RNA Editing

Occasionally researches encounter a gene with a sequence of nucleotides that does not match exactly that in its RNA product:

messenger RNA (mRNA) or
ribosomal RNA (rRNA) or
transfer RNA (tRNA)

If the product is mRNA, some of the codons in the open reading frame (ORF) of the gene specify different amino acids from those in the protein translated from the mRNA of the gene.

The reason is RNA editing: the alteration of the sequence of nucleotides in the RNA

after it has been transcribed from DNA but
before it is translated into protein

RNA editing occurs by two distinct mechanisms:

Substitution Editing: chemical alteration of individual nucleotides (the equivalent of point mutations).
These alterations are catalyzed by proteins that recognize a specific target sequence of nucleotides (much like restriction enzymes).
Insertion/Deletion Editing: insertion or deletion of nucleotides in the RNA.
These alterations are mediated by guide RNA molecules that
- base-pair as best they can with the RNA to be edited and
- serve as a template for the addition (or removal) of nucleotides in the target

Substitution Editing

Example: the human APO-B gene

Humans have a single locus encoding the APOB gene.

It contains 29 exons (separated by 28 introns).
The exons contain a total of 4564 codons.
Codon 2153 is CAA, which is a codon for the amino acid glutamine (Gln).
The gene is expressed in cells of both the liver and the intestine.
In both locations, transcription produces a pre-messenger RNA that must be spliced to produce the mRNA to be translated into protein.
Link to discussion of RNA processing.
In the Liver. Here the process occurs normally producing apolipoprotein B-100 - a protein, containing 4,563 amino acids, that is essential for the transport of cholesterol and other lipids in the blood.
Link to discussion of the role of apolipoprotein B-100 in cholesterol metabolism.
In the Intestine.
- In the cells of the intestine, an additional step of pre-mRNA processing occurs: the chemical modification of the C nucleotide in Codon 2153 (CAA) into a U.
- This RNA editing changes the codon from one encoding the amino acid glutamine (Gln) to a STOP codon (UAA)
- The modification is catalyzed by the enzyme cytidine deaminase that
  - recognizes the sequence of the RNA at that one place in the molecule and
  - catalyzes the deamination of C thus forming U
- Translation of the mRNA stops at codon #2153 forming apolipoprotein B-48 - a protein, containing 2152 amino acids that aids in the absorption of dietary lipids from the contents of the intestine.

B cells express another cytidine deaminase that is essential for both class switching and somatic mutation of antibody genes. Humans with disabling mutations in the gene for this enzyme produce only IgM antibodies. Whether this enzyme is acting as an RNA editing enzyme is not yet known.

Some other examples of substitution editing

Some mRNAs, tRNAs, and rRNAs in both the mitochondria and chloroplasts of plants
mRNAs encoding subunits of some receptors of neurotransmitters in the mammalian brain, e.g.,
- the AMPA receptor for Glu. [Link]
- a serotonin receptor
a tRNA in the mitochondria of the duckbill platypus
some mRNAs of HIV-1, the cause of AIDS.

Insertion/Deletion Editing

Example: the gene (in the mitochondria of Trypanosoma brucei) for one of the subunits of cytochrome c oxidase

Link to a view of mitochondrial genes.

Several genes encoded in the mitochondrial DNA of this species (the cause of sleeping sickness in humans) encode transcripts that must be edited to make the mRNA molecules that will be translated into protein.

Editing requires a special class of RNA molecules called guide RNA (gRNA).

These small molecules have sequences that are complementary to the region around the site to be edited.

The guide RNA base-pairs - as best it can - with this region.

(Note that in addition to the usual purine-pyrimidine pairing of C-G and A-U, G-U base-pairing can also occur.)

Because of the lack of precise sequence complementarity, bulges occur either

in the guide RNA where, usually, there are As not found in the transcript to be edited (as shown here) or
in the transcript to be edited.

The bulges are eliminated by cutting the backbone of the shorter molecule and inserting complementary bases.

In the first case (shown here) this produces insertions (here of Us)
In the second case (not shown) this produces deletions.

Note that in the example shown here, the insertion of 4 nucleotides has created a frameshift so that the amino acids encoded downstream (after Val) in the edited RNA are entirely different from those specified by the gene itself.

Some other examples of insertion/deletion editing

Insertion/deletion editing has also been found occur with

mRNA, rRNA, and tRNA transcripts in the mitochondria of the slime mold Physarum polycephalum.
in measles virus transcripts.

Why RNA Editing?

Good question. Some possibilities:

Perhaps it gives the cell an opportunity to try out slightly different versions of a protein without irrevocably abandoning the original version.
Perhaps it is an efficient way to create proteins with slightly different functions to use in specialized circumstances.
- The ability to synthesize two versions (with different functions) of apolipoprotein B from a single gene - as shown above - is an example. Note that in this case, RNA editing has accomplished the same result as alternative splicing.
- There is evidence that Drosophila uses editing to create subtle differences in the organization of neurons in its brain.

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6 November 2000