The essential Gcd10p–Gcd14p nuclear complex is required for 1-methyladenosine modification and maturation of initiator methionyl-tRNA

Anderson, James T.; Phan, Lon; Cuesta, Rafael; Carlson, Bradley A.; Pak, Marie; Asano, Katsura; Björk, Glenn R.; Tamame, Mercedes; Hinnebusch, Alan G.

doi:10.1101/gad.12.23.3650

Cited by 238 publications

(344 citation statements)

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“…We found that reduced synthesis of G nucleotides in gua1-G388D cells impairs the processing of pre-tRNA i Met and precursors of certain elongator tRNA species (Figure 7). The predicted reduction in SAM biosynthesis and hypomethylation of pre-tRNAs might impede their proper folding and processing, as occurs in gcd10 and gcd14 mutants defective in methylation of m1A 58 (Anderson et al 1998;Calvo et al 1999). It is also interesting to note that Ran-dependent nucleocytoplasmic transport is dependent on both GTP-and GDPbound forms of the Ran GTPase, and that defects in tRNA maturation have been observed in nucleoporin mutants (Gorlich et al 1996;Sharma et al 1996;Izaurralde et al 1997).…”

Section: Resultsmentioning

confidence: 98%

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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Purine nucleotides are structural components of the genetic material, function as phosphate donors, participate in cellular signaling, are cofactors in enzymatic reactions, and constitute the main carriers of cellular energy. Thus, imbalances in A/G nucleotide biosynthesis affect nearly the whole cellular metabolism and must be tightly regulated. We have identified a substitution mutation (G388D) that reduces the activity of the GMP synthase Gua1 in budding yeast and the total G-nucleotide pool, leading to precipitous reductions in the GDP/GTP ratio and ATP level in vivo. gua1-G388D strongly reduces the rate of growth, impairs general protein synthesis, and derepresses translation of GCN4 mRNA, encoding a transcriptional activator of diverse amino acid biosynthetic enzymes. Although processing of pre-tRNA i Met and other tRNA precursors, and the aminoacylation of tRNA iMet are also strongly impaired in gua1-G388D cells, tRNA i GTP complex (TC) and the multifactor complex (MFC) required for translation initiation accumulate $10-fold in gua1-G388D cells and, to a lesser extent, in wild-type (WT) cells treated with 6-azauracil (6AU). Consistently, addition of an external supply of guanine reverts all the phenotypes of gua1-G388D cells, but not those of gua1-G388D Dhpt1 mutants unable to refill the internal GMP pool through the salvage pathway. These and other findings suggest that a defect in guanine nucleotide biosynthesis evokes a reduction in the rate of general protein synthesis by impairing multiple steps of the process, disrupts the gene-specific reinitiation mechanism for translation of GCN4 mRNA and has far-reaching effects in cell biology and metabolism.

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Section: Resultsmentioning

confidence: 98%

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

et al. 2011

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“…Gcd10p/Gcd14p catalyzes formation of m 1 A 58 in a number of tRNAs (Anderson et al 1998(Anderson et al , 2000, and is essential for modification of tRNA i Met (Calvo et al 1999), and Tad2p/Tad3p catalyzes formation of I 34 in the wobble position of the anticodon of tRNA Ala (Gerber and Keller 1999), and is presumably essential for proper decoding during translation. Strains lacking each of three other modification enzymes are viable, but have distinct growth defects (Lecointe et al 1998;Bjork et al 2001;Pintard et al 2002), whereas lack of most other modification proteins has only subtle growth defects.…”

Section: Discussionmentioning

confidence: 99%

tRNA^His maturation: An essential yeast protein catalyzes addition of a guanine nucleotide to the 5′ end of tRNA^His

Gu¹,

Jackman²,

Lohan³

et al. 2003

Genes Dev.

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199

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“…Furthermore, in their report, the A59 requirement of archaeal TrmI is structurally revealed; the His-78 residue is involved in the A59 recognition (58). It should be mentioned that the eukaryotic counterpart of m 1 A58 methylation in tRNA is a hetero-subunit enzyme, Trm6 (gcd10-gcd14 complex in yeast) (59,60). In the case of m 1 A58 modification, the eukaryotic enzyme probably has a different RNA recognition mechanism from those of the eubacterial and archaeal TrmI enzymes.…”

Section: Discussionmentioning

confidence: 98%

Substrate tRNA Recognition Mechanism of a Multisite-specific tRNA Methyltransferase, Aquifex aeolicus Trm1, Based on the X-ray Crystal Structure

Awai

Ochi

Ihsanawati

et al. 2011

Journal of Biological Chemistry

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Archaeal and eukaryotic tRNA (N 2 ,N 2 -guanine)-dimethyltransferase (Trm1) produces N 2 ,N 2 -dimethylguanine at position 26 in tRNA. In contrast, Trm1 from Aquifex aeolicus, a hyper-thermophilic eubacterium, modifies G27 as well as G26. Here, a gel mobility shift assay revealed that the T-arm in tRNA is the binding site of A. aeolicus Trm1. To address the multisite specificity, we performed an x-ray crystal structure study. The overall structure of A. aeolicus Trm1 is similar to that of archaeal Trm1, although there is a zinc-cysteine cluster in the C-terminal domain of A. aeolicus Trm1. The N-terminal domain is a typical catalytic domain of S-adenosyl-L-methionine-dependent methyltransferases. On the basis of the crystal structure and amino acid sequence alignment, we prepared 30 mutant Trm1 proteins. These mutant proteins clarified residues important for S-adenosyl-L-methionine binding and enabled us to propose a hypothetical reaction mechanism. Furthermore, the tRNA-binding site was also elucidated by methyl transfer assay and gel mobility shift assay. The electrostatic potential surface models of A. aeolicus and archaeal Trm1 proteins demonstrated that the distribution of positive charges differs between the two proteins. We constructed a tRNA-docking model, in which the T-arm structure was placed onto the large area of positive charge, which is the expected tRNA-binding site, of A. aeolicus Trm1. In this model, the target G26 base can be placed near the catalytic pocket; however, the nucleotide at position 27 gains closer access to the pocket. Thus, this docking model introduces a rational explanation of the multisite specificity of A. aeolicus Trm1.Methylation is one of the most common chemical modifications that occurs in a broad range of biomolecules, including nucleic acids, proteins, lipids, and small compounds. It is implicated in a variety of cellular processes, such as translation, transcription, processing of RNA, epigenetics, development, carcinogenesis, neurotransmission, cellular transport, infection, and bacterial host defense. Among the RNA species, methylated nucleotides appear in most noncoding RNAs, constituting more than half of the post-transcriptional modifications identified so far. In particular, tRNA contains abundant methylated nucleotides, which stabilize the L-shaped tRNA structure and improve their molecular recognition (1-3).Among the methylated nucleotides in tRNA, N 2 ,N 2

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The essential Gcd10p–Gcd14p nuclear complex is required for 1-methyladenosine modification and maturation of initiator methionyl-tRNA

Cited by 238 publications

References 46 publications

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

tRNA^His maturation: An essential yeast protein catalyzes addition of a guanine nucleotide to the 5′ end of tRNA^His

Substrate tRNA Recognition Mechanism of a Multisite-specific tRNA Methyltransferase, Aquifex aeolicus Trm1, Based on the X-ray Crystal Structure

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The essential Gcd10p–Gcd14p nuclear complex is required for 1-methyladenosine modification and maturation of initiator methionyl-tRNA

Cited by 238 publications

References 46 publications

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

Guanine Nucleotide Pool Imbalance Impairs Multiple Steps of Protein Synthesis and Disrupts GCN4 Translational Control in Saccharomyces cerevisiae

tRNAHis maturation: An essential yeast protein catalyzes addition of a guanine nucleotide to the 5′ end of tRNAHis

Substrate tRNA Recognition Mechanism of a Multisite-specific tRNA Methyltransferase, Aquifex aeolicus Trm1, Based on the X-ray Crystal Structure

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tRNA^His maturation: An essential yeast protein catalyzes addition of a guanine nucleotide to the 5′ end of tRNA^His