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Despite a recent surge of reports about how microRNAs might regulate translation, the question has not been answered. The proposed mechanisms contradict one another, and none is supported by strong evidence. This review explains some deficiencies in the experiments with microRNAs. Some of the problems are traceable to bad habits carried over from older studies of translational regulation, here illustrated...
Some popular ideas about translational regulation in eukaryotes have been recognized recently as mistakes. One example is the rejection of a long-standing idea about involvement of S6 kinase in translation of ribosomal proteins. Unfortunately, new proposals about how S6 kinase might regulate translation are based on evidence that is no better than the old. Recent findings have also forced rejection...
Real progress in understanding translational regulatory mechanisms lags behind the claims of progress. Novel mechanisms were proclaimed in recent months for some important regulatory proteins from Drosophila (e.g. Bruno, Sex-lethal, Reaper), but the evidence is thin. Many flaws in the design and interpretation of new experiments can be traced to older experiments which came to be accepted, not because...
The mechanism of initiation of translation differs between prokaryotes and eukaryotes, and the strategies used for regulation differ accordingly. Translation in prokaryotes is usually regulated by blocking access to the initiation site. This is accomplished via base-paired structures (within the mRNA itself, or between the mRNA and a small trans-acting RNA) or via mRNA-binding proteins. Classic examples...
The belief that initiation of translation requires communication between the 5′ and 3′ ends of the mRNA guides—or misguides—the interpretation of many experiments. The closed-loop model for initiation creates the expectation that sequences at the 3′ end of eukaryotic mRNAs should regulate translation. This review looks closely at the evidence in three prominent cases where such regulation is claimed...
Translation of some mRNAs is postulated to occur via an internal initiation mechanism which is said to be augmented by a variety of RNA-binding proteins. A pervasive problem is that the RNA sequences to which the proteins bind were not rigorously proven to function as internal ribosome entry sites (IRESs). Critical examination of the evidence reveals flaws that leave room for alternative interpretations,...
Selection of the translational initiation site in most eukaryotic mRNAs appears to occur via a scanning mechanism which predicts that proximity to the 5′ end plays a dominant role in identifying the start codon. This ‘position effect’ is seen in cases where a mutation creates an AUG codon upstream from the normal start site and translation shifts to the upstream site. The position effect is evident...
Some diseases are caused by mutations that perturb the initiation step of translation by changing the context around the AUGSTART codon or introducing upstream AUG codons. The scanning mechanism provides a framework for understanding the effects of these and other structural changes in mRNAs derived from oncogenes, tumor suppressor genes, and other key regulatory genes. In mRNAs from mutated as well...
The validity of the scanning mechanism for initiation of translation has been questioned based on a compilation of human cDNA sequences that showed a high frequency of upstream ATG codons. However, closer scrutiny of those cDNAs upholds the opposite view: the 5′UTRs on most cDNAs are compatible with standard rules for initiation of translation, and those rules can be used to flag anomalous cDNAs that,...
The mechanisms whereby ribosomes engage a messenger RNA and select the start site for translation differ between prokaryotes and eukaryotes. Initiation sites in polycistronic prokaryotic mRNAs are usually selected via base pairing with ribosomal RNA. That straightforward mechanism is made complicated and interesting by cis- and trans-acting elements employed to regulate translation.Initiation sites...
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