Why drug discovery is so hard: reason #20 — competitive endogenous RNAs

The chemist will appreciate le Chatelier’s principle in action in what follows.  We are far from knowing all the players controlling cellular behavior.  So how in the world will we find drugs to change cellular behavior when we don’t know all the things affecting it.  The latest previously unknown cellular player to enter the lists are competitive endogenous RNAs (ceRNAs).  For details see Cell vol. 147 pp. 344 – 357, 382 – 395 ’11.   The background the pure chemist needs for what follows can all be found in the category “Molecular Biology Survival Guide.

Recall that microRNAs are short (20 something) polynucleotides which bind to the 3′ untranslated region (3′ UTR) of mRNA, and either (1) inhibit its translation into protein (2) cause its degradation.  In each case, less of the corresponding protein is made.  The microRNA and the appropriate sequence in the 3′ UTR of the mRNA form an RNA-RNA double helix (G on one strand binding to C on the other, etc.). Visualizing such helices is duck soup for a chemist.

Molecular biology is full of such semantic cherry bombs as nonCoding DNA (which meant DNA which didn’t cord for protein), a subset of Junk DNA.  Another is the pseudogene — these are genes that look like they should code for protein, except that they don’t because of lack of an initiation codon or a premature termination codon.  Except for these differences, they have the nucleotide sequence to code for a known protein.  It is estimated that the human genome contains as many pseudogenes (20,000) as it contains true protein coding genes [ Genome Res. vol. 12 pp. 272 – 280 ’02 ].  We now know that well over half the genome is transcribed into mRNA, including the pseudogenes.

PTEN (you don’t want to know what it stands for) is a 403 amino acid protein which is one of the most commonly mutated proteins in human cancer.  Our genome also contains a pseudogene for it (called PTENP).  Interestingly deletion of PTENP (not PTEN) is found in some cancers.  However PTENP deletion is associated with decreased amounts of the PTEN protein itself, something you don’t want as PTEN is a tumor suppressor.  How PTEN accomplishes this appears to be fairly well known, but is irrelevant here.

Why should loss of PTENP decrease PTEN itself?  The reason is because the mRNA made from PTENP, even though it has a premature termination codon, and can’t be made into protein, is just as long, so it also contains the 3’UTR of PTEN.  This means PTENP is sopping up microRNAs which would otherwise decrease the level of PTEN.  Think of PTENP mRNA as a sponge.

Subtle isn’t it?  But there’s far more.  At least PTENP mRNA closely resembles the PTEN mRNA.   However other mRNAs coding for completely different proteins, also have binding sites in their 3’UTR for the microRNA which binds to the 3UTR of PTEN, resulting in its destruction.   So transcription of a completely different gene  (the example of ZEB2 is given)  can control the abundance of another protein.  Essentially its mRNA is acting as a sponge, sopping up the killer microRNA.

It gets worse.  Most microRNAs have binding sites on the mRNAs of many different proteins, and PTEN itself has a 3’UTR which binds to 10 different microRNAs.

So here is a completely unexpected mechanism of control of protein levels in the cell.  The general term for this is competitive endogenous RNA (ceRNA).    Two years ago the number of human microRNAs was thought to be around 1,000.  Unlike protein coding genes, it’s far from obvious how to find them by looking at the sequence of our genome, so there may be quite a few more.

So most microRNAs bind the 3’UTR of more than one protein (the average number is unclear at this point), and most proteins have binding sites for microRNAs in their 3’UTR (again the average number is unclear).  What a mess.  What subtlety.  What an opportunity for the regulation of cellular function.  Who is going to be smart enough to figure out a drug which will change this in a way that we want.  Absence of evidence of a regulatory mechanism is not evidence of its absence.  A little humility is in order.

9 Feb ’12 — my wife just sent me the following quote “Nature does nothing uselessly”  — Aristotle

For a list of the other 19 reasons and links please see https://luysii.wordpress.com/2011/11/21/a-new-category/

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