tRNA modification and cancer: potential for therapeutic prevention and intervention

Abstract

Transfer RNAs (tRNAs) undergo extensive chemical modification within cells through the activity of tRNA methyltransferase enzymes (TRMs). Although tRNA modifications are dynamic, how they impact cell behavior after stress and during tumorigenesis is not well understood. This review discusses how tRNA modifications influence the translation of codon-biased transcripts involved in responses to oxidative stress. We further discuss emerging mechanistic details about how aberrant TRM activity in cancer cells can direct programs of codon-biased translation that drive cancer cell phenotypes. The studies reviewed here predict future preventative therapies aimed at augmenting TRM activity in individuals at risk for cancer due to exposure. They further predict that attenuating TRM-dependent translation in cancer cells may limit disease progression while leaving noncancerous cells unharmed.

Keywords: anticodon; cancer; codon-bias; modification; oxidative stress; tRNA.

Figure 1.. The degeneracy of the Universal Genetic Code.

More than one codon, varying at the third base, or wobble position, can decode that same amino acid. Different amino acids that share the same first two bases and vary only at the wobble position reside in split-codon boxes (hatched lines); their specific decoding is influenced by wobble base tRNA modifications [5]. Codons found enriched in transcripts linked to the stress response or tumor promotion are in bold.

Figure 2.. A model of tRNA modifications in response to oxidative stress.

Oxidative stress either activates or augments the activity of TRMs that target specific tRNAs for modification (e.g., Um₃₄) particularly at the wobble position. These modified tRNAs enhance the translation of transcripts with a codon bias that carry out various cellular activities including reactive oxygen species mitigation and promoting cancerous phenotypes. TRM: tRNA methyltransferase enzyme.

Figure 3.. tRNA methyltransferase activity in cancer cells.

tRNA methyltransferase enzymes catalyze specific chemical modifications on tRNAs to direct translational programs that are either tumor suppressive (unfilled) or oncogeneic (filled) in cancer cells. CBT: Codon-biased translation; tRF: Small tRNA-derived fragment.