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Extracurricular Functions of Trna Modifications in Microorganisms

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Extracurricular Functions of Trna Modifications in Microorganisms G C A T T A C G G C A T genes Review Extracurricular Functions of tRNA Modifications in Microorganisms Ashley M. Edwards, Maame A. Addo and Patricia C. Dos Santos * Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27101, USA; [email protected] (A.M.E.); [email protected] (M.A.A.) * Correspondence: [email protected]; Tel.: +1-336-702-1944 Received: 10 July 2020; Accepted: 2 August 2020; Published: 7 August 2020 Abstract: Transfer RNAs (tRNAs) are essential adaptors that mediate translation of the genetic code. These molecules undergo a variety of post-transcriptional modifications, which expand their chemical reactivity while influencing their structure, stability, and functionality. Chemical modifications to tRNA ensure translational competency and promote cellular viability. Hence, the placement and prevalence of tRNA modifications affects the efficiency of aminoacyl tRNA synthetase (aaRS) reactions, interactions with the ribosome, and transient pairing with messenger RNA (mRNA). The synthesis and abundance of tRNA modifications respond directly and indirectly to a range of environmental and nutritional factors involved in the maintenance of metabolic homeostasis. The dynamic landscape of the tRNA epitranscriptome suggests a role for tRNA modifications as markers of cellular status and regulators of translational capacity. This review discusses the non-canonical roles that tRNA modifications play in central metabolic processes and how their levels are modulated in response to a range of cellular demands. Keywords: tRNA modification; 2-thiouridine; 4-thiouridine; queuosine; 2-methylthio-N6-(cis- hydroxyisopentenyl) adenosine; uridine 5-oxyacetic acid; 2-thioribothymidine; epitranscriptome 1. Introduction Post-transcriptional modifications expand the role of ribonucleic acids (RNAs) by introducing additional chemical functionalities to their associated nucleotides. Thus far, over 150 modifications have been discovered in RNA, 93 of which are exclusively found in transfer RNAs (tRNAs) [1]. A large number of these modifications have been characterized and range from simple methylations to more complex hypermodified species such as wybutosine (yW) and queuosine (Q) [2–5]. Modifications are present throughout the tRNA structure (Figure1) and their functions can be predicted based on their locations within the molecule [6]. The presence of these modifications, along with the widely conserved 30-CCA sequence used for aminoacylation, serve as prerequisites for fully functional tRNAs used during protein synthesis [7]. Specific modifications found within the anticodon loop influence translational accuracy and/or efficiency [8]. Modifications located in the acceptor stem, the D-loop, and the TYC-loop are often involved in structural stabilization and can also serve as identification elements during RNA–protein recognition events [6,9,10]. Genes 2020, 11, 907; doi:10.3390/genes11080907 www.mdpi.com/journal/genes Genes 2020, 11, 907 2 of 19 Genes 2020, 11, x FOR PEER REVIEW 2 of 19 FigureFigure 1. SchematicSchematic of of the the tRNA tRNA secondary secondary structure structure and location of modified modified bases. Each Each structural structural domaindomain of of tRNA tRNA is is represented represented in in a a different different color color and and modified modified bases bases known known to to be be affected affected by by environmentalenvironmental and/or and/or nutritional conditions are highlighted. OneOne way modifications modifications in in tRNA guarantee fidelity fidelity of translation is is by influencing influencing codon discrimination.discrimination. This This is isimportant important in insituations situations when when two two amino amino acids acids are defined are defined by codons by codons that vary that byvary only by one only nucleotide, one nucleotide, such as such methionine as methionine (AUG) and (AUG) isoleucine and isoleucine (AUA/U/C). (AUA In /bacteria,U/C). In accurate bacteria, recognitionaccurate recognition of the AUA of thecodon AUA requires codon requirestRNAIle2 tRNAto haveIle2 2-lysidineto have 2-lysidine (k2C) at position (k2C) at position34 to prevent 34 to misacylationprevent misacylation by methionyl-tRNA by methionyl-tRNA synthetase synthetase (MetRS) (MetRS) [11]. Additionally, [11]. Additionally, the N4-acetylcytidine the N4-acetylcytidine (ac4C) modification(ac4C) modification at position at position 34 of tRNA 34 ofMet tRNA acts asMet a actspositive as a positiveidentity determinant identity determinant for MetRS for [12]. MetRS Wobble [12]. baseWobble modifications base modifications also tune alsothe reactivity tune the reactivityof cognate of tRNA cognate substrates tRNA substratesin aminoacyl in tRNA aminoacyl synthetase tRNA 2 (aaRS)synthetase reactions. (aaRS) Specifically, reactions. G34 Specifically, and k2C G34constitute and k recognitionC constitute elements recognition for IleRS elements to discriminately for IleRS to aminoacylatediscriminately tRNA aminoacylateIle1 and tRNA tRNAIle2Ile1, respectivelyand tRNAIle2 [13,14]., respectively In the [13archaea,14].In Thermus the archaea thermophilusThermus, agmatidinethermophilus (agm, agmatidine2C34) is (agmfound2C34) at the is foundwobble at position the wobble of tRNA positionIle2 ofand tRNA similarlyIle2 and decodes similarly the decodes minor AUAthe minor isoleucine AUA isoleucinecodon, while codon, directly while intera directlycting interacting with 70S ribosomal with 70S ribosomalRNA (rRNA) RNA [15]. (rRNA) [15]. TheThe presence presence and and conservation conservation of selected selected modifi modifieded bases bases serves serves as as an an identity identity determinant determinant for for aaRSsaaRSs (Figure 2 2).). 2-thiouridine2-thiouridine (s (s22U),U), anotheranother wobblewobble modification,modification, is is required required for for efficient efficient charging charging of oftRNA tRNAGlnGlnand and it affects it affects interactions interactions with elongationwith elongation factor-tu factor-tu (Ef-Tu) [(Ef-Tu)16]. In Escherichia [16]. In Escherichia coli, the presence coli, the of presencebase-stacked of U35base-stacked/U36 found perpendicularU35/U36 found to and inperpendicular tandem with 5-methylaminomethyl-2-thiouridineto and in tandem with 5- methylaminomethyl-2-thiouridine(mnm5s2U34) in tRNALys is essential (mnm for LysRS5s2U34) recognition in tRNA andLys bindingis essential [17]. Likewise,for LysRS 2-methyladenosine recognition and binding(m2A37) [17]. and pseudouridineLikewise, 2-methyladenosine ( 38) in tRNAGln (mserve2A37) as stabilizingand pseudouridine agents for ( anticodonψ38) in tRNA loopGln nucleotides serve as stabilizingand are necessary agents forfor effi cientanticodon GlnRS loop aminoacylation nucleotides [18 ].and 5-methyluridine are necessary (m 5forU54) efficient is necessary GlnRS for aminoacylationtRNA interactions [18]. with 5-methyluridine Ef-Tu in the archaea (m5U54)Thermus is necessary aquaticus byfor altering tRNA interactions their binding with interface Ef-Tu contacts in the archaeaand energies Thermus [19]. aquaticus Structural by changes altering resultingtheir binding from photochemicalinterface contacts reactions and energies of 4-thiouridine [19]. Structural (s4U8) changesimpairs tRNAresulting interactions from photochemi with PheRScal and reactions ProRS [of20 4-thiouridine]. These and other (s4U8) additional impairs examplestRNA interactions provided within this PheRS review and show ProRS that [20]. the These prevalence and other of these additional modifications examples not provided only impacts in this the review tRNA’s show ability that to theinteract prevalence with their of correspondingthese modifications aaRSs, not but only also withimpacts essential the tRNA’s partners ability including to interact tRNA-modifying with their correspondingenzymes, Ef-Tu, aaRSs, ribosomes but also and with coding essential RNA sequences partners including (Figure2)[ tRNA-modifying17,19,21]. enzymes, Ef-Tu, ribosomes and coding RNA sequences (Figure 2) [17,19,21]. GenesGenes2020 2020,,11 11,, 907 x FOR PEER REVIEW 33 ofof 1919 Figure 2. Modifications throughout the tRNA structure are importantrecognition elements for interactionFigure 2. Modifications with a variety ofthroughout partners inthe translation. tRNA structure The tRNA are structureimportant (PDB recognition 1u0b) shows elements domains for colorinteraction coded with in accordance a variety of with partners Figure in1. translat m 5U54ion. confers The bindingtRNA structure with T. aquaticus(PDB 1u0b)Ef-Tu shows [19]; domains s4U8 is necessarycolor coded for in structural accordance stability with Figure impacting 1. m interactions5U54 confers withbindingE. coli withPheRS T. aquaticus and ProRS Ef-Tu [20 [19];]; U35 s4/U8U36, is alongnecessary with for mnm structural5s2U34, arestability major impacting identity elements interactions for E. with coli E.LysRS coli PheRS binding and [17 ProRS]; agm 2[20];C34 U35/U36, interacts withalong the withT. thermophilus mnm5s2U34,70S are ribosome major identity [15]; k 2elementsC34 is required for E. coli for codonLysRS discriminationbinding [17]; agm by IleRS2C34 ininteractsE. coli andwithB. the subtilis T. thermophilus[14]; s2U34, 70S m 2ribosomeA37, and [15]; 38 k are2C34 required is required for E. for coli codonGlnRS discrimination substrate recognition by IleRS in and E. aminoacylationcoli and B. subtilis effi [14];ciency s2U34, [16,18 m];2A37, ms2 iand6A37 ψ directly38 are required interacts for with E. coli cognate GlnRS mRNA substrate bases recognition in E, P and and A sitesaminoacylation
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