Modification of Transfer RNA Levels Affects Cyclin Aggregation and the Correct Duplication of Yeast Cells

Abstract

Codon usage bias (the preferential use of certain synonymous codons (optimal) over others is found at the organism level (intergenomic) within specific genomes (intragenomic) and even in certain genes. Whether it is the result of genetic drift due to GC/AT content and/or natural selection is a topic of intense debate. Preferential codons are mostly found in genes encoding highly-expressed proteins, while lowly-expressed proteins usually contain a high proportion of rare (lowly-represented) codons. While optimal codons are decoded by highly expressed tRNAs, rare codons are usually decoded by lowly-represented tRNAs. Whether rare codons play a role in controlling the expression of lowly- or temporarily-expressed proteins is an open question. In this work we approached this question using two strategies, either by replacing rare glycine codons with optimal counterparts in the gene that encodes the cell cycle protein Cdc13, or by overexpression the tRNAGly that decodes rare codons from the fission yeast, Schizosaccharomyces pombe. While the replacement of synonymous codons severely affected cell growth, increasing tRNA levels affected the aggregation status of Cdc13 and cell division. These lead us to think that rare codons in lowly-expressed cyclin proteins are crucial for cell division, and that the overexpression of tRNA that decodes rare codons affects the expression of proteins containing these rare codons. These codons may be the result of the natural selection of codons in genes that encode lowly-expressed proteins.

Ushering in the era of tRNA medicines

“…Arias et al . ( 40 ) showed that the stability of the yeast cell-cycle protein Cdc13 may depend in part on two nonoptimal glycine codons. Although overexpression of the cognate tRNAs did not seem to impact the amount of protein produced, up to half of the resulting protein was in the aggregated fraction.…”

Non-Coding RNAs: Regulators of Stress, Ageing, and Developmental Decisions in Yeast?

“…New discoveries in the field of tRNA biology in recent decades have led to a model in which the cell can modify the translation profile by altering the amount or properties of tRNAs (reviewed in [21][22][23][24][25]) (Figure 1). According to this model, because the rate of translation depends on the concentration of cognate aminoacyl-tRNAs, differences in the amount of individual tRNAs lead to an alteration in the decoding capacity (i.e., the ability to translate mRNA with a certain codon composition) of the cellular tRNA pool and thus to faster translation of mRNAs whose codon composition matches the composition of the cellular tRNA pool.…”

“…Another example comes from a study on the regulation of the major B-type cyclin Cdc13, which drives the cell cycle and mitotic entry in fission yeast [24,56]. The gene cdc13 contains the non-optimal glycine codons GGA and GGG, both of which are decoded by tRNA Gly UCC .…”

“…Overexpression of tRNA Gly UCC or replacement of the non-optimal codons with a preferred glycine codon resulted in a cell cycle defect and slow growth due to Cdc13 aggregation. Interestingly, the abundance of tRNA Gly UCC increases under oxidative stress [24]. A possible model suggests that stress-induced tRNA production leads to cyclin inactivation due to an altered translation rate and thus to delayed cell cycle progression.…”

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

“…Modification of tRNA is related to the cell cycle. The level of tRNA modifications affected the aggregation status of Cdc13 and cell division [64]. It has been found that irreversible cell cycle arrests both in G1 and G2 in tad3-1 mutant cells because of an impairment in the A to I conversion at position 34 of tRNA [65].…”