Methylation of the ribosyl moiety at position 34 of selenocysteine tRNA[Ser]Sec is governed by both primary and tertiary structure

Kim, Lark Kyun; Matsufuji, Tamiko; Matsufuji, Senya; Carlson, Bradley A.; Kim, Sukwon S.; Hatfield, Dolph L.; Lee, Byeong Jae

doi:10.1017/s1355838200000388

Cited by 65 publications

(63 citation statements)

References 27 publications

(16 reference statements)

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“…The final step in tRNA [Ser]Sec maturation, with methylation of mcm 5 U at position U34, requires other prior base modifications (e.g., pseudouridine [pψ] and 1-methyladenosine [pm1A] at positions 55 and 58, respectively) (7), intact secondary and tertiary structures (10), and aminoacylation of tRNA [Ser]Sec (11). To investigate base modifications, radiolabeled tRNA…”

Section: Resultsmentioning

confidence: 99%

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Schoenmakers¹,

Carlson²,

Agostini³

et al. 2016

Journal of Clinical Investigation

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International audienceSelenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome–encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2′-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis

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Section: Resultsmentioning

confidence: 99%

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Schoenmakers¹,

Carlson²,

Agostini³

et al. 2016

Journal of Clinical Investigation

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“…mcm 5 U serves as a precursor of mcm 5 Um, and Um34 methylation is the last step in the maturation of tRNA [Ser]Sec . The synthesis of Um34 requires the presence of other modifications and intact secondary and tertiary structures (178) and, in addition, that tRNA [Ser]Sec be aminoacylated (177). Moreover, two major tRNA [Ser]Sec isoforms, each containing either mcm 5 U or mcm 5 Um at position 34, exist in mammalian cells, and their relative distribution is influenced by Se status (58,82,131).…”

Section: Ser]secmentioning

confidence: 99%

Selenoproteins: Molecular Pathways and Physiological Roles

Labunskyy

Hatfield

Gladyshev³

2014

Physiological Reviews

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835

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Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a seleniumcontaining amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

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“…For example, Um34 affects Sec tRNA [Ser]Sec mcmUm secondary and tertiary structure (18). Um34 addition is dependent on the prior synthesis of the four modified bases found in tRNA [Ser]Sec and on an intact tertiary structure (19). Synthesis of all other modified nucleosides of Sec tRNA [Ser]Sec , including mcm 5 Um, is less stringently associated with primary and tertiary structure.…”

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confidence: 99%

Selective Restoration of the Selenoprotein Population in a Mouse Hepatocyte Selenoproteinless Background with Different Mutant Selenocysteine tRNAs Lacking Um34

Carlson

Moustafa

Sengupta

et al. 2007

Journal of Biological Chemistry

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108

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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 (34T3 A) or 37 (37A3 G) in tRNA[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 75 Se 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.There are 24 known selenoproteins in rodents and 25 in humans (1). The targeted removal of specific selenoproteins has shown that some are essential in development, whereas others appear to be nonessential. For example, the loss of selenoproteins glutathione peroxidase 4 (GPx4) (2) or thioredoxin reductase 1 (TR1 or Txnrd1) (3) or 2 (TR3 or Txnrd2) (4) is embryonic lethal, whereas the loss of glutathione peroxidase 1 (GPx1) (5) or 2 (GPx2) (6) appears to be of little or no consequence. Other studies, however, suggest that those selenoproteins whose loss results in little or no phenotypic change may function in protective mechanisms against certain environmental stresses (see Ref. 6 and references therein). There are selenoproteins whose removal or mutation results in dramatic effects on health. For example, knock-out of selenoprotein P (SelP) 6 causes neurological problems (7, 8), and knock-out of type 2 iodothyronine deiodinase results in a variety of defects, including an impaired adaptive thermogenesis and hypothermia in cold-exposed mice (see Ref. 9 and references therein), retarded cochlear development and hearing loss (10), and a pituitary resistance to thyroxine (11). Mutations affecting selenoprotein N (SelN) result in several muscle disorders (12, 13).LoxP-Cre technology, which allows the removal of embryonic lethal genes in specific tissues and organs (3,4,14), has been used to examine the roles of essential sele...

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Methylation of the ribosyl moiety at position 34 of selenocysteine tRNA[Ser]Sec is governed by both primary and tertiary structure

Cited by 65 publications

References 27 publications

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis

Selenoproteins: Molecular Pathways and Physiological Roles

Selective Restoration of the Selenoprotein Population in a Mouse Hepatocyte Selenoproteinless Background with Different Mutant Selenocysteine tRNAs Lacking Um34

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