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Review
. 2016 Jan 28;4(1):e1143076.
doi: 10.1080/21690731.2016.1143076. eCollection 2016 Jan-Jun.

tRNA wobble modifications and protein homeostasis

Namit Ranjan  1 , Marina V Rodnina  1
Affiliations
Review

tRNA wobble modifications and protein homeostasis

Namit Ranjan et al. Translation (Austin). .

Abstract

tRNA is a central component of the protein synthesis machinery in the cell. In living cells, tRNAs undergo numerous post-transcriptional modifications. In particular, modifications at the anticodon loop play an important role in ensuring efficient protein synthesis, maintaining protein homeostasis, and helping cell adaptation and survival. Hypo-modification of the wobble position of the tRNA anticodon loop is of particular relevance for translation regulation and is implicated in various human diseases. In this review we summarize recent evidence of how methyl and thiol modifications in eukaryotic tRNA at position 34 affect cellular fitness and modulate regulatory circuits at normal conditions and under stress.

Keywords: HIV-1; decoding; ribosomal frameshifting; ribosome profiling; tRNA modifications; translation regulation.

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Figures

Figure 1.
Figure 1.
Modifications in cytoplasmic tRNAs in S. cerevisiae. A. Positions of various modifications in tRNA. Nucleotides are shown as circles, the residues 34, 35, and 36 in the anticodon are labeled in addition to several other positions for better orientation. Abbreviations used: Ψ - pseudouridine; Cm - 2′-O-methylcytidine; Am - 2′-O-methyladenosine; m1G - 1-methylguanosine; m2G - N2-methylguanosine; ac4C - N4-acetylcytidine; D - dihydrouridine; Gm – 2′-O-methylguanosine; m2,2G – N2,N2-dimethylguanosine; m3C – 3-methylcytidine; I – inosine; m5C – 5-methylcytidine; mcm5U – 5-methoxycarbonylmethyluridine; mcm5s2U - 5-methoxycarbonylmethyl-2-thiouridine; ncm5U - 5-carbonylmethyluridine; ncm5Um - 5-carbonylmethyl-2′-O-methyluridine; m1I – 1-methylinosine; i6A – N6-isopentenyladenosine; yW – wybutosine; t6A – N6-threonylcarbamoyladenosine; m7G – 7-methylguanosine; Um – 2′-O-methyluridine; m1A – 1-methyladenosine; rT – ribothymidine; Ar(p) – 2′-oribosyladenosine (phosphate). B. Chemical structures of m5C and mcm5s2U tRNA modifications. Unmodified nucleosides and nucleobases are depicted in black. Changes introduced by the modification are shown in red.
Figure 2.
Figure 2.
Modification pathway for mcm5s2U34- and m5C34-containing tRNAs. A. Proteins required for mcm5 modification (left) and s2 modification (right) of U34. Acetyl-CoA acts as a donor for cm5 modification, and SAM as a methyl donor to form mcm5U34. For s2 modification, cysteine acts as sulfur donor. Modified side groups are shown in red. B. Trm4p catalyzed cm5C34 modification where SAM acts as a methyl donor. Modified side group is shown in red.
Figure 3.
Figure 3.
Cellular outcomes of tRNA hypomodification. Loss of tRNA modification upon stress or gene deletion leads to slow translation, which can cause recoding, synthesis of incorrect proteins and changes in the cellular proteome.
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