Low-fidelity DNA polymerases

Abstract

What are they? Low-fidelity DNA polymerases are recently discovered DNA polymerases that function very inefficiently and inaccurately on undamaged DNA but, unlike replicative polymerases, are able to synthesise DNA past damaged bases.Also known as…. Translesion synthesis polymerases. There are two of them in Escherichia coli, polymerases IV and V, and five in human cells, polymerases ζ, η, τ, κ and Rev1 (so a knowledge of the Greek alphabet is essential when discussing them). Except for polymerase ζ, they fall into a new DNA polymerase family, designated the Y-family. Depending on the lesion, polymerase and context, they either insert the correct or an incorrect nucleotide opposite a damaged base. In the latter instances, they are responsible for generating mutations.When were they discovered? As recently as 1999, in both E. coli and man. Their discovery overturned 30 years of dogma, which was that damaged bases were bypassed by altering replicative polymerases to reduce their stringency. This turned out to be wrong. The new polymerases displace the replicative polymerase in order to get past the block caused by the damage (Figure 1Figure 1). Although the genes encoding the E. coli translesion synthesis polymerases – dinB, umuC and umuD – were known about for many years, sequence analysis had not revealed that they were polymerases. The Y-family polymerases have no sequence similarity to classical polymerases, although their three-dimensional structure subsequently revealed that they have the ‘finger’, ‘palm’ and ‘thumb’ domains characteristic of classical polymerases.Figure 1Translesion synthesis. TLS, translesion synthesis; pol, polymerase.View Large Image | View Hi-Res Image | Download PowerPoint SlideWhy do we need so many of them? Good question. Each polymerase appears to have a different substrate specificity. For example, polymerase η can bypass the major UV photoproduct very efficiently, usually inserting the correct nucleotides. It is less efficient with most other types of damage. Other polymerases work best on other substrates. Furthermore, translesion synthesis consists of two steps, insertion opposite the damaged base and extension from the inserted nucleotide. Polymerase τ can only insert, whereas polymerase ζ seems to be an extender, so they may act in concert.Any medical interest? Definitely. Polymerase η is defective in the variant form of the highly skin-cancer-prone genetic disorder, xeroderma pigmentosum. So polymerase η helps to prevent UV-induced mutations and cancer. In its absence, one of its cousins is thought to substitute for it, but does not do a very good job, so mutations and cancer result. Because of their intricate involvement in mutagenesis, the low-fidelity polymerases are possible candidate targets for cancer therapy.What else do they do? Somatic hypermutation is one of the mechanisms used to generate diversity during development of the immune response, and low-fidelity polymerases seem like ideal candidates for generating mutations at high frequency. Although none of the polymerases has been definitively implicated, available evidence suggests that several of them might be involved with redundant functions.