Codon-Specific Translation by m1G37 Methylation of tRNA

Hou, Ya‐Ming; Masuda, Isao; Gamper, Howard

doi:10.3389/fgene.2018.00713

Cited by 21 publications

(16 citation statements)

References 69 publications

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“…In support of the possibility for regulatory control, there are precedents for the regulation of translation by the modulation of tRNA modifications at position 34, which directly affects wobble position interactions with the codon 45 , 46 , and at position 37. For example, modulation of m 1 G37 levels is implicated in the control of Mg 2+ homeostasis in Salmonella enterica , which greatly impacts virulence 47 , 48 . Likewise, modulation of i 6 A37 levels impacts global translation profiles and cellular metabolism in fission yeast 49 .…”

Section: Discussionmentioning

confidence: 99%

A substrate binding model for the KEOPS tRNA modifying complex

et al. 2020

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The KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms examined. In humans, pathogenic mutations in KEOPS genes lead to Galloway–Mowat syndrome, an autosomal-recessive disease causing childhood lethality. Kae1 catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine, but the precise roles of all other KEOPS subunits remain an enigma. Here we show using structure-guided studies that Cgi121 recruits tRNA to KEOPS by binding to its 3’ CCA tail. A composite model of KEOPS bound to tRNA reveals that all KEOPS subunits form an extended tRNA-binding surface that we have validated in vitro and in vivo to mediate the interaction with the tRNA substrate and its modification. These findings provide a framework for understanding the inner workings of KEOPS and delineate why all KEOPS subunits are essential.

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Section: Discussionmentioning

confidence: 99%

A substrate binding model for the KEOPS tRNA modifying complex

et al. 2020

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“…Modifications at both positions affect the structure and conformational dynamics of the ASL and provide chemical groups for the non-canonical interactions with the mRNA ( Agris, 2008 ). The modifications at position 37 are mainly associated with reading frame maintenance ( Agris et al, 2018 ; Hou et al, 2019 ). The N6-threonylcarbamoyladenosine-(t6A) modification, which is commonly found at position 37 of Arg-, Asn-, Ile-, Lys-, Met-, and Ser-tRNAs, is essential for the viability of E. coli ( Juhling et al, 2009 ; Thiaville et al, 2015 ); t6A-deficient yeast strains are viable but have increased protein aggregation due to global mistranslation ( Pollo-Oliveira et al, 2020 ).…”

Section: Non-uniform Rate Of Translation and Translational Efficiencymentioning

confidence: 99%

Translational Control by Ribosome Pausing in Bacteria: How a Non-uniform Pace of Translation Affects Protein Production and Folding

et al. 2021

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Protein homeostasis of bacterial cells is maintained by coordinated processes of protein production, folding, and degradation. Translational efficiency of a given mRNA depends on how often the ribosomes initiate synthesis of a new polypeptide and how quickly they read the coding sequence to produce a full-length protein. The pace of ribosomes along the mRNA is not uniform: periods of rapid synthesis are separated by pauses. Here, we summarize recent evidence on how ribosome pausing affects translational efficiency and protein folding. We discuss the factors that slow down translation elongation and affect the quality of the newly synthesized protein. Ribosome pausing emerges as important factor contributing to the regulatory programs that ensure the quality of the proteome and integrate the cellular and environmental cues into regulatory circuits of the cell.

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“…Position 37 of tRNA is semi-conserved that they can be either A or G (Chan & Lowe, 2016;Boccaletto et al, 2018). For tRNA Phe (GAA), position 37 is G. Considering that m 1 G37 is a conserved modification and occurs in an earlier step during tRNA maturation (Hou et al, 2018), we tried to test whether the m 1 G37 modification has an impact on the formation of Gm34. Herein, we introduced m 1 G37 to tRNA Phe (GAA) via E. coli TrmD (UniProt: P0A873) to generate tRNA Phe (GAA) carrying m 1 G37 (m 1 G37_tRNA Phe (GAA) ( Fig 4A).…”

Section: Ftsj1 Directly Binds To Wdr6mentioning

confidence: 99%

Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs

Wang

et al. 2020

EMBO Reports

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tRNA modifications at the anti-codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2 0-Omethyltransferase. tRNA Phe (GAA) from intellectual disability patients with mutations in ftsj1 lacks 2 0-O-methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro. Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2 0-O-methylation activity of the FTSJ1-WDR6 complex in vitro, which occurs at position 34 of specific tRNAs with m 1 G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo. We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNA Phe (GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT-biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development.

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Codon-Specific Translation by m1G37 Methylation of tRNA

Cited by 21 publications

References 69 publications

A substrate binding model for the KEOPS tRNA modifying complex

A substrate binding model for the KEOPS tRNA modifying complex

Translational Control by Ribosome Pausing in Bacteria: How a Non-uniform Pace of Translation Affects Protein Production and Folding

Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs

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