The human tRNA(m22G26)dimethyltransferase: functional expression and characterization of a cloned hTRM1 gene

Liu, Jianming; Stråby, Kerstin B.

doi:10.1093/nar/28.18.3445

Cited by 61 publications

(58 citation statements)

References 51 publications

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“…This list includes intellectual disability associated with a point mutation in hADAT3 , the predicted homolog of a subunit of the yeast tRNA A 34 deaminase (Alazami et al 2013); a frameshift mutation in hTRMT1 (Najmabadi et al 2011), which has tRNA m 2,2 G 26 (N 2 ,N 2 -dimethylguanosine) methyltransferase activity (Liu and Strâby 2000); mutations in NSUN2 (AbbasiMoheb et al 2012;Khan et al 2012;Martinez et al 2012), which modifies C 34 , C 48 , C 49 , and C 50 on target tRNAs to m 5 C; and mutations in hELP2 (Najmabadi et al 2011), a member of the ELP complex responsible for formation of the cm 5 U moiety found on mcm 5 U 34 , ncm 5 U 34 , mcm 5 s 2 U 34 and related modifications. In addition, familial disautonomia is associated with mutations in hELP1 (IKBAKP) (Anderson et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Guy

Phizicky

2014

RNA

103

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Post-transcriptional tRNA modifications are critical for efficient and accurate translation, and have multiple different roles. Lack of modifications often leads to different biological consequences in different organisms, and in humans is frequently associated with neurological disorders. We investigate here the conservation of a unique circuitry for anticodon loop modification required for healthy growth in the yeast Saccharomyces cerevisiae. S. cerevisiae Trm7 interacts separately with Trm732 and Trm734 to 2 ′ -O-methylate three substrate tRNAs at anticodon loop residues C 32 and N 34 , and these modifications are required for efficient wybutosine formation at m 1 G 37 of tRNA Phe . Moreover, trm7Δ and trm732Δ trm734Δ mutants grow poorly due to lack of functional tRNA Phe . It is unknown if this circuitry is conserved and important for tRNA Phe modification in other eukaryotes, but a likely human TRM7 ortholog is implicated in nonsyndromic X-linked intellectual disability. We find that the distantly related yeast Schizosaccharomyces pombe has retained this circuitry for anticodon loop modification, that S. pombe trm7Δ and trm734Δ mutants have more severe phenotypes than the S. cerevisiae mutants, and that tRNA Phe is the major biological target. Furthermore, we provide evidence that Trm7 and Trm732 function is widely conserved throughout eukaryotes, since human FTSJ1 and THADA, respectively, complement growth defects of S. cerevisiae trm7Δ and trm732Δ trm734Δ mutants by modifying C 32 of tRNA Phe , each working with the corresponding S. cerevisiae partner protein. These results suggest widespread importance of 2 ′ -O-methylation of the tRNA anticodon loop, implicate tRNA Phe as the crucial substrate, and suggest that this modification circuitry is important for human neuronal development.

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Section: Discussionmentioning

confidence: 99%

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Guy

Phizicky

2014

RNA

103

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“…In contrast, S. pombe Tgs1, the only other cap-specific N2 methyltransferase that has been characterized (6), is able to catalyze two sequential N2 methylations leading to TMG cap formation. tRNA-specific guanine-N2 methyltransferases also fall into two classes, depending on whether they catalyze either one methylation step to form 2-methylguanosine (21) or two sequential steps to generate 2,2-dimethylguanosine (22)(23)(24)(25). The rRNA-specific guanine-N2 methyltransferase RsmC performs only one methylation step to generate 2-methylguanosine (26).…”

Section: Discussionmentioning

confidence: 99%

Giardia lamblia RNA Cap Guanine-N2 Methyltransferase (Tgs2)

Hausmann

Shuman

2005

Journal of Biological Chemistry

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Tgs1 is the enzyme responsible for converting 7-methylguanosine RNA caps to the 2,2,7-trimethylguanosine cap structures of small nuclear and small nucleolar RNAs. but is unreactive with GDP, GTP, GpppA, ATP, CTP, or UTP. We find that the conserved residues Asp-68, Glu-91, and Trp-143 are essential for Tgs2 methyltransferase activity in vitro. The m 2,7 GDP product formed by Tgs2 can be converted to m 2,2,7 GDP by S. pombe Tgs1 in the presence of excess AdoMet. However, Giardia Tgs2 itself is apparently unable to add a second methyl group at guanine-N2. This result implies that 2,2,7-trimethylguanosine caps in Giardia are either synthesized by Tgs1 alone or by the sequential action of Tgs2 and Tgs1. The specificity of Tgs2 raises the prospect that some Giardia mRNAs might contain dimethylguanosine caps.Many small noncoding eukaryotic RNAs contain a hypermodified 2,2,7-trimethylguanosine (TMG) 2 5Ј-cap structure (1, 2). TMG caps are also found on nematode mRNAs generated via trans-splicing (3). TMG cap formation in Saccharomyces cerevisiae depends on the Tgs1 protein (4). The presence of a putative AdoMet binding motif in the Tgs1 polypeptide, the mutation of which affects TMG formation in vivo (4, 5), suggested that Tgs1 might be directly involved in TMG formation. Biochemical studies of Schizosaccharomyces pombe Tgs1 showed that it is indeed a catalyst of TMG synthesis (6). Methylation of guanine-N2 by S. pombe Tgs1 in vitro is strictly dependent on the prior methylation of guanine-N7, indicating that TMG caps are formed by post-transcriptional methylation of standard m 7 G caps (6). Guanine-N2 methylation by S. pombe Tgs1 in vitro requires no RNA component and no protein cofactor (6). Although early models suggested that the TMG synthase reaction might require cis-acting RNA signals or the assembly of specific ribonucleoprotein structures (7-10), the recent work on S. pombe Tgs1 instates a more conservative model in which ribonucleoprotein components might simply target Tgs1 to a particular subset of cellular RNAs that already have an m 7 G cap. Given the ubiquity of TMG caps in eukaryotic species, it is surprising that an S. cerevisiae tgs1 deletion mutant is viable, even though the small nuclear RNAs and small nucleolar RNAs in the tgs1⌬ strain lack TMG caps (4). Genetic analysis indicates that Tgs1 is also nonessential for growth of S. pombe.3 In contrast, TMG synthesis is essential in Drosophila, where mutations in the putative Tgs1 active site cause lethality at the early pupal stage of development that correlates with depletion of TMG-containing RNAs (11).The protozoan parasite Giardia lamblia is posited to occupy a deeply branching position in eukaryotic phylogeny. Analysis of the Giardia genome is providing important insights to the early origins of RNA processing mechanisms that are regarded as uniquely eukaryotic (12). Although there had been some debate whether Giardia mRNAs even have a 5Ј-cap structure (13,14), recent studies show that Giardia does possess the enzymatic machinery for m 7 G cap synth...

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“…Because this enzyme may represent a target for HIV treatment, it is important to determine if the human homologs of the yeast enzyme encode a functional m A58 methyltransferase is now the fourth tRNA methyltransferase from humans to be cloned and characterized, and only the second to be purified (Liu and Straby 2000;Alexandrov et al 2002;Brule et al 2004).…”

Section: Introductionmentioning

confidence: 99%

The bipartite structure of the tRNA m¹A58 methyltransferase from S. cerevisiae is conserved in humans

Ozanick¹,

Krecic²,

Andersland³

et al. 2005

RNA

130

114

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Among all types of RNA, tRNA is unique given that it possesses the largest assortment and abundance of modified nucleosides. The methylation at N 1 of adenosine 58 is a conserved modification, occurring in bacterial, archaeal, and eukaryotic tRNAs. In the yeast Saccharomyces cerevisiae, the tRNA 1-methyladenosine 58 (m 1 A58) methyltransferase (Mtase) is a two-subunit enzyme encoded by the essential genes TRM6 (GCD10) and TRM61 (GCD14). While the significance of many tRNA modifications is poorly understood, methylation of A58 is known to be critical for maintaining the stability of initiator tRNA Met in yeast. Furthermore, all retroviruses utilize m 1 A58-containing tRNAs to prime reverse transcription, and it has been shown that the presence of m 1 A58 in human tRNA 3 Lys is needed for accurate termination of plus-strand strong-stop DNA synthesis during HIV-1 replication. In this study we have identified the human homologs of the yeast m

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The human tRNA(m22G26)dimethyltransferase: functional expression and characterization of a cloned hTRM1 gene

Cited by 61 publications

References 51 publications

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Giardia lamblia RNA Cap Guanine-N2 Methyltransferase (Tgs2)

The bipartite structure of the tRNA m¹A58 methyltransferase from S. cerevisiae is conserved in humans

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The human tRNA(m22G26)dimethyltransferase: functional expression and characterization of a cloned hTRM1 gene

Cited by 61 publications

References 51 publications

Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes

Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes

Giardia lamblia RNA Cap Guanine-N2 Methyltransferase (Tgs2)

The bipartite structure of the tRNA m1A58 methyltransferase from S. cerevisiae is conserved in humans

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Product

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Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

Conservation of an intricate circuit for crucial modifications of the tRNA^Phe anticodon loop in eukaryotes

The bipartite structure of the tRNA m¹A58 methyltransferase from S. cerevisiae is conserved in humans