Unifying concept of DNA repair: The polymerase scanning hypothesis

Abstract

According to a series of experiments on untransformed mouse embryonic fibroblasts, quiescent mouse cells lack global genomic repair (GGR) of premutagenic DNA damage. The gene used to assess mutation and premutagenic DNA damage was the lacI transgene incorporated permanently in the DNA in a lambda shuttle vector. The transgene lacks mammalian transcription signals and thus is unexpressed in the cells. Although the cells conducted transcription-coupled repair (TCR) of UV damage, the transgene was not repaired over a 4-day interval. These cells are not terminally differentiated and can readily be induced to resume cellular division. In this article, we discuss the interpretation of these results and suggest a new hypothesis for DNA scanning, the mechanism by which cells discover DNA damage and initiate DNA repair. Our hypothesis, which we call the polymerase scanning hypothesis, is that GGR is initiated in very much the same way as TCR, by a polymerase complex encountering the damage. We call the two together polymerase-coupled repair (PC repair). In the case of GGR, it would be the DNA replication complex during the S-phase. This is, we suggest, the dominant mechanism of repair of DNA at low doses for untranscribed genes. Evidence contrary to this hypothesis exists, which we discuss, but it should be noted that existing hypotheses about DNA scanning and DNA repair cannot account for the results that we have obtained.