11.3: RNA Editing

RNA editing is a post-transcriptional modification where a precursor mRNA (pre-mRNA) nucleotide sequence is changed by base insertion, deletion, or modification. The extent of RNA editing varies from a few hundred bases, in mitochondrial DNA of trypanosomes, to a just single base, in nuclear genes of mammals. Even a single base change in the pre-mRNA can convert a codon for one amino acid into the codon for another amino acid or a stop codon. This type of re-coding can significantly affect the structure and function of a protein and may lead to the production of multiple variants of a protein from a single gene.

Insertional and Deletional RNA Editing

Insertional and deletional RNA editing involves the addition and deletion of specific nucleotides or sequences of nucleotides from pre-mRNA. In RNA editing in the mitochondria of some pathogenic trypanosomes, hundreds of noncoding uridines are added and specific uridine residues are deleted from the pre-mRNA. These additions and deletions are performed by an enzyme complex, called the editosome. The editosome is guided by a special RNA transcript known as guide RNA (gRNA). gRNA attaches to the target pre-mRNA region with the help of a complementary anchor sequence, which is 10-15 nucleotides long. gRNA also has a template sequence that instructs the editosome as to the location and number of uridine residues to be added or deleted in the pre-mRNA. More than 50% of the mitochondrial RNA of some trypanosomes is formed by the addition of uridine residues.

Substitutional RNA Editing

Substitutional RNA editing by base modifications is observed In higher eukaryotes, where the base is modified without changing the length of the pre-mRNA. In vertebrates, deamination reactions involving adenosine and cytidine are the most common type of RNA editing. Adenosine is deaminated to inosine by a single enzyme known as adenosine deaminase acting on RNA (ADAR). To recognize the editing site, ADAR needs a double-stranded RNA structure formed between the target region and the downstream complementary intron region of the pre-mRNA. There are three types of ADAR enzymes found in vertebrates. ADAR1 and ADAR2 enzymes are found in various tissues whereas ADAR3 is specific to the brain of some species. Another less common type of RNA editing is observed in the ApoB gene of mammals where cytidine is modified to uridine. This is accomplished by a complex of enzymes including apolipoprotein B mRNA editing enzyme catalytic polypeptide 1 (APOBEC1). Though RNA editing is a relatively rare phenomenon in vertebrates, defects in the process can cause several diseases associated with the central nervous system, such as amyotrophic lateral sclerosis, epilepsy, depression, and schizophrenia.

RNA editing is a process where a nucleotide sequence in precursor, or pre-mRNA, is changed after transcription. It allows an organism to produce different forms of a protein without altering the DNA sequence.

mRNA editing in vertebrates is the result of site-specific base deamination, a reaction where an amino group is removed from a nitrogenous base, adenine or cytosine.

When adenosine is deaminated, it is converted to inosine. Inosine closely resembles guanosine and can trick the translation machinery into reading inosine as guanosine. 

This reaction is the most common type of RNA editing in animals and is catalyzed by the enzyme, adenosine deaminase acting on RNA or ADAR.

The ADAR recognizes a pre-mRNA hairpin loop formed at an exon-intron junction and edits a specific adenine present on the exon.   

In vertebrates, ADAR edits the pre-mRNA of the glutamate receptor. A specific C-A-G codon is modified to C-I-G, which is then read as C-G-G by the ribosome. This substitution replaces a glutamine with an arginine in the final protein.

The second type of mRNA editing occurs when cytidine is deaminated to uridine.  The editing of the apolipoprotein B pre-mRNA is a well-studied example. 

There are two types of apolipoprotein B – the larger, liver-specific ApoB-100 and the smaller, intestine-specific ApoB-48.  

The same pre-mRNA encodes both proteins; however, an intestine-specific complex of enzymes acts on a specific cytosine near the middle of the pre-mRNA turning a CAA codon into UAA, a stop codon.

This results in the truncated ApoB-48 protein being produced in the intestine, whereas the unaltered apolipoprotein B pre-mRNA produces the full-length ApoB-100 protein in the liver.