolite analysis of TOR-suppressed lines revealed that TOR regulates development and life span in Arabidopsis by restructuring cell growth, carbon and nitrogen metabolism, gene expression, and rRNA and protein synthesis. Gain-and loss-of-function Ribosomal Protein S6 (RPS6) mutants additionally show that TOR function involves RPS6-mediated nutrition and light-dependent growth and life span in Arabidopsis. INTRODUCTIONAmong all extant organisms, many of the longest living species are plants. For example, a creosote bush (Larrea tridentata) called King Clone, which has lived for over 10,000 years, was found in the Mojave Desert (Vasek, 1980). The giant redwood trees in California (Sequoia sempervirens) live for well over 2000 years (Scheres, 2007) and several other tree species have a long life span. However, the mechanisms that underpin longevity in plants are not known. Dissecting the control mechanisms of growth and life span in plants has many implications. It will provide a framework for addressing the key components and regulators of life span in plants. Engineering life span in plants has multiple applications, including early maturation for short seasons, long-lasting horticultural plants, and trees of desirable life span in silviculture (McCouch, 2004;Neale, 2007;Takeda and Matsuoka, 2008;Sonah et al., 2011). Recent work identified genetic factors that can be modified via breeding techniques to improve crop yield through modulating the growth phases (Moose and Mumm, 2008). Uauy et al. (2006) showed that a NAC transcription factor-mediated acceleration of senescence impacted nutrient remobilization in wheat (Triticum aestivum), resulting in significant increase in protein content and micronutrients in the grains (Uauy et al., 2006). Thus, life span alteration can have several beneficial outcomes.Plants are distinct from most other multicellular eukaryotes in having a modular body plan with immortal totipotent stem cells, sessile but autotrophic lifestyle, and very extensive biosynthetic capabilities ...

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“…To further explore the physiological roles of asymmetric arginine dimethylation, we attempted to system-atically identify in vivo substrates of PRMT-1. As we reported previously (9), nematode C. elegans PRMT-1 is the predominant type I arginine methyltransferase, and the prmt-1(ok2710) null mutant is viable, unlike lethal phenotypes of PRMT-1-deficient mouse and Drosophila (7,8). We therefore employed C. elegans as an ideal animal model for screening in vivo substrates of PRMT-1 with the strategy of a two-dimensional (2-D) proteomic analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We therefore employed C. elegans as an ideal animal model for screening in vivo substrates of PRMT-1 with the strategy of a two-dimensional (2-D) proteomic analysis (Fig. 1A) combining Sypro Ruby protein stain and Western blotting against two distinct asymmetric dimethylarginine antibodies, ASYM24 (9,25,26) and ASYM26. Two-dimensional electrophoresis (2-DE) followed by Western blotting against ASYM24 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Among them, PRMT-1 is known to be the predominant type I enzyme in mammalian cells, whereas its physiological significance at the whole-body level has remained unclear due to embryonic lethality in the null mutants of mouse and Drosophila (6)(7)(8). Meanwhile, we have previously reported that the loss-of-function mutants of nematode PRMT-1 in Caenorhabditis elegans are viable (9). This finding led us to use C. elegans as an ideal model for further investigating the physiological functions of asymmetric arginine dimethylation in vivo.…”

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Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

Luo

Daitoku

Araoi

et al. 2017

Molecular and Cellular Biology

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Protein arginine methyltransferase 1 (PRMT-1) catalyzes asymmetric arginine dimethylation on cellular proteins and modulates various aspects of biological processes, such as signal transduction, DNA repair, and transcriptional regulation. We have previously reported that the null mutant of prmt-1 in Caenorhabditis elegans exhibits a slightly shortened life span, but the physiological significance of PRMT-1 remains largely unclear. Here we explored the role of PRMT-1 in mitochondrial function as hinted by a two-dimensional Western blot-based proteomic study. Subcellular fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that PRMT-1 is almost entirely responsible for asymmetric arginine dimethylation on mitochondrial proteins. Importantly, isolated mitochondria from prmt-1 mutants represent compromised ATP synthesis in vitro, and wholeworm respiration in prmt-1 mutants is decreased in vivo. Transgenic rescue experiments demonstrate that PRMT-1-dependent asymmetric arginine dimethylation is required to prevent mitochondrial reactive oxygen species (ROS) production, which consequently causes the activation of the mitochondrial unfolded-protein response. Furthermore, the loss of enzymatic activity of prmt-1 induces food avoidance behavior due to mitochondrial dysfunction, but treatment with the antioxidant N-acetylcysteine significantly ameliorates this phenotype. These findings add a new layer of complexity to the posttranslational regulation of mitochondrial function and provide clues for understanding the physiological roles of PRMT-1 in multicellular organisms. KEYWORDS Caenorhabditis elegans, PRMT-1, asymmetric arginine methylation, mitochondriaA rginine methylation has drawn attention as a widespread posttranslational modification that often occurs in RNA-binding proteins, signaling molecules, DNA repair machinery, and transcriptional factors (1-5). This modification is classified according to the number and position of the methyl groups on a guanidino nitrogen of arginine residue, namely, monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), or symmetric dimethylarginine (SDMA). A family of protein arginine methyltransferases (PRMT) is responsible for catalyzing first the formation of an MMA as an intermediate, and subsequently type I enzymes, including further catalyze the generation of ADMA, while type II enzymes, including PRMT-5, PRMT-7, and FBXO11, catalyze the generation of SDMA (5). Among them, PRMT-1 is known to be the predominant type I enzyme in mammalian cells, whereas its physiological significance at the whole-body level has remained unclear due to embryonic

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Asymmetric Arginine Dimethylation Determines Life Span in C. elegans by Regulating Forkhead Transcription Factor DAF-16

Cited by 73 publications

References 41 publications

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

Target of Rapamycin Signaling Regulates Metabolism, Growth, and Life Span in Arabidopsis

Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

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