Retrovirus Transposition

Retroviruses of vertebrates are, perhaps, the most widely studied class of eukaryotic transposable elements. These RNA viruses use reverse transcriptase to synthesize a circular duplex DNA, which can integrate into many sites of the host cell chromosome. The integrated retroviral genome bears remarkable resemblance to a bacterial composite transposon (compare Figure 25.38 with Figure 25.35).

The prototypical retroviral genome has three structural genes:

> 1. gag, which encodes a polyprotein that undergoes cleavage to give virion core proteins;

> 2. pol, which encodes the viral polymerase, or reverse transcriptase

> 3. env, which encodes the major glycoprotein of the viral envelope.

Flanking these structural genes are two direct repeats, the long terminal repeats (LTRs) of about 250 to 1400 base pairs each. Each LTR is flanked in turn by short inverted repeat sequences, 5 to 13 base pairs in length. Integration occurs by a mechanism that duplicates the target site, so that the integrated viral sequence, called a provirus, is flanked by direct repeats of host cell DNA (5 to 13 base pairs each).

Just as bacterial transposons can carry other genes, so also can retroviruses. In Rous sarcoma virus, the src oncogene (a gene that can cause cancer) lies to the 3' side of the env gene. Other tumorigenic viruses contain the oncogene either inserted into or substituting for one of the genes gag, pol, and env. Because the loss of an essential gene makes it impossible for the virus to replicate, the latter class of viruses can grow only in a cell coinfected with a helper virus, a related retrovirus that provides the missing function(s).

An additional mechanism for the retroviral stimulation of cell transformation may be due to activation of cellular genes by insertion of proviral DNA. The leftmost LTR in an integrated provirus contains the transcriptional activator, or promoter, for the adjacent gag gene and the downstream pol and env genes. Because the LTRs are direct repeats, the rightmost LTR can activate transcription of cellular genes downstream (3' to) from the integration site. If these cellular genes include those involved in metabolic regulation, their overexpression may unbalance metabolism in some still undefined way and, hence, contribute to oncogenesis.

Transposable elements in eukaryotic cells show striking resemblances to retroviruses in sequence organization. The term retrotransposon is used to denote this class of elements. These similarities are illustrated in Figure 25.39 for two retroviruses; Ty, a transposon of yeast; copia and 412, transposable elements in Drosophila; and IAP, a transposon found in the mouse genome.

See also: Transposable Genetic Elements, Site-Specific Recombination

INTERNET LINKS:

> 1. HIV Insite

> 2. General Replication Strategies for RNA Viruses