Molecular mechanisms of nucleic acid integration.

There are three known mechanisms by which foreign DNA can be made a permanent part of the genome of an animal cell, and their properties are summarized in this report. Naked DNA introduced into cells is usually rapidly lost, but a small fraction can be integrated by illegitimate recombination, usually accompanied by major and unpredictable rearrangements in both inserted DNA and target. This mechanism, although inefficient and disruptive, accounts for virtually all integrated DNA seen in virus infections, and is often used for making cell lines carrying specific genes as well as transgenic mice. Homologous recombination between inserted and resident DNA is much rarer but can be detected and put to use. The best understood mechanism is that employed by retroviruses and related elements. In contrast to the other mechanisms, retroviral integration results in a predictable, stable association between virus and cell DNA with only minor sequence changes. However, it occurs only when the DNA is derived by reverse transcription of the RNA in an incoming viral particle and contains the correct sequences at its ends. Thus, from a standpoint of vaccine safety, only the first of the three mechanisms is at all relevant. Based on some prior experimentation in animals, the risk of introduction of activated oncogenes or other dangerous sequences by this means is extremely small.