Mammalian Trit1 is a tRNA[Ser]Sec-isopentenyl transferase required for full selenoprotein expression

Fradejas, Noelia; Carlson, Bradley A.; Rijntjes, Eddy; Becker, Niels-Peter; Tobe, Ryuta; Schweizer, Ulrich

doi:10.1042/bj20121713

Cited by 47 publications

(40 citation statements)

References 32 publications

(41 reference statements)

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“…The ferroptosis-inducing compound FIN56 depletes CoQ 10 by modulating squalene synthase activity (SQS), which in part drives accumulation of lethal lipid peroxidation (Shimada et al, 2016b). Statin drugs, which inhibit HMG CoA reductase, the rate-limiting enzyme of the mevalonate pathway, sensitize cells to ferroptosis, presumably by depleting CoQ 10 , and possibly by also inhibiting downstream tRNA isopentenylation via TRIT1, which is required for the biosynthesis of GPX4 (Fradejas et al, 2013; Shimada et al, 2016b; Viswanathan et al, 2017). …”

Section: The Biochemical Control Of Ferroptosismentioning

confidence: 99%

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Stockwell

Angeli

Bayır

et al. 2017

Cell

4,785

4,352

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Summary Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and that cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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Section: The Biochemical Control Of Ferroptosismentioning

confidence: 99%

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Stockwell

Angeli

Bayır

et al. 2017

Cell

4,785

4,352

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“…[Ser]Sec hypomodification and selenoprotein expression but did not examine other potential substrates, such as the tRNA Ser tRNAs identified here (22,23).…”

Section: Discussionmentioning

confidence: 99%

“…The tumorigenic potential of A549 cells in nude mice was reduced by ectopic expression of TRIT1 (20), and genetic linkage disequilibrium refined a region responsible for cancer progression on chromosome 1p34 that includes a TRIT1 rare mutation allele associated with poor survival in some ethnic groups (21). Human TRIT1 was confirmed to be an IPTase by complementation of a suppressor tRNA Ser UCA-mediated phenotype in mod5-deficient S. cerevisiae (20) and by a direct IPTase activity assay of recombinant TRIT1 protein (18).Selenocysteine tRNA (tRNA [Ser]Sec ) is the only tRNA known to contain i6A37 in mammals (22,23). Human TRIT1 has not been examined for its activity with native tRNA [Ser]Sec and other potential human tRNA substrates.…”

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confidence: 99%

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Human Cells Have a Limited Set of tRNA Anticodon Loop Substrates of the tRNA Isopentenyltransferase TRIT1 Tumor Suppressor

Lamichhane

Mattijssen

Maraia

2013

Molecular and Cellular Biology

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Human TRIT1 is a tRNA isopentenyltransferase (IPTase) homologue of Escherichia coli MiaA, Saccharomyces cerevisiae Mod5, Schizosaccharomyces pombe Tit1, and Caenorhabditis elegans GRO-1 that adds isopentenyl groups to adenosine 37 (i6A37) of substrate tRNAs. Prior studies indicate that i6A37 increases translation fidelity and efficiency in codon-specific ways. TRIT1 is a tumor suppressor whose mutant alleles are associated with cancer progression. We report the systematic identification of i6A37-containing tRNAs in a higher eukaryote, performed using small interfering RNA knockdown and other methods to examine TRIT1 activity in HeLa cells. Although several potential substrates contained the IPTase recognition sequence A36A37A38 in the anticodon loop, only tRNA Ser AGA, tRNA Ser CGA, tRNA Ser UGA, and selenocysteine tRNA with UCA (tRNA [Ser]Sec UCA) contained i6A37. This subset is a significantly more restricted than that for two distant yeasts (S. cerevisiae and S. pombe), the only other organisms comprehensively examined. Unlike the fully i6A37-modified tRNAs for Ser, tRNA[Ser]Sec UCA is partially (ϳ40%) modified. Exogenous selenium and other treatments that decreased the i6A37 content of tRNA [ T ranslation of mRNA should be faithful in order to produce functional proteins, as codon misreading can lead to misfolding and aggregation, yet quality control must be balanced with speed and efficiency in fast-growing cells (1-3). Modifications of the tRNA anticodon loop at positions 34 and 37 contribute to efficiency and fidelity in a codon-specific manner. In addition, these modifications can extend or restrict the potential for wobble base recognition of cognate and noncognate codons and thus contribute to deciphering the genetic code (4,5). A deficiency of different types of tRNA wobble base U34 modification can have different mRNA-specific effects, with consequent effects on phenotypes, as different subsets of mRNAs are overenriched in the cognate codons (6)(7)(8). A link between tRNA modification and specific mRNA subsets was recently extended to the A37 position in the anticodon loop (9).Three types of complex modifications can exist at position 37: N 6 -isopentenyladenosine (i6A37); N 6 -threonylcarbamoyladenosine (t6A37) or its cyclized derivative, ct6A, in archaea and bacteria; and wybutosine (yW37). These are present in distinct subsets of tRNAs in all three domains of life (10-12). The importance of the A37 modification in mammals is illustrated by tRNA Lys UUU, which contains a methyl-sulfur derivative of t6A37, ms2t6A37. Cdkal1 was identified as an enzyme of unknown function that was associated with diabetes risk. It was later found to be the enzyme that adds the methylsulfur group to t6A37 of tRNA Lys UUU and that its deletion from pancreatic ␤ cells causes type 2 diabetes in mice (13,14).Evidence from the fission yeast Schizosaccharomyces pombe indicates that i6A37 increases the specific activity of its tRNAs, increasing fidelity at cognate codons, decreasing fidelity at noncognate codons, and promotin...

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“…Um34 methylation of tRNA [Ser]Sec requires aminoacylated tRNA [Ser]Sec , most likely with Sec [34]. Recently, it was shown that N6-isopentenylation of base A37 is catalyzed by Trit1, a dimethylallyl:tRNA [Ser]Sec -transferase [35]. …”

Section: Selenium In Biomoleculesmentioning

confidence: 99%

Selenium. Role of the Essential Metalloid in Health

Kurokawa

Berry

2013

Metal Ions in Life Sciences

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Selenium is an essential micronutrient in mammals, but is also recognized as toxic in excess. It is a non-metal with properties that are intermediate between the chalcogen elements sulfur and tellurium. Selenium exerts its biological functions through selenoproteins. Selenoproteins contain selenium in the form of the 21st amino acid, selenocysteine (Sec), which is an analog of cysteine with the sulfur-containing side chain replaced by a Se-containing side chain. Sec is encoded by the codon UGA, which is one of three termination codons for mRNA translation in non-selenoprotein genes. Recognition of the UGA codon as a Sec insertion site instead of stop requires a Sec insertion sequence (SECIS) element in selenoprotein mRNAs and a unique selenocysteyl-tRNA, both of which are recognized by specialized protein factors. Unlike the 20 standard amino acids, Sec is biosynthesized from serine on its tRNA. Twenty-five selenoproteins are encoded in the human genome. Most of the selenoprotein genes were discovered by bioinformatics approaches, searching for SECIS elements downstream of in-frame UGA codons. Sec has been described as having stronger nucleophilic and electrophilic properties than cysteine, and Sec is present in the catalytic site of all selenoenzymes. Most selenoproteins, whose functions are known, are involved in redox systems and signaling pathways. However, several selenoproteins are not well characterized in terms of their function. The selenium field has grown dramatically in the last few decades, and research on selenium biology is providing extensive new information regarding its importance for human health.

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Mammalian Trit1 is a tRNA[Ser]Sec-isopentenyl transferase required for full selenoprotein expression

Cited by 47 publications

References 32 publications

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Human Cells Have a Limited Set of tRNA Anticodon Loop Substrates of the tRNA Isopentenyltransferase TRIT1 Tumor Suppressor

Selenium. Role of the Essential Metalloid in Health

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