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An interplay between transcription, processing, and degradation determines tRNA levels in yeast

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tRNA biogenesis in yeast involves the synthesis of the initial transcript by RNA polymerase III followed by processing and controlled degradation in both the nucleus and the cytoplasm. A vast landscape of regulatory elements controlling tRNA stability in yeast has emerged from recent studies. Diverse pathways of tRNA maturation generate multiple stable and unstable intermediates. A significant impact on tRNA stability is exerted by a variety of nucleotide modifications. Pre‐tRNAs are targets of exosome‐dependent surveillance in the nucleus. Some tRNAs that are hypomodified or bear specific destabilizing mutations are directed to the rapid tRNA decay pathway leading to 5′→3′ exonucleolytic degradation by Rat1 and Xrn1. tRNA molecules are selectively marked for degradation by a double CCA at their 3′ ends. In addition, under different stress conditions, tRNA half‐molecules can be generated by independent endonucleolytic cleavage events. Recent studies reveal unexpected relationships between the subsequent steps of tRNA biosynthesis and the mechanisms controlling its quality and turnover. WIREs RNA 2013, 4:709–722. doi: 10.1002/wrna.1190 This article is categorized under: RNA Processing > tRNA Processing RNA Turnover and Surveillance > Regulation of RNA Stability

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Maturation of intron‐containing tRNA. After transcription by RNA polymerase III (Pol III) subsequent steps of end maturation take place in the nucleus, next precursor is exported to the cytoplasm where intron is spliced, and tRNA can be charged and directed to further processes. Enzymes responsible for each processing step are listed above corresponding arrows. Modifications that can be added in each step of tRNA biosynthesis are not presented in the scheme.
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An interplay between tRNA biosynthesis and degradation in yeast. Primary tRNA transcript is synthesized by RNA polymerase III (Pol III), which is regulated by Maf1 protein. Following the initial processing steps in the nucleus, where the 5′ leader and 3′ trailer are removed, the tRNA precursor is moved to the cytoplasm. CCA on the 3′ terminus and some modifications are added to the tRNA precursor. Introns are spliced on the outer surface of the mitochondrial membrane. tRNA is charged by the tRNA synthetase, bound by elongation factor (eEF1A), and delivered to the ribosome for translation. Mature tRNA under stress can be cleaved into tRNA halves. Turnover of tRNA is controlled by several pathways. In the nucleus, pre‐tRNA can be degraded by the exosome complex or subjected to rapid tRNA decay (RTD) with Rat1 exonuclease. In the cytoplasm, mature tRNAs can be directed to cytoplasmic RTD by Xrn1 exonuclease. Uncovered/emerging interactions between transcription, processing, and decay pathways, which are described in detail in the text, are marked with green dashed lines.
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Current model of tRNA degradation during lifecycle. Newly transcribed tRNA precursor (pre‐tRNA) can be polyadenylated on the 3′ end by TRAMP (Trf4/Air2/Mtr4 polyadenylation) complex and targeted to degradation by exosome. During early steps of processing defective intermediate can undergo exosomal degradation after marking with poly A tail. If the particle is unstable it can be marked with additional CCA sequence and directed to the rapid tRNA decay (RTD) pathway and/or polyadenylated and degraded by the exosome. As relationships of additional CCA marking of tRNA with RTD or exosome and correlation between exosome and RTD are unclear, they are marked on the scheme with dashed green lines. Lack of some modifications or mutations causing structural defects of mature tRNA results in instability of tRNA particle which is directed to RTD pathway. How mature stable tRNA is directed to degradation is still unknown.
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Representation of forms and fragments of precursors and mature tRNAs that accumulated or appeared in yeast mutants or under specific conditions. An example of Northern analysis of tRNAPhe(GAA) in a wild‐type strain is given on the left. Bands on the blot represent unprocessed initial transcripts (designated ), 5′‐end‐matured intron‐containing pre‐tRNAs (designated ), end‐matured intron‐containing pre‐tRNAs (designated ), and mature tRNAs (designated ). A graphical version of Northern blots reported previously for mutants defective in tRNA biosynthesis displays various intermediate forms designated by the respective symbols. Positions of tRNA forms which were not detected by the given probes on Northern blots from cited articles were designated as ‘Not shown’. The band size is proportional to the wild type, in exception of those that are from in vitro studies. Each lane represents pre‐tRNA and tRNA forms and the amount of each form found in defined mutants as follows: Maf1—tRNAPhe(GAA) in maf1Δ; Bdp1—tRNAIle(UAU) in bdp1Δ253‐269; RNase P—tRNALeu(CAA) at 38°C; Lhp1—tRNATyr(GUA) in lhp1Δ; Rex1—tRNALys(UUU) in rex1Δ; Lhp1 and Rex1—tRNALys(UUU) in lhp1Δ rex1Δ; Lsm—tRNALeu(CAA) after 6 h in glucose in GAL::lsm3; Sen2—tRNALeu(CAA) in sen2‐3; Sen2—tRNATyr in Sen2 (His297Ala), in vitro study; Sen34—tRNATyr in Sen34 (His217Ala) in vitro study; Trl1—tRNALeu(CAA) in trl1‐4 with empty vector at 37°C; and stress‐induced cleavage—tRNAHis(GTG) in hts1.1 after 15 min at 39°C.
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RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Processing > tRNA Processing

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