Mutation and Dna Repair: From the Green Pamphlet to 2005

Abstract

The early conceptual basis of gene structure and mutation were laid down in a handful of seminal papers, one of the best remembered being the "Green Pamphlet" of 1935 by N.V. Timofeeff-Ressovsky, K.G. Zimmer and M. Delbrück entitled "On the Nature of Gene Mutation and Gene Structure". The concepts of a molecular basis for the gene and its mutability have expanded hugely since then and have generated the entire field of DNA repair. Here, two current insights into DNA repair and mutation are displayed. Replication repair is a newly established mode of recombination repair that works through a copy-choice (templateswitching) mechanism and that has been reconstructed in vitro using the enzymes of DNA replication elaborated by bacteriophage T4. In contrast, a pathological mode of primer-strand switching generates templated complex mutations, and these greatly increase in frequency when the shepherding proteins of replication repair are disabled. At the same time, many spectra are found to contain a different kind of complex mutation whose components are more widely scattered. These are argued to arise mostly through transient bouts of hypermutation and are likely to contribute to carcinogenesis and to the virulence of microbial pathogens.