Why RNA editing exists at all is a mystery. One idea is that it arose in evolution to correct “mistakes” in the genome. Another is that it arose as a somewhat slapdash way for the cell to produce subtly different proteins from the same gene. A third possibility is that RNA editing originally evolved as a defense mechanism against retroviruses and retrotransposons and was later adapted by the cell to change the meanings of certain mRNAs. Indeed, RNA editing still plays important roles in cell defense. Some retroviruses, including HIV, are extensively edited after they infect cells. This hyperediting creates many harmful mutations in the viral RNA genome and also causes viral mRNAs to be retained in the nucleus, where they are eventually degraded. Although some modern retroviruses protect themselves against this defense mechanism, RNA editing presumably helps to hold many viruses in check.
rnA transport from the nucleus Can Be regulated
It has been estimated that in mammals only about one-twentieth of the total mass of RNA synthesized ever leaves the nucleus. We saw in Chapter 6 that most mammalian RNA molecules undergo extensive processing and that the “leftover” RNA fragments (excised introns and RNA sequences 3ʹ to the cleavage/poly-A site) are degraded in the nucleus. Incompletely processed and otherwise damaged RNAs are also eventually degraded as part of the quality control system for RNA production.
As described in Chapter 6, the export of RNA molecules from the nucleus is delayed until processing has been completed. However, mechanisms that deliberately override this control point can be used to regulate gene expression. This strategy forms the basis for one of the best-understood examples of regulated nuclear transport of mRNA, which occurs in the human AIDS virus, HIV.
As we saw in Chapter 5, HIV, once inside the cell, directs the formation of a double-stranded DNA copy of its genome, which is then inserted into the genome of the host (see Figure 5–62). Once inserted, the viral DNA can be transcribed as one long RNA molecule by the host cell’s RNA polymerase II. This transcript is then spliced in many different ways to produce over 30 different species of mRNA, which in turn are translated into a variety of different proteins (Figure 7–62). In order to make progeny virus, entire, unspliced viral transcripts must be exported from the nucleus to the cytosol, where they are packaged into viral capsids and serve as the viral genome. This large transcript, as well as alternatively spliced HIV mRNAs that the virus needs to move to the cytoplasm for protein synthesis, still carries complete introns. The host cell’s normal block to the nuclear export of unspliced RNAs therefore presents a special problem for HIV.
Figure 7–61 C-to-U RNA editing produces a truncated form of apolipoprotein B.
integrated into host genome1,000 nucleotide pairs
The block is overcome in an ingenious way. The virus encodes a protein (called Rev) that binds to a specific RNA sequence (called the Rev responsive element, RRE) located within a viral intron. The Rev protein interacts with a nuclear export receptor (Crm1), which directs the movement of viral RNAs through nuclear pores into the cytosol despite the presence of intron sequences. We discuss in detail the way in which export receptors function in Chapter 12.