Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34

Bradley A. Carlson, Mohamed E. Moustafa, Aniruddha Sengupta, Ulrich Schweizer, Rajeev Shrimali, Mahadev Rao, Nianxin Zhong, Shulin Wang, Lionel Feigenbaum, Jae Lee Byeong, Vadim N. Gladyshev, Dolph L. Hatfield

Research output: Contribution to journalArticle

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Abstract

Novel mouse models were developed in which the hepatic selenoprotein population was targeted for removal by disrupting the selenocysteine (Sec) tRNA[Ser]Sec gene (trsp), and selenoprotein expression was then restored by introducing wild type or mutant trsp transgenes. The selenoprotein population was partially replaced in liver with mutant transgenes encoding mutations at either position 34 (34T→A) or 37 (37A→G) intRNA [Ser]Sec.The A34 transgene product lacked the highly modified 5-methoxycarbonylmethyl-2′-O-methyluridine, and its mutant base A was converted to I34. The G37 transgene product lacked the highly modified N 6-isopentenyladenosine. Both mutant tRNAs lacked the 2′-methylribose at position 34 (Um34), and both supported expression of housekeeping selenoproteins (e.g. thioredoxin reductase 1) in liver but not stress-related proteins (e.g. glutathione peroxidase 1). Thus, Um34 is responsible for synthesis of a select group of selenoproteins rather than the entire selenoprotein population. The ICA anticodon in the A34 mutant tRNA decoded Cys codons, UGU and UGC, as well as the Sec codon, UGA. However, metabolic labeling of A34 transgenic mice with 75Se revealed that selenoproteins incorporated the label from the A34 mutant tRNA, whereas other proteins did not. These results suggest that the A34 mutant tRNA did not randomly insert Sec in place of Cys, but specifically targeted selected selenoproteins. High copy numbers of A34 transgene, but not G37 transgene, were not tolerated in the absence of wild type trsp, further suggesting insertion of Sec in place of Cys in selenoproteins.

Original languageEnglish
Pages (from-to)32591-32602
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number45
DOIs
Publication statusPublished - 09-11-2007

Fingerprint

Selenoproteins
Restoration
Hepatocytes
Transgenes
Selenocysteine
Population
Transfer RNA
Liver
Isopentenyladenosine
RNA, Transfer, Cys
Thioredoxin Reductase 1
Anticodon
selenocysteinyl-tRNA
Housekeeping
Terminator Codon
Independent component analysis
Heat-Shock Proteins
Codon
Labeling
Transgenic Mice

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Carlson, Bradley A. ; Moustafa, Mohamed E. ; Sengupta, Aniruddha ; Schweizer, Ulrich ; Shrimali, Rajeev ; Rao, Mahadev ; Zhong, Nianxin ; Wang, Shulin ; Feigenbaum, Lionel ; Byeong, Jae Lee ; Gladyshev, Vadim N. ; Hatfield, Dolph L. / Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 45. pp. 32591-32602.
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abstract = "Novel mouse models were developed in which the hepatic selenoprotein population was targeted for removal by disrupting the selenocysteine (Sec) tRNA[Ser]Sec gene (trsp), and selenoprotein expression was then restored by introducing wild type or mutant trsp transgenes. The selenoprotein population was partially replaced in liver with mutant transgenes encoding mutations at either position 34 (34T→A) or 37 (37A→G) intRNA [Ser]Sec.The A34 transgene product lacked the highly modified 5-methoxycarbonylmethyl-2′-O-methyluridine, and its mutant base A was converted to I34. The G37 transgene product lacked the highly modified N 6-isopentenyladenosine. Both mutant tRNAs lacked the 2′-methylribose at position 34 (Um34), and both supported expression of housekeeping selenoproteins (e.g. thioredoxin reductase 1) in liver but not stress-related proteins (e.g. glutathione peroxidase 1). Thus, Um34 is responsible for synthesis of a select group of selenoproteins rather than the entire selenoprotein population. The ICA anticodon in the A34 mutant tRNA decoded Cys codons, UGU and UGC, as well as the Sec codon, UGA. However, metabolic labeling of A34 transgenic mice with 75Se revealed that selenoproteins incorporated the label from the A34 mutant tRNA, whereas other proteins did not. These results suggest that the A34 mutant tRNA did not randomly insert Sec in place of Cys, but specifically targeted selected selenoproteins. High copy numbers of A34 transgene, but not G37 transgene, were not tolerated in the absence of wild type trsp, further suggesting insertion of Sec in place of Cys in selenoproteins.",
author = "Carlson, {Bradley A.} and Moustafa, {Mohamed E.} and Aniruddha Sengupta and Ulrich Schweizer and Rajeev Shrimali and Mahadev Rao and Nianxin Zhong and Shulin Wang and Lionel Feigenbaum and Byeong, {Jae Lee} and Gladyshev, {Vadim N.} and Hatfield, {Dolph L.}",
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Carlson, BA, Moustafa, ME, Sengupta, A, Schweizer, U, Shrimali, R, Rao, M, Zhong, N, Wang, S, Feigenbaum, L, Byeong, JL, Gladyshev, VN & Hatfield, DL 2007, 'Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34', Journal of Biological Chemistry, vol. 282, no. 45, pp. 32591-32602. https://doi.org/10.1074/jbc.M707036200

Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34. / Carlson, Bradley A.; Moustafa, Mohamed E.; Sengupta, Aniruddha; Schweizer, Ulrich; Shrimali, Rajeev; Rao, Mahadev; Zhong, Nianxin; Wang, Shulin; Feigenbaum, Lionel; Byeong, Jae Lee; Gladyshev, Vadim N.; Hatfield, Dolph L.

In: Journal of Biological Chemistry, Vol. 282, No. 45, 09.11.2007, p. 32591-32602.

Research output: Contribution to journalArticle

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T1 - Selective restoration of the selenoprotein population in a mouse hepatocyte selenoproteinless background with different mutant selenocysteine tRNAs lacking Um34

AU - Carlson, Bradley A.

AU - Moustafa, Mohamed E.

AU - Sengupta, Aniruddha

AU - Schweizer, Ulrich

AU - Shrimali, Rajeev

AU - Rao, Mahadev

AU - Zhong, Nianxin

AU - Wang, Shulin

AU - Feigenbaum, Lionel

AU - Byeong, Jae Lee

AU - Gladyshev, Vadim N.

AU - Hatfield, Dolph L.

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N2 - Novel mouse models were developed in which the hepatic selenoprotein population was targeted for removal by disrupting the selenocysteine (Sec) tRNA[Ser]Sec gene (trsp), and selenoprotein expression was then restored by introducing wild type or mutant trsp transgenes. The selenoprotein population was partially replaced in liver with mutant transgenes encoding mutations at either position 34 (34T→A) or 37 (37A→G) intRNA [Ser]Sec.The A34 transgene product lacked the highly modified 5-methoxycarbonylmethyl-2′-O-methyluridine, and its mutant base A was converted to I34. The G37 transgene product lacked the highly modified N 6-isopentenyladenosine. Both mutant tRNAs lacked the 2′-methylribose at position 34 (Um34), and both supported expression of housekeeping selenoproteins (e.g. thioredoxin reductase 1) in liver but not stress-related proteins (e.g. glutathione peroxidase 1). Thus, Um34 is responsible for synthesis of a select group of selenoproteins rather than the entire selenoprotein population. The ICA anticodon in the A34 mutant tRNA decoded Cys codons, UGU and UGC, as well as the Sec codon, UGA. However, metabolic labeling of A34 transgenic mice with 75Se revealed that selenoproteins incorporated the label from the A34 mutant tRNA, whereas other proteins did not. These results suggest that the A34 mutant tRNA did not randomly insert Sec in place of Cys, but specifically targeted selected selenoproteins. High copy numbers of A34 transgene, but not G37 transgene, were not tolerated in the absence of wild type trsp, further suggesting insertion of Sec in place of Cys in selenoproteins.

AB - Novel mouse models were developed in which the hepatic selenoprotein population was targeted for removal by disrupting the selenocysteine (Sec) tRNA[Ser]Sec gene (trsp), and selenoprotein expression was then restored by introducing wild type or mutant trsp transgenes. The selenoprotein population was partially replaced in liver with mutant transgenes encoding mutations at either position 34 (34T→A) or 37 (37A→G) intRNA [Ser]Sec.The A34 transgene product lacked the highly modified 5-methoxycarbonylmethyl-2′-O-methyluridine, and its mutant base A was converted to I34. The G37 transgene product lacked the highly modified N 6-isopentenyladenosine. Both mutant tRNAs lacked the 2′-methylribose at position 34 (Um34), and both supported expression of housekeeping selenoproteins (e.g. thioredoxin reductase 1) in liver but not stress-related proteins (e.g. glutathione peroxidase 1). Thus, Um34 is responsible for synthesis of a select group of selenoproteins rather than the entire selenoprotein population. The ICA anticodon in the A34 mutant tRNA decoded Cys codons, UGU and UGC, as well as the Sec codon, UGA. However, metabolic labeling of A34 transgenic mice with 75Se revealed that selenoproteins incorporated the label from the A34 mutant tRNA, whereas other proteins did not. These results suggest that the A34 mutant tRNA did not randomly insert Sec in place of Cys, but specifically targeted selected selenoproteins. High copy numbers of A34 transgene, but not G37 transgene, were not tolerated in the absence of wild type trsp, further suggesting insertion of Sec in place of Cys in selenoproteins.

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