The SEC isn’t the only regulatory news: RNA Binding Proteins Are Extensive Regulators

RNAs have a reputation as the unemployed brother-in-laws of genetic molecules; sort of around all the time, but no one can figure out what they really do. The intellectually easy way is to think of them as mere intermediaries from DNA on the way to protein. No more. Big news: RNA regulation is big, important, and will have drug companies salivating. This is like discovering your unemployed brother in law actually is building Google in the garage all this time, and not just playing WoW.

nasty&remote” by crowjay (via Flickr, creative commons attribution license)

Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO (2008) Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an  extensive regulatory system. PLoS Biol 6(10): e255. doi:10.1371/journal.pbio.0060255
doi:10.1371/journal.pbio.0060255

Hogan et al, researchers from Stanford and  Switzerland, used yeast as a model system to study RNA binding proteins and post-translational genetic regulation. That means fooling with the DNA->RNA->protein system at the RNA level.  Molecular genetics at its wonkiest; strictly non-Mendelian at its core, and likely key in developmental/tissue specific protein expression.

Here’s what Hogan et al. found:

One, how do RNA binding proteins recognize RNA to bind to it? By consensus RNA sequences. RNAs, like the code of a computer program, have sequences which are found on a variety of RNAs, but are all similar enough to be recognized by the same RNA binding protein. (This isn’t that surprising, although it hasn’t been studied systematically); and,

Two, and this is the kicker, these consensus sequences are found in RNAs which encode proteins with similar biological functions. For instance, cell-wall modulating RNA/proteins had similar RNA-binding-protein-recognition-sites.  So, one RNA binding protein may bind all RNAs that encode proteins important for cell walls. More bluntly, let’s say you are a yeast cell and you want to bud: find the RNA binding protein that binds that consensus sequence on RNAs instrumental in budding. (I’m guessing – it’s an illustration).

If you are a drug company, what this means: R&D, start you engines. Make drugs targeted to the RNA consensus sequences (recognized by RNA binding proteins), or the RNA binding protein sites which recognize the consensus sequences on the RNAs.  Agonists, antagonists, reverse agonists, reverse antagonists – this is raw meat to a biopharma R&D department (assuming there are any R&D departments left, it may be left to academics and start ups).  The “-omics” groups are going to be parsing through all the libraries trying to find new RNA consensus sequences where the RNA binding proteins may bind, and figure out biological functions.

This is different from RNA interference molecules, I would think, in that the targeted function is not so much interfering with RNA, but interfering with RNA regulation. RNAi and siRNAs have had ups and downs as far as drug development, and RNA binding proteins and their corresponding consensus recognition sites may be the practical answer. (RNAis, I think, were found to cause a generalized immune response, at one point, and I haven’t really followed the research).

The key here seems to be selectivity — you probably want to target the cells, and control the timing. So, for instance, if you made an RNA binding molecule which is esterified, so that the RNA is turned off in the presence of an esterase (a typical pro-drug formulation), you may be able to target the RNA translation.  (That is, once the ester is knocked off, the RNA binding molecule can work to bind the RNA and prevent translation).  Perhaps hook that to an antibody-like molecule which recognizes the cell-surface marker of a particular kind of cell.

Or there are other ways to make antibody-like binding molecules (peptibodies, etc.) and derivatize those to modulate the delivery space and time.  Once you know what to shoot for, then you can take the arsenal of pharmaceutical drug delivery mechanisms and do the trial and error to figure out what works the way you want it to.

I would think AIDS and cancer would be big targets here, although very long term. Shorter term, how about a nice wrinkle cream, or a hair growth topical application? Non-reimbursables are the fastest growing area in biopharma, even in a bad economic climate.

Regulate your RNA, regulate the SEC, bah, it’s all the same.

From the Public Library of Science  press release :

Diverse RNA-Binding Proteins Interact with Functionally Related Sets of RNAs, Suggesting an Extensive Regulatory System

RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs.  Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. The authors identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 39-untranslated regions, others in 59-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

Citation: Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO (2008) Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an  extensive regulatory system. PLoS Biol 6(10): e255. doi:10.1371/journal.pbio.0060255
http://dx.plos.org/10.1371/journal.pbio.0060255

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