In our earlier episodes, we covered the fascinating journey of information from DNA to proteins through RNA. Let's explore one of the changes that RNA undergoes during this voyage. We have likened DNA to scripts, being read into RNA acting both as messages as well as the messengers of the information, finally ending up in the creation of proteins. But imagine if RNA gets a little playful and edits the message from DNA a little, all for a greater purpose, of course!
RNA is very faithful with the information that it is entrusted with and such instances where a few nucleotides in the RNA get edited such as A-to-I (Remember the nucleotides we briefly talked about in our first episode!) , is often extremely limited in humans and many other mammals. However, cephalopods or octopus, cuttlefish etc. are notorious for extensive RNA editing.
While a typical mammal edits RNA at a few hundred sites, the squid makes some 57,000 such edits with the number increasing to 80,000 - 130,000 in cuttlefish and octopus.
But what unique powers does it lend to creatures like octopus? Well I am sure once in your life you must’ve heard about Octopus having eight brains or being extremely intelligent. One hilarious short reel I saw on instagram showed an octopus randomly hitting a fish out of boredom. Not only this there are many behaviours exhibited by these creatures which simply can’t be expected out of an average aquatic being. Some scientists find octopus startlingly stranger even more than the sci-fi aliens. You guessed it right! This high intellect is often hypothesized to be a result of RNA editing. Another strong evidence to believe that cephalopods are leveraging RNA editing indeed, it has stayed largely unaltered or well preserved over the course of millions of years among many cephalopods. It has been proved that this editing has been playing a major role in putting together the nervous system in these creatures.
By changing their RNA instead of DNA they are at a big advantage - from the same gene they could make different proteins, responding much quickly to shifts in temperatures. The best part is these changes are like a switch, conveniently flipped on or off circumstantially and are temporary. They instead have gone to far greater extents to keep their DNA preserved and stagnant as when it produces RNA, there are several cues embedded in the sequences which guide the RNA editing enzymes to these single nucleotide - ‘A’ and edit it. This enzyme has a name - ADAR.
What if humans somehow increased the levels of A-to-I editing in them, could we all be as smart as Bill Gates or Daniel Golman? Well it has quite different implications in humans.
Increased levels of RNA editing have been found to correlate with enhanced tumor formation in cancer. RNA forming multiple proteins are direct candidates of ADAR1 and this process often ends up in introduction of a unit in the protein which is associated with cancer development. It has also been associated with neurological diseases. However, as mentioned above there still are a few hundred sites that exist in humans and other organisms. What roles do these sites play then?
These ‘just enough’ sites regulate some of the biological processes. Studies in animal models (Drosophila and mice) implicated ADARs and A-to-I editing post-transcriptionally regulates circadian rhythm and sleep. ADAR1 deficiency in Drosophila led to constitutive release of neurotransmitters in glutamatergic neurons promoting sleep. During development and normal function, RNA editing acts as a regulator of neurotransmission and signal transduction by editing many neuronal receptor subunits at making them impermeable to Ca2+, whilst regulating Ca2+ influx; a prerequisite for normal neuronal function.
RNA editing is also being talked about as a potential editing tool in diseases such that it could allow clinicians to make temporary fixes that eliminate mutations in proteins, halt their production or change the way that they work in specific organs and tissues. This can be likened to the DNA editing tool widely used in the field today - CRISPR. Because cells quickly degrade unused RNAs, any errors introduced by a therapy would be washed out, rather than staying with a person forever. ADARs (especially ADAR1 isoforms) target RNA viruses like measles virus, influenza A virus, lymphocytic choriomeningitis virus (LCMV) and hepatitis C virus (HCV) by A-to-I hypermutation. However, they also exhibit a significant degree of proviral effects.
Hence, it has crucial roles in other organisms but the extent to which cephalopods have utilized this process to increase adaptability is unparalleled.
References:
Christofi, T., Zaravinos, A. RNA editing in the forefront of epitranscriptomics and human health. J Transl Med 17, 319 (2019). https://doi.org/10.1186/s12967-019-2071-4
Sara Reardon, Step aside CRISPR, RNA editing is taking off. Nature article (2020) https://www.nature.com/articles/d41586-020-00272-5
Kung, Maggi Jr, Webber The Role of RNA Editing in Cancer Development and Metabolic Disorders (2018) https://doi.org/10.3389/fendo.2018.00762
https://www.theatlantic.com/science/archive/2017/04/octopuses-do-something-really-strange-to-their-genes/522024/
N. Liscovitch-Brauer, S. Alon, H. T. Porath, B. Elstein, R. Unger, T. Ziv, A. Admon, E. Y. Levanon, J. J. C. Rosenthal, E. Eisenberg,Trade-off between transcriptome plasticity and genome evolution in cephalopods. Cell169,191–202.e11 (2017).
Octopuses and squids can rewrite their RNA. Is that why they’re so smart? https://www.independent.co.uk/news/science/octopuses-and-squids-can-rewrite-their-rna-is-that-why-they-re-so-smart-a7688431.html
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