excerpt from recent paper by Bruce Futcher and colleagues:

"Monkey on a Typewriter

What is the point of having an RNA binding protein that slightly destabilizes hundreds or thousands of mRNAs via a frequently-occurring four or five nucleotide motif? It is natural to suppose that such an RNA binding protein might be used to co-ordinately regulate its targets, and this might be true. However, in the case of Whi3 and its targets, it is not easy to ascribe any overall function to the target mRNAs, and furthermore, despite some recent progress suggesting Whi3 could be regulated by phosphorylation [20], [59] (Cai and Futcher, unpublished), there is no clear idea of when and how Whi3 activity is regulated, if indeed it is regulated at all. Furthermore, other investigations of yeast RNA binding proteins and their targets have likewise found an enormous number of targets for many of the RNA binding proteins, with no readily definable overall function for these targets. Here, as a speculation, or perhaps just as a null hypothesis, we would like to state the “monkey on a typewriter” hypothesis, which is the opposite of the “co-ordinate regulation” hypothesis. One can imagine that each mRNA in the cell would have an optimum average half-life, and of course this would vary gene by gene, according to the function of the gene. But what is the mechanism by which one mRNA comes to have a different half-life from another? We suggest that if there is an array of different RNA binding proteins, and some of these increase half-life and some decrease half-life, and if each RNA binding protein recognizes a short motif of four or five nucleotides, then each mRNA can evolve to contain a set of short motifs targeting it to some subset of the RNA binding proteins such that, overall, the mRNA achieves its optimal half-life. In this hypothesis, the clients of a particular mRNA binding protein need have no common function, and need not be co-ordinately regulated. They are independently seeking their optimum half-life. One could say that the RNA binding protein “regulates” its client’s abundance, but over evolutionary time. The fact that the binding motifs are short is consistent with this hypothesis–the shortness of the motif is evidence that the RNA binding protein is not highly specific. (A monkey on a typewriter will only rarely produce “Hamlet”, but will often produce “GCAU”–particularly if the keyboard has only four letters!) The ARE hypothesis–that mRNAs are destabilized by very short AU-rich elements [16]–is a branch of this hypothesis."

A Wonderful poetic discussion from the always thoughtful Bruce Futcher. The aggregation of multiple weak effects to give rise to mRNA stability and translatability (could that be a word?!?) could explain why so few translational regulators show up in forward genetic screens. The geometric decrease in frequency down to only 4 bp means these regulators are largely binding everywhere, just not in the same amount. So, the effects have to be weak almost by definition. In contrast, TF binding is some much more specific so it can be strong giving over 10-fold increases by the binding of a single protein...

AuthorJan Skotheim