The Small Guys That Help Regulate Protein Synthesis

If you have an interest in cellular biology, the chances are you've come across the different types of nucleic acids that are used to code for proteins and control certain activities of the cell. However, what might be new to you is the existence of MicroRNA or miRNA, in its common notation. Essentially these are regular strands of RNA but very small - in fact a regular sized RNA molecule may be around 100 times longer than the average length miRNA. As miRNA are single stranded, the molecules tend to quite flexible, in contrast to the well known rigid DNA double helix molecule. Originally, scientists tended to believe that in eukaryotic cells at least, there were only two types of RNA: ribosomal RNA and messenger RNA. At first, miRNA were seen to be RNA that were too insignificant to have any real function, they were considered free clumps of nucleotides in short.

Now the importance of miRNA molecules has been realised, thanks to cutting edge research on a particular type of nematode worm - specifically Caenorhabditis elegans. In 1993, the first miRNA identified was named lin-4. What scientists found is that somehow, these minute molecules prevent the development of the larvae. 

After these baby steps into this field of research, the year 2000 saw the discovery of the miRNA molecule let-7. This was found to 'regulate development in C.elegans'. What was more significant however, was that this molecule could be found in all animal and plant cells. But what do we mean by 'regulate development'? This particular miRNA molecule is found to be responsible for controlling aspects of the cell cycle and cell differentiation. But healthy functioning cells doesn't rely on a single miRNA molecule - many different molecules working together ensure cellular processes go on as intended.

But how do miRNA's work?

In an average human cell, over 1000 different miRNA molecules can be found. Each of these specific strands seek to target a particular RNA molecule. With over 60% of RNA molecules being targeted by miRNAs, it could be said that controlling protein synthesis is a very organised and vast operation. What is important to note, is that miRNA molecules are encoded by genes, a lot like proteins in fact. It follows that these genes are present in the cell's DNA.

To synthesise miRNA, firstly one long strand of specially structured RNA is manufactured from miRNA genes. These could be considered the precursors of miRNA (Pri-miRNA) and are subsequently lysed by enzymes and transported from the nucleus, into the cytoplasm. Any two different  miRNAs can align through regular RNA-RNA hydrogen bonded base-pairing. However in some parts, there may be some non-complementary base pairing which would lead to bulges from the molecule. Using specific enzymes, the hydrogen bonds can be broken to leave two separate miRNA molecules which can go on to target their designated RNA molecule.

Due to inconsistencies in base pairing with an mRNA molecule, miRNAs have been found to inhibit protein synthesis by preventing the ribosome translating the RNA molecule. But another way miRNA's function is that they can achieve complete complementary base pairing with an mRNA molecule. Specific degrading enzymes can then recognise this situation and destroy the miRNA-mRNA complex, preventing the protein ever being synthesised.

(Two examples of pri-miRNA - sequences in red represent 'mature' miRNA. Notice there are bulges where there is no complementary base pairing - WIkipedia - microRNA)

Extended research has shown that 'malfunction of miRNAs is implicated in some liver diseases, diseases of the nervous system, cardiovascular disease, cancer and obesity'. One example given in the September issue of the Biological Sciences Review is miRNAs affecting normal nervous function. Individuals with mental retardation sometimes have whats called "fragile X syndrome", where as implied, the X chromosome tends to break easily. In association with this, it has been found that in the nerve cells of these individuals, miRNA molecules have prevented the synthesis of an essential protein by binding with mRNA.

Even miRNA has been believed to be the culprit in some cancers. It isn't always bad that an miRNA molecule binds to RNA - some miRNAs suppress tumour growth whilst others promote it.

At present, it may be difficult to see how miRNAs can be used to treat disease, but I believe there is no doubt that it could one day be widely use to diagnose them. Cancers are a good example. It has been observed that particular concentrations of a miRNA can correlate with different rates of growth of malignant tumours. From miRNA analysis, it may be possible for doctors to predict the best treatment options for patients.

However this does't mean treatment isn't possible! According to Professor Sheila Graham of the University of Glasgow, new research has revealed the potential of "miRNA sponges" in cells. These are non-functioning RNA molecules that "mop up" specific miRNA molecules so that they can't interrupt the synthesis of essential proteins.



Credit to Professor Sheila Graham for her article 'MicroRNAs - small players in big diseases' published in the Biological Sciences Review (Volume 27, Number 1).