Abstract
Earlier studies showed that the redundancy of ACG initiation codons enhanced the efficiency of translation initiation by 3- to 6-fold. Evidence presented here shows that this "redundancy effect" can be attributed to a favorable sequence context and, to a lesser extent, remedial initiation. In the case of redundant ACG initiator codons, the second ACG not only acts as a remedial initiation site for scanning ribosomes that skip the first ACG but also enhances the activity of the preceding initiator by providing a preferable "A" at its relative +4 position. Hence, non-successive ACG codons can be as effective as successive ACG codons in initiation, if positioned within a similar context. In contrast, redundant GUG initiation codons (GUG/GUG) bear an unfavorable "G" nucleotide at both the +4 and -3 positions relative to the first and second GUGs, respectively, such that redundant GUG codons act more poorly as translation initiation sites than does a single GUG with a favorable "A" nucleotide in the +4 position ( approximately 2.5-fold). Thus, the sequence context plays a much more important role than remedial initiation in modulating the efficiency of translational initiation from redundant non-AUG codons.
Highlights
Aminoacyl-tRNA synthetases are a group of primordial enzymes, each of which catalyzes the attachment of a specific amino acid to its cognate tRNAs
The mitochondrial form of the enzyme is translated from the first AUG on “long” mRNAs, while the cytosolic form is translated from the second AUG on “short” mRNAs, the 5Ј-ends of which are located between the first and second AUG initiator codons
In contrast to the scenario of ACG initiation, where redundancy of ACG initiation codons significantly enhances the translational efficiency, we present evidence that a redundancy of GTG initiation codons does not enhance the translational efficiency at all, but instead lowers the translational efficiency (Fig. 1)
Summary
ValRS, valyl-tRNA synthetase; aaRS, aminoacyltRNA synthetase; ADH, alcohol dehydrogenase; AlaRS, alanyl-tRNA synthetase; GlyRS, glycyl-tRNA synthetase; YPG, yeast extract-peptone-glycerol. Some reports have suggested that sequences immediately preceding the initiation codon may play a role in modulating the efficiency of AUG translation initiation in yeast, the magnitude of this context effect appears relatively insignificant (20 –22). Further studies showed that redundant ACGs contain stronger initiation activity than does a single ACG and can functionally substitute for the alternative AUG initiator codons of VAS1 (coding for mitochondrial and cytoplasmic isoforms of ValRS) in vivo. This feature of redundancy of non-AUG initiator codons may in itself represent a novel mechanism to improve the overall efficiency of a poor initiation event [29]. Our results suggested that a redundancy of non-AUG initiation codons does not always significantly enhance the translational efficiency and does so only when the first nucleotide of the initiation codons is an “A.”
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