Academic journal article Genetics

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the Yeast Saccharomyces Cerevisiae

Academic journal article Genetics

Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the Yeast Saccharomyces Cerevisiae

Article excerpt

ABSTRACT Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post-transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 3' mature sequence and, for tRNA^sup His^, addition of a 5' G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which ~15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain.

THE primary function of eukaryotic transfer RNAs (tRNAs) is the essential role of delivering amino acids, as specified by messenger RNA (mRNA) codons, to the cytoplasmic and organellar protein synthesis machineries. However, it is now appreciated that eukaryotic tRNAs serve additional functions in processes such as targeting proteins for degradation via the N-end rule pathway, signaling in the general amino acid control pathway, and regulation of apoptosis by binding cytochrome C (Varshavsky 1997; Dever and Hinnebusch 2005; Mei et al. 2010). tRNAs are also employed as reverse transcription primers and for strand transfer during retroviral replication (Marquet et al. 1995; Piekna-Przybylska et al. 2010). Newly discovered pathways that generate tRNA fragments document roles of the fragments in translation regulation and cellular responses to stress (Yamasaki et al. 2009; reviewed in Parker 2012). Due to all these functions, alterations in the rate of tRNA transcription or defects in various of the post-transcriptional processing steps results in numerous human diseases including neuronal disorders (reviewed in Lemmens et al. 2010) and pontocerebellar hypoplasia (Budde et al. 2008). Despite the importance and medical implications, much remains to be learned about tRNA biosynthesis, turnover, and subcellular dynamics.

Cytoplasmic tRNAs are transcribed in the nucleus by a DNA-dependent RNA polymerase, Pol III, that is dedicated to transcription of small RNAs. After transcription, tRNAs undergo a bewildering number of post-transcriptional alterations. Recent discoveries have uncovered many roles for tRNA modifications. Since nuclear-encoded tRNAs function in the cytoplasm or in organelles, additional steps are required to deliver the processed or partially processed tRNAs to the correct subcellular location. Subcellular tRNA trafficking is surprisingly complex because it is now known not to be solely unidirectional from the nucleus to the cytoplasm. Finally, although it has been the conventional wisdom that tRNAs are highly stable molecules, recent studies have discovered multiple pathways that degrade partially processed or misfolded tRNAs and therefore serve in tRNA quality control. …

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