Skilful Squid Can Edit Their Own Genetic Instructions

A new study published in Nucleic Acid Research outlines the discovery that squid are able to "edit" their messenger RNA (mRNA) to an astonishing degree – several orders of magnitude more than humans. 

"Rocking" the central dogma

In simplistic terms, the classic central dogma of biology outlines the coordinated passing of genetic information from DNA to messenger RNA (mRNA) which leads to the downstream synthesis of proteins, the cellular "machines" that determine a cell, tissue or organism's physiology.

Biochemical changes can occur as this process moves through the "RNA stage", known as RNA editing. The most commonly occurring form of RNA editing in multicellular organisms is hydrolytic deamination (the removal of the amino group) of the adenosine to form the nucleoside inosine, A – I; catalyzed by the ADAR enzyme family.

This process was thought to be a nuclear reaction, i.e., it only occurs in the nucleus. Whilst mRNAs and their encoding proteins can be sorted between cellular regions, the information itself was believed to remain the same.

Scientists at the Marine Biological Laboratory (MBL), Woods Hole, in collaboration with researchers at Tel Aviv University and The University of Colorado, have found evidence that "rocks" the central dogma. Their research suggests that ADAR2 is expressed outside of the nucleus in squid (Doryteuthis pealeii) neurons.

Squid can modify RNA out in the periphery of the cell

"We thought all the RNA editing happened in in the nucleus, and then the modified messenger RNAs are exported out to the cell," says Joshua Rosenthal, senior author of the study.

The data from the study suggests that region-specific RNA editing can occur in the axons of the squid, the slender portion of a nerve cell that transmits electrical impulses to other neurons.

"Now we are showing that squid can modify the RNAs out in the periphery of the cell. That means, theoretically, they can modify protein function to meet the localized demands of the cell. That gives them a lot of latitude to tailor the genetic information, as needed," Rosenthal adds.

Their suggestion is based on the following findings in the study:

• SqADAR2 protein is present in the cytoplasm of nerve cell bodies in both the stellate gallion of the peripheral nervous system and the optic lobe of the central nervous system
  
  
• Axoplasm from the giant axon can catalyze the hydrolytic deamination of A→I in a perfect RNA duplex
  
  
• Axoplasm from the giant axon can catalyze site-specific RNA editing in a squid K+ channel substrate
  
  
• RNA editing at known sites is generally higher in the giant axon than its cell bodies. Editing almost certainly occurs in the nucleus as well

In the discussion portion of the paper, the authors do note that, due to the expression of SqADAR2 in many nuclei across the regions of the nervous system in the study, the possibility that all editing occurs in the nucleus, and that edited messages get preferentially sorted to the axon, cannot be excluded. They comment, "However, it seems unlikely that this mechanism could fully explain the observed differences in the editing patterns, given that axoplasm has active A→I conversion activity."

It's possible that the natural RNA editing process that seems to be taking place in squid could be harnessed for biotherapeutic applications. There are several disorders of the nervous system in humans that are characterized by axon dysfunction.

The scientists nod to the fact that this research may also open doors to further examination in different organisms: "Does extranuclear recoding occur in other organisms? ADAR localization has only been examined in a few cases, under a small number of experimental conditions," they add in their discussion.

Reference: Isabel C. Vallecillo-Viejo, et al. (2020) Spatially regulated editing of genetic information with a neuron. Nucleic Acids Research. doi: 10.1093/nar/gkaa172