Base excision repair in a network of defence and tolerance

Abstract

Survival of a species depends on balanced generation of genetic variation but at the same time on the protection of the genome from changes that cause disease and fitness reduction. DNA repair pathways limit mutations but do not totally eliminate them. In fact, some DNA repair pathways are error prone. DNA repair thus has a central function not only in protecting the genome, but also in the generation of genetic diversity. Expression of DNA repair proteins is subject to a delicate balance where both too few and too many of a type may result in increased cytotoxicity and/or mutation (1–4). DNA repair is integrated with transcription, replication, cell cycle control and apoptosis in complex networks (5), a full discussion of which is beyond the scope of this article, and our abilities. While DNA repair is an ancient and conserved defence mechanism, various pathways, and additions to basic pathways, have evolved during different time periods (6). Furthermore, the pathways have overlapping specificities and function as back-up systems for each other. Thus, cytotoxic and mutagenic abasic sites (AP sites) may be dealt with by the relatively accurate mechanisms nucleotide excision repair (NER) (7,8), base excision repair (BER) and recombination repair, as well as by highly error-prone translesion DNA synthesis (TLS) (Figure 1; 9). In addition, different enzymes may substitute for each other in a specific pathway, or variants of a pathway. Conditions that govern the selection of a pathway in each case are not well understood. Furthermore, components of DNA repair systems, such as error-prone DNA polymerases, may also cause untargeted mutations at sites where no apparent damage is present. In this commentary we will address functional aspects of BER and different complementary functions in the light of recent discoveries with regard to mutations, cancer, evolution and ageing.