General principles of DNA repair in microorganisms and implications for future research

The analysis of DNA repair and mutagenesis in organisms that have high resolution genetic and molecular biological systems has led, and will continue to lead, to major advances in our understanding of these processes. It is striking that almost all of the major insights highlighted in this chapter have been gained within the last 10 years and, in fact, several of the discoveries described here occurred during the actual writing of this report. It is worth reflecting that in the mid 1970s there was a widely held view that the essential elements of DNA repair in E. coli were well understood and, at that time, a considerable number of investigators shifted their focus to systems that did not offer the high resolution genetic and molecular biologic tools of E. coli and S. cerevisiae. The remarkable progress achieved over the past ten years underscores the limitations of that viewpoint. It is difficult, and probably unwise, to pinpoint specific issues in DNA repair in E. coli and S. cerevisiae as special targets for future research since so much remains to be learned. Most of the striking discoveries outlined in this chapter have come from skilled investigators using the full range of high resolution genetic, molecular biologic, and biochemical tools to address fundamental problems in DNA repair and mutagenesis. In most cases, it would have been impossible to have predicted the critical discoveries that have been made. For example, UV and chemical mutagenesis require the induction of a pair of genes, mediated by DNA-damage-stimulated proteolytic cleavage of a repressor and then the subsequent activation of one of these gene products by a mechanistically related proteolytic cleavage. In 1975 an hypothesis proposing such a mechanism for UV and chemical mutagenesis would have been dismissed as being utterly fanciful. Yet this is the current reality. As in the cases of the other findings detailed here, the key insights came not from the testing of fanciful hypotheses but rather from systematic scientific studies of fundamental problems. Funding in this area should then support inquiries of fundamental issues in DNA repair and mutagenesis by investigators who are skilled at using the full range of sophisticated experimental tools available for these organisms. It is worth noting that supporting this type of research will shed light not only on mechanisms of DNA repair and mutagenesis but also on more fundamental issues in the biology of living organisms.(ABSTRACT TRUNCATED AT 400 WORDS)