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CiteWeb id: 19890000142

CiteWeb score: 3336

The small (40S) subunit of eukaryotic ribo- somes is believed to bind initially at the capped 5'-end of messenger RNA and then migrate, stopping at the first AUG codon in a favorable context for initiating translation. The first-AUG rule is not absolute, but there are rules for breaking the rule. Some anomalous observations that seemed to contradict the scanning mechanism now appear to be artifacts. A few genuine anomalies remain unexplained. T HE scanning mechanism for initiation of translation in eukaryotes was proposed 10 years ago (112). Support- ing evidence has accumulated at a slower rate than one might have wished, but a trickle sustained over 10 yr forms a decent-sized pond. Some remarkable experiments now be- ing carried out in yeasts are yielding important new insights about scanning and other aspects of initiation, and the power of the yeast system promises additional breakthroughs in the coming years. Thus, it seems a good time to review what we've learned so far about how eukaryotic ribosomes select a particular AUG codon as the start site for translation. Evidence from Higher Eukaryotes The scanning model states that the 40S ribosomal subunit (carrying Met-tRNA~ me, and various initiation factors) binds initially at the 5'-end of mRNA and then migrates, stopping at the first AUG codon in a favorable context for initiating translation. The model thus posits that both position (prox- imity to the 5'-end) and context contribute to selection of the initiation site. The simplest evidence of the importance of position is that the "first-AUG rule" holds for some 90-95 % of the hundreds of vertebrate mRNA sequences that have been analyzed (127). A detailed discussion of position ef- fects, along with an explanation for the 5-10% deviation from the first-AUG rule, will follow after a brief introduction to the context requirements for initiation. From a recent survey of 699 vertebrate mRNAs (127), GCCGCC~CCAUGG emerged as the consensus sequence for initiation in higher eukaryotes, confirming and extending previously noted trends (117, 120). Site-directed mutagenesis experiments in which the expression of a cloned preproinsu- lin gene was monitored in transfected COS cells have confirmed the importance of G +4 as well as each of the con- sensus nucleotides from position -1 through -6 (122, 126)'. The importance of context was demonstrated by tar- geting mutations to the vicinity of the AUG initiator codon for preproinsulin as well as by targeting an upstream, out-of- 1. Numbering begins with the A of the AUG codon as position +1; nucleo-

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