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Selective Inhibition of Selenocysteine tRNA Maturation and Selenoprotein Synthesis in Transgenic Mice Expressing Isopentenyladenosine-Deficient Selenocysteine tRNA
Open accessAbstract
Selenocysteine (Sec) tRNA (tRNA([Ser]Sec)) serves as both the site of Sec biosynthesis and the adapter molecule for donation of this amino acid to protein. The consequences on selenoprotein biosynthesis of overexpressing either the wild type or a mutant tRNA([Ser]Sec) lacking the modified base, isopentenyladenosine, in its anticodon loop were examined by introducing multiple copies of the corresponding tRNA([Ser]Sec) genes into the mouse genome. Overexpression of wild-type tRNA([Ser]Sec) did not affect selenoprotein synthesis. In contrast, the levels of numerous selenoproteins decreased in mice expressing isopentenyladenosine-deficient (i(6)A(-)) tRNA([Ser]Sec) in a protein- and tissue-specific manner. Cytosolic glutathione peroxidase and mitochondrial thioredoxin reductase 3 were the most and least affected selenoproteins, while selenoprotein expression was most and least affected in the liver and testes, respectively. The defect in selenoprotein expression occurred at translation, since selenoprotein mRNA levels were largely unaffected. Analysis of the tRNA([Ser]Sec) population showed that expression of i(6)A(-) tRNA([Ser]Sec) altered the distribution of the two major isoforms, whereby the maturation of tRNA([Ser]Sec) by methylation of the nucleoside in the wobble position was repressed. The data suggest that the levels of i(6)A(-) tRNA([Ser]Sec) and wild-type tRNA([Ser]Sec) are regulated independently and that the amount of wild-type tRNA([Ser]Sec) is determined, at least in part, by a feedback mechanism governed by the level of the tRNA([Ser]Sec) population. This study marks the first example of transgenic mice engineered to contain functional tRNA transgenes and suggests that i(6)A(-) tRNA([Ser]Sec) transgenic mice will be useful in assessing the biological roles of selenoproteins.
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“The transcription factor Nrf2 is considered as a redox switch regulating the expression of antioxidant enzymes, GSH-synthesizing enzymes, and detoxifying Phase 2 enzymes (175), while the specific selenocysteine tRNA is needed for the synthesis of selenoproteins such as GPx or Trx reductase, which reduces oxidized Trx (133) (Fig. 2).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [133]
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Metadata
- Authors
- Moustafa, M. E., Carlson, B. A., El-Saadani, M. A., Kryukov, G. V., Sun, Q.-A., Harney, J. W., Hill, K. E., Combs, G. F., Feigenbaum, L., Mansur, D. B., Burk, R. F., Berry, M. J., Diamond, A. M., Lee, B. J., Gladyshev, V. N., & Hatfield, D. L.
- Affiliations
- National Institutes of Health (US)
- Alexandria University (EG)
- University of Nebraska–Lincoln (US)
- Brigham and Women's Hospital (US)
- Vanderbilt University (US)
- Cornell University (US)
- Leidos (United States) (US)
- Washington University in St. Louis (US)
- University of Illinois Chicago (US)
- Seoul National University (KR)
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-06-01
- Volume
- 21
- Issue
- 11
- Pages
- 3840-3852
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC87048
- OpenAlex
- W2141386840
- Cited by
- 131
- References
- 47
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 3 · 2021: 5 · 2019: 2 · 2018: 3 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 6.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lincoln (University of Nebraska) (submittedVersion)
- Funders
- American Institute for Cancer Research
- National Institutes of Health (DK47320, ES02497)
- National Cancer Institute (CAA81153)
- National Institute of General Medical Sciences (GM616603)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 47320, R56DK047320, R01DK047320)
- National Institute of Environmental Health Sciences (ES-02497, R37ES002497, R01ES002497)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Physical Sciences › Chemistry › Organic Chemistry › Organoselenium and organotellurium chemistry
- Keywords
- selenocysteine tRNA, selenoprotein biosynthesis, isopentenyladenosine, tRNA maturation, glutathione peroxidase, transgenic mice, feedback regulation, anticodon loop, tissue-specific gene expression
- MeSH terms
- Animals, Base Sequence, Isopentenyladenosine, Mice, Transgenic, Molecular Sequence Data, Nucleic Acid Conformation, Proteins, RNA, Transfer, Amino Acid-Specific, Selenium, Protein Biosynthesis, Blotting, Northern, Gene Expression, Selenoproteins, Mice
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