Mature cytosolic tRNAs, which average 75–80 nucleotides in length, are produced from larger precursors (pre-tRNAs) synthesized by RNA polymerase III in the nucleoplasm. Mature tRNAs contain numerous modified bases that are not present in tRNA primary transcripts. Cleavage and base modification occur during processing of all pre-tRNAs; some pre-tRNAs are also spliced during processing. All of these processing and modification events occur in the nucleus.

A 5′ sequence of variable length that is absent from mature tRNAs is present in all pre-tRNAs (Figure 1). These extra 5′ nucleotides are present because the 5′ end of a mature tRNA is generated by an endonucleolytic cleavage specified by the tRNA three-dimensional structure, rather than by the start site of transcription. The extra nucleotides are removed by ribonuclease P (RNase P), a ribonucleoprotein endonuclease. Studies with E. coli RNase P indicate that at high Mg2+ concentrations, its RNA component alone can recognize and cleave E. coli pre-tRNAs. The RNase P poly peptide increases the rate of cleavage by the RNA, allowing cleavage to proceed at physiological Mg2+ concentrations. A comparable RNase P functions in eukaryotes.

Fig1. Changes that occur during the processing of tyrosine pre-tRNA. A 14-nucleotide intron (blue) in the anticodon loop is removed by splicing. A 16-nucleotide sequence (green) at the 5′ end is cleaved by RNase P. U residues at the 3′ end are replaced by the CCA sequence (red) found in all mature tRNAs. Numerous bases in the stem-loops are converted to characteristic modified bases (yel low). Not all pre-tRNAs contain introns that are spliced out during processing, but they all undergo the other types of changes shown here. D = dihydrouridine; Ψ = pseudouridine.

About 10 percent of the bases in pre-tRNAs are modified enzymatically during processing. Three classes of base modifications occur (see Figure 1):

1. U residues at the 3′ end of pre-tRNA are replaced with a CCA sequence. The CCA sequence is found at the 3′ end of all tRNAs and is required for their charging by aminoacyl tRNA synthetases during protein synthesis. This step in tRNA synthesis probably functions as a quality-control point, since only properly folded tRNAs are recognized by the CCA addition enzyme.

 2. Methyl and isopentenyl groups are added to the hetero cyclic ring of purine bases, and the 2′-OH groups in the ribose of specific residues are methylated.

3. Specific uridines are converted to dihydrouridine, pseudouridine, or ribothymidine residues. The functions of these base and ribose modifications are not well under stood, but since they are highly conserved, they probably have a positive influence on protein synthesis.

As shown in Figure 1, the pre-tRNA expressed from the yeast tyrosine tRNA (tRNATyr) gene contains a 14-base intron that is not present in mature tRNATyr. Some other eukaryotic tRNA genes and some archaeal tRNA genes also contain introns. The introns in nuclear pre-tRNAs are shorter than those in pre-mRNAs and lack the consensus splice-site sequences found in pre-mRNAs. Pre-tRNA introns are also clearly distinct from the much longer self-splicing group I and group II introns found in chloroplast and mi tochondrial pre-rRNAs. The mechanism of pre-tRNA splicing differs in three fundamental ways from the mechanisms used by self-splicing introns and spliceosomes (see Figure2). First, splicing of pre-tRNAs is catalyzed by proteins, not by RNAs. Second, a pre-tRNA intron is excised in one step that entails simultaneous cleavage at both ends of the intron. Finally, hydrolysis of GTP and ATP is required to join the two tRNA halves generated by cleavage on either side of the intron.

Fig2. Splicing mechanisms in group I and group II self splicing introns and in spliceosome-catalyzed splicing of pre-mRNA. The intron is shown in gray, the exons to be joined in red. In group I introns, a guanosine cofactor (G) that is not part of the RNA chain as sociates with the active site. The 3′-hydroxyl group of this guanosine participates in a transesterification reaction with the phosphate at the 5′ end of the intron; this reaction is analogous to that involving the 2′-hydroxyl groups of the branch-point As in group II introns and pre mRNA introns spliced in spliceosomes. The subsequent transesterification that links the 5′ and 3′ exons is similar in all three splicing mechanisms. Note that spliced-out group I introns are linear structures, unlike the branched intron products in the other two cases. See P. A. Sharp, 1987, Science 235:769.

After pre-tRNAs are processed in the nucleoplasm, the mature tRNAs are transported to the cytoplasm through nuclear pore complexes by exportin-t, an exportin dedicated to the nuclear export of tRNAs. In the cytoplasm, tRNAs are passed between aminoacyl tRNA synthetases, elongation factors, and ribosomes during protein synthesis. Thus tRNAs are generally associated with proteins and spend little time free in the cell, as is also the case for mRNAs and rRNAs.

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مواضيع ذات صلة

Self-Splicing Group I Introns Were the First Examples of Catalytic RNA

Small Nucleolar RNAs Assist in Processing Pre-rRNAs

Pre-rRNA Genes Function as Nucleolar Organizers

Localization of mRNAs Permits Production of Proteins at Specific Regions Within the Cytoplasm

Surveillance Mechanisms Prevent Translation of Improperly Processed mRNAs

Sequence-Specific RNA-Binding Proteins Control Translation of Specific mRNAs

Protein Synthesis Can Be Globally Regulated

Cytoplasmic Polyadenylation Promotes Translation of Some mRNAs

RNA Interference Induces Degradation of Precisely Complementary mRNAs

Alternative Polyadenylation Increases miRNA Control Options

Micro-RNAs Repress Translation and Induce Degradation of Specific mRNAs

Degradation of mRNAs in the Cytoplasm Occurs by Several Mechanisms