tRNA structural and functional changes induced by oxidative stress

Abstract

Oxidatively damaged biomolecules impair cellular functions and contribute to the pathology of a variety of diseases. RNA is also attacked by reactive oxygen species, and oxidized RNA is increasingly recognized as an important contributor to neurodegenerative complications in humans. Recently, evidence has accumulated supporting the notion that tRNA is involved in cellular responses to various stress conditions. This review focuses on the intriguing consequences of oxidative modification of tRNA at the structural and functional level.

Fig. 1

Triggers of tRNA cleavage. Various stress conditions induce cleavage of tRNAs in the anticodon loop

Fig. 2

tRNAs are cleaved by specific enzymes. Bacterial endonucleases, PrrC, colicin D, and colicin E5, cleave specific subsets of bacterial tRNAs of invading species in the anticodon region. A similar tRNA endonuclease activity is mediated by γ-toxin from the dairy yeast Kluyveromyces lactis, to arrest the growth of Saccharomyces cerevisiae. Under oxidative stress, tRNAs are cleaved by Rny1 in yeast and by angiogenin in mammalian cells. The nucleolytic activity of angiogenin is further regulated by RNH1, an inhibitory protein, and by tRNA methylation

Fig. 3

Functions of damaged tRNAs. The nicked anticodon loop in cleaved tRNA prevents correct interaction with its respective codon and elongation is stalled. The 5′-half tRNA halves induce the assembly of stress granules, cytoplasmic aggregates which associate with P-bodies to function in selective degradation of mRNA. At least one tRNA-derived fragment was required for the proliferation of prostate cancer cells. In association with specialized proteins, tRNA halves contribute to the regulation of gene expression by guiding endonucleolytic cleavage of target mRNAs

Fig. 4

The structures of sulfur- and selenium-containing pyrimidine nucleosides. S2U and Se2U nucleosides present in transfer RNAs, according to Agris et al., http://rna-mdb.cas.albany.edu/RNAmods/ [43] and Dunin-Horkawicz et al., http://modomics.genesilico.pl/ [44]

Fig. 5

Transformation of 2-thiouridine and 2′-deoxy-2-thiouridine to products of desulfuration. The oxidative dethiolation of S2U (dS2U) results in the production of 4-pyrimidinone nucleoside H2U (dH2U) and uridine U (2′-deoxyuridine, dU)

Fig. 6

Crystal structure of H2U. The crystal structure shows conformational details with respect to the plane passing through atoms C1′, C4′ and O4′ (C2′-endo)

Fig. 7

Possible hydrogen bonding pattern between S2U, U and 4-pyrimidinone nucleoside (H2U) and Watson–Crick pairing adenosine or wobble pairing guanosine units. a Base pairs of U, S2U and H2U with adenosine. b Base pairs of U, S2U and H2U with guanosine. R–sugar moiety