RNA :: Génétique Le Début

 

RNA  ::  The Ancestor of DNA

DNA contains the instructions for the building and functioning of not only our bodies but also those of most organisms. In some primitive organisms (prokaryotes), like bacteria, though, one will not find DNA. 

So then, what transmits the genetic information for such ancient organisms? 

A single strand, or maybe two, of RNA (RiboNucleic Acid). 

An illustration of an RNA molecule under a microscope

RNA, along with DNA, forms a dynamic duo, reputed for being the only known molecules that are able to transmit genetic information (called nucleic acids). It is the only known nucleic acid that can exist as a single strand, and also as a double strand. Its essential structure is similar to that of DNA :: nucleotides, which are units comprising a nitrogenous base, a sugar (ribose), and a phosphate group, connected through the phosphate group, through a phosphodiester bond (such a name is due to the analogy it draws to the structure of esters as shown below). 

An ester (on the left side) and a phosphate ester (right side) ; Both are essentially negatively charged radicals derived from carboxylic acids and phosphoric acid attached to a separate group. 

However, there are tangible differences between RNA and DNA. 

First, and foremost, have you noticed that DNA is essentially RiboNucleic Acid, but with a 'deoxy-' suffix? This suffix signifies an important structural difference. 

As seen in the picture below, the ribose sugar, found in RNA, contains '-OH' groups at the 2' and 3'- carbons (numbering is anticlockwise from the right). But deoxyribose, the analogue of ribose in DNA, lacks the 2' -OH group. 

The sugars found in DNA (left) and RNA (right) respectively; the difference is

highlighted in red.

Meanwhile, we had talked about how DNA possesses four nitrogenous bases :- Adenine (A) and Guanine (G) (purines) and Cytosine (C) and Thymine (T) (pyrimidines). In RNA, instead of thymine, uracil (U) is found. 

This, while makes the molecule far more reactive and unstable, also allows for rapid mutations (changes in the original genome) which increases the rate of evolution of organisms eg:- RNA viruses like COVID-19. 

Why was it so hard to weed out the virus in its first wave back in 2020? 

How did it strike back so hard in 2021? 

Of course, the rapid mutations in a small fragment of viral RNA.  

For those interested to know more details, the viral RNA was 29,860 base pairs long and the mutation occurred in the "K" (spike) gene, which was responsible for the way it interacted with proteins inside a human cell. 

It modified the spike proteins, which are responsible for the way the virus enters human cells and affects its response to the immune system; in this case it increased its ability to evade our immune system. To be precise, at exactly the 452 nd position (from 5' -> 3'), a thymine (T) base was replaced with a guanine (G) base, which resulted in a change in the amino acid produced (L452G; leucine (L) became glycine (G)). 

I have explained about amino acids in short, in my blog on Molecular Genetics. Read at your leisure!

TYPES OF RNA

Unlike DNA, which has a very similar skeletal structure across all organisms, there are multiple types of RNA, based on their function. The major types of RNA molecules are :- tRNA (transfer RNA), mRNA (messenger RNA) and rRNA (ribosomal RNA). 

Transfer RNA (tRNA)

tRNA (transfer RNA) is mainly important for the transportation of amino acids to ribosomes during the process of translation. It is a single-stranded RNA, composed of three complete loops and an open loop, much like an incomplete four-leaf clover leaf. The three complete loops have different functions :- the "D" loop, also called the 'aminoacyl synthetase' loop, is used for the binding of the enzyme, aminoacyl synthetase, which is vital in the process of 'charging' of tRNA i.e. it makes the molecule capable of accepting the amino acid at the 3'- site (notice the 5'- CCA-3' segment on the open loop at the top end), before detaching from the loop after the formation of the amino acid- tRNA complex. This allows the tRNA to carry the amino acid to the ribosome, where the amino acid is transferred to an existing protein chain, through the process of translation. This process has been explained in detail in the blog on Molecular Genetics.

Illustrations of tRNA :- (Top) AA-tRNA complex; (Bottom) The different loops of tRNA

Messenger RNA (mRNA)

mRNA (messenger RNA) is the molecule that is responsible for carrying the information, about the polypeptide chain to be created in the ribosome. It is formed through the process of transcription, which, along with translation, I have elaborated upon in my blog on Molecular Genetics. It is transported throughout the body in, essentially, fat droplets called 'lipid nanoparticles', to allow its entry into the lipid-based cell membrane by decreasing its overall polarity and attraction to water molecules (hydrophilicity). It is, arguably, one of the most important molecules in the entire living world, as it is the blueprint for the proteins that determine what we become, our natural lifespan and many other important traits. Based on the number of programmable units, called 'cistrons', each of which constitutes one protein chain, there are two types :- monocistronic mRNA, which codes for one protein only and is found in eukaryotes, and polycistronic mRNA, which codes for multiple proteins and is found only in prokaryotes.

 An illustration of monocistronic (top)  and polycistronic (bottom) mRNA

 

Ribosomal RNA (rRNA)

rRNA (ribosomal RNA) is a non-coding nucleic acid that forms the two main subunits of ribosomes, the 'coding experts' that read mRNA molecules and summon the adapters of amino acids which are the tRNA molecules. It is the most stable type of RNA, which facilitates the binding of mRNA and tRNA during the process of translation by providing their respective sites. We could say, then, that rRNA acts like an enzyme, which provides binding sites to substrate molecules and processes them to form the final product, the polypeptide chain. We do have a term for that, "ribozyme". 

There are four types of eukaryotic rRNA :- 5S, 5.8S, 18S and 28S, which are synthesized by RNA polymerase type III. This classification is based on the size of the subunit of rRNA, where the 'S' stands for 'Svedberg constant', which is a measure of the time it takes for these particles to settle to the bottom of a flask during centrifugation. The larger the constant, the faster it sediments and is hence indicative of a larger, denser subunit. 

WHY DOES RNA PREFER TO BE A BACHELOR ?

RNA can be single-stranded or double stranded, while DNA is always double-stranded. It is not unusual for this question to arise; after all, DNA can never exist as a single strand, and RNA has a very similar structure. There are a few reasons for that.

We know that nitrogenous bases, more precisely adenine with thymine and cytosine with guanine, form complementary hydrogen bonds with each other. It can also happen that in a single strand, two complementary bases, found relatively close to each other, can form bonds, causing the strand to close on itself, forming stable structures such as loops and hairpins, which decreases the reactivity of single-stranded RNA. The stability is determined thermodynamically and sterically (the bulkiness of a chemical group; the more bulky group, the less stable its pairing with another group). 

The single-stranded nature allows for greater rate of mutations, due to its reactivity and exposure, which was required in the extreme conditions of Earth, for adaptating to the rapidly changing conditions on Earth, around a few million years after it was formed. 

An illustration of a single-stranded RNA molecule; notice the loop and H-bonds within the loop

DNA, hypothetically, can form as single-stranded molecules, specifically hairpins. This has been used as an efficient vector in gene therapy. However, it has been observed that, compared to a hairpin structure, the double helix is thermodynamically favoured, due to its greater stabilty and more hydrogen bonding. It is also more efficient, as it can carry more genetic information in a smaller region, over a longer term. In contrast, the hairpin lasts for a shorter period of time, which is not favoured as most organisms with DNA are multicellular and require mutations only over a longer period of time. 

CONCLUSION

From this blog, it can be understood that RNA is a remarkable, underappreciated molecule that plays a vital role in the intricate machinery of life. It plays an instrumental role in protein synthesis, which controls gene regulation and, hence, what we become. Its potential therapeutic applications are currently being explored, which will be covered in a future blog. But that's it from my side, for now. And I will see you in the next one!!