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      Identification of pararosaniline as a modifier of RNA splicing in Caenorhabditis elegans

      G3: Genes|Genomes|Genetics
      Oxford University Press
      toxcast, RNA splicing, C. elegans, pararosaniline, aging, stress

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          Posttranscriptional splicing of premessenger RNA (mRNA) is an evolutionarily conserved eukaryotic process for producing mature mRNA that is translated into proteins. Accurate splicing is necessary for normal growth and development, and aberrant splicing is increasingly evident in various human pathologies. To study environmental factors that influence RNA splicing, we employed a fluorescent Caenorhabditis elegans in vivo splicing reporter as a biomarker for splicing fidelity to screen against the US EPA ToxCast chemical library. We identified pararosaniline hydrochloride as a strong modifier of RNA splicing. Through gene expression analysis, we found that pararosaniline activates the oxidative stress response and alters the expression of key RNA splicing regulator genes. Physiological assays show that pararosaniline is deleterious to C. elegans development, reproduction, and aging. Through a targeted RNAi screen, we found that inhibiting protein translation can reverse pararosaniline's effect on the splicing reporter and provide significant protection against long-term pararosaniline toxicity. Together, this study reveals a new chemical modifier of RNA splicing and describes translation inhibition as a genetic mechanism to provide resistance.

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          Most cited references36

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          Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C.elegans are large.
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            Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

            In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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              Expansion of the eukaryotic proteome by alternative splicing.

              The collection of components required to carry out the intricate processes involved in generating and maintaining a living, breathing and, sometimes, thinking organism is staggeringly complex. Where do all of the parts come from? Early estimates stated that about 100,000 genes would be required to make up a mammal; however, the actual number is less than one-quarter of that, barely four times the number of genes in budding yeast. It is now clear that the 'missing' information is in large part provided by alternative splicing, the process by which multiple different functional messenger RNAs, and therefore proteins, can be synthesized from a single gene.

                Author and article information

                Role: Editor
                G3 (Bethesda)
                G3: Genes|Genomes|Genetics
                Oxford University Press (US )
                December 2023
                19 October 2023
                19 October 2023
                : 13
                : 12
                : jkad241
                Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, SK S7N 5B4, Canada
                Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, SK S7N 5B4, Canada
                Toxicology Centre, University of Saskatchewan , Saskatoon, SK S7N 5B3, Canada
                Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan , Saskatoon, SK S7N 5E5, Canada
                Author notes
                Corresponding author: University of Saskatchewan, Veterinary Biomedical Sciences, 52 Campus Drive, Saskatoon, SK S7N5B4, Canada. Email: michael.wu@ 123456usask.ca

                Conflicts of interest statement The author(s) declare no conflict of interest.

                Author information
                © The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 13 September 2023
                : 11 October 2023
                : 02 November 2023
                Page count
                Pages: 10
                Funded by: Caenorhabditis Genetic Centre;
                Funded by: University of Minnesota, DOI 10.13039/100007249;
                Funded by: NIH Office of Research Infrastructure Programs;
                Funded by: an NSERC Discovery;
                Funded by: Canada Foundation for Innovation, DOI 10.13039/501100000196;
                Funded by: a WCVM graduate scholarship;

                toxcast,rna splicing,c. elegans,pararosaniline,aging,stress
                toxcast, rna splicing, c. elegans, pararosaniline, aging, stress


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