The Sceptical Chymist | Chemiotics: The further uses of redundancy

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Remember noncoding DNA? For protein that is. That’s 98% of our genome. It now appears that at least half of our genome is transcribed into RNA. Is this a case of transcription machinery gone wild? One type of RNA made from the 98% is called microRNA (after it is cut from a larger precursor). MicroRNAs are only 21-23 nucleotides long. They aren’t used to make proteins (which would be at most 7 amino acids long anyway). Instead they bind to complementary sequences in messenger RNA by classic Watson-Crick base pairing, and inhibit the translation of the mRNA into protein by the ribosome. So although microRNAs don’t code for proteins, they help determine how much of them are made.

Until recently, microRNA binding to mRNA was thought to occur at the tail end (which does not code for protein). Two recent papers show that microRNAs also bind to the amino acid coding sequences of some proteins [Nature vol. 455 pp. 1124-1128, 2008 and PNAS vol. 105 pp. 20297-20302, 2008]. Change one synonymous codon to another, and the microRNA no longer binds and the level of the protein changes. So this is the third code written into our DNA.

What’s so remarkable about that? Pop a DVD of a movie into a player. You are given choices of subtitles, language, etc… All these modalities are coded on separate tracks and blended together by the player after you choose. DNA is just one track and is coding for subtitles, sound and pictures by the same sequence of nucleotides. A given DNA sequence is capable of being read at least 3 ways — amino acid, exonic splicing enhancers and inhibitors, and microRNA — (and who’s to say that these are the only ways DNA can be read).

The examples in the Nature paper are far from trivial as they involve Nanog, Sox2 and Oct4. So what? These three genes are crucial for stem cell function, and with a fourth have been used to transform normal cells into ‘stemlike’ cells (induced pluripotent cells — iPSs). What could be sexier than that? MicroRNA-control of these proteins has to be important.

There has recently been a good deal of interest in diversity oriented synthesis of small molecules — see [Nature vol. 457 pp. 153-154, 2009] and the ‘In the Pipeline’ blog post of 20 Jan, along with the more than 40 comments it brought forth. The hope is to create a wider variety of small molecules which can interact with proteins than we’ve been used to — and which might be useful drugs.

Turn the problem on its head and give it a twist. How could you use an RNA sequence to make a polynucleotide which interacts with the small molecule of your choice? RNA isn’t a very promising starting material. It’s highly negatively charged because of the phosphates, so to bind to anything anionic, positive counterions would be needed. Not much functionality either, a vicinal diol on the ribose, some pi-electron systems, the phosphodiester, an amine, a ketone (and the tautomers), some nitrogens and oxygens here and there. No carboxylic acids, not even a methyl group.

How would you find an RNA sequence specific enough to bind just to a single small molecule, say thiamine, or B12 and nothing else in the complicated chemical soup of the cell. A tough problem, definitely. Not to worry — nature has solved it, and uses the solution (called a riboswitch) to control protein expression in the cell. Most riboswitches have been found in bacteria, but some have been found in fungi and plants. Riboswitches are found in mRNA before the part which codes for protein. The RNA of the riboswitch undergoes a huge conformational change on binding the small molecule, controling whether a protein is made or not. So this is a fourth type of code in DNA — reversible RNA conformation on ligand binding. Unlike the other 3 codes, it probably is only read in the context of itself (unlike the synonymous codons which can be read 3 ways).

Well, if RNA sequences can be arranged so they change conformation on binding a small molecule, then it is at least possible that small molecules (which get into cells much more easily than anything else) can be found which alter the conformation of RNAs — such as microRNAs. This is basically an entirely unexplored field of chemistry. In contast, we’ve been throwing small molecules at proteins, proteins at polynucleotides and studying the results for decades.

Why would you want to throw a small molecule at a microRNA? It’s early times, but it seems clear most microRNAs control the levels of many proteins. Moreover, the proteins controlled usually have related functions in the cell. In this sense the microRNA can be considered the cellular analogue of the bacterial operon, which usually controls many of the enzymes in a given biosynthetic pathway. Our genome codes for at least 500 different microRNAs, and the physiologic effects of knocking different ones out (or overexpressing them) are quite different, just as mutations in different genes produce radically different effects.

MicroRNAs are drugable targets, largely unexplored, and sure to be a field day for the organic chemist, physical chemist and biochemist. I wouldn’t have thought it possible to even consider this possibility, if nature hadn’t shown us that it can be done with the riboswitch. Sorry Einstein, ‘the old one’ wasn’t a mathematician or a physicist, he was a chemist.

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