The mechanism of transduction of proto-oncogene c-src by avian retroviruses

Chicken c-src sequences have been transduced by avian leukosis viruses (ALV) and by partial src-deletion (td) mutants of Rous sarcoma virus in several independent events. Analyses of the recombination junctions in the genomes of src-containing viruses and the c-src DNA have shed light on the mechanism of transduction, which involves at least two steps of recombination. The initial recombination between a viral genome and the 5' region of c-src appears to occur at the DNA level. This step does not require extensive homology and can be mediated by stretches of sequences with only partial homology. The 5' recombination junction can also be formed by splicing between viral and c-src sequences. The second recombination is presumed to occur between the transducing ALV or td viral RNA and the viral-c-src hybrid RNA molecule generated from the initial recombination. This step involving recombination at the 3' ends of those molecules restores the 3' viral sequences essential for replication to the viral-c-src hybrid molecule. High frequency of c-src transduction by partial td mutants suggests that the second recombination is greatly enhanced when there is sequence homology between the transducing virus and the 3' region of c-src. Incorporation of the c-src sequences into an ALV genome results in greatly elevated expression of the gene. However, increased expression of c-src alone is insufficient to activate its transforming potential. Structural changes in c-src are necessary to convert it into a transforming gene. The changes can be as small as single nucleotide changes resulting in single amino aid substitutions at certain positions. Mutations can occur rapidly during viral replication after c-src is incorporated into the viral genome. Therefore, it is most likely that transduction of c-src by ALV is followed by subsequent mutation and selection for the sarcomagenic virus. In the case of transduction by td viruses that retain certain src sequences, joining of these sequences with the transduced c-src apparently is sufficient to activate its transforming potential.