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Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA

  1. Author:
    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.

  2. Author Address

    NCI, Sect MolBiol Selenium, Basic Res Lab, NIH, Bldg 37, Room 2D09, Bethesda, MD 20892 USA. NCI, Sect MolBiol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Univ Alexandria, Fac Sci, Dept Biochem, Alexandria, Egypt. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Thyroid, Boston, MA 02115 USA. Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA. Cornell Univ, Div Nutr Sci, Dept Nutr, Ithaca, NY 14853 USA. Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD 21702 USA. Washington Univ, Radiat Oncol Ctr, St Louis, MO 63110 USA. Univ Illinois, Dept Human Nutr, Chicago, IL 60612 USA. Seoul Natl Univ, Sch Biol Sci, Genet Mol Lab, Seoul 151742, South Korea. Hatfield DL NCI, Sect MolBiol Selenium, Basic Res Lab, NIH, Bldg 37, Room 2D09, Bethesda, MD 20892 USA.
    1. Year: 2001
  2. Journal: Molecular and Cellular Biology
    1. 21
    2. 11
    3. Pages: 3840-3852
  4. Type of Article: Article
  1. Abstract:

    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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