Mutagens contribute to the human burden of heritable birth defects and cancer and probably to heart disease as well. Most mutagens in most organisms act by triggering a process called error-prone repair (EPR). Such mutagens' primary action is to damage DNA in ways that block the progress of the DNA replication complex. EPR then facilitates damage bypass in a poorly templated (and therefore mutagenic) manner. Thus, the DNA polymerase is expected to play a crucial role in EPR. We have recently found that certain mutations of the bacteriophage T4 DNA polymerase gene can enhance or suppress EPR. The enhancing mutation, hm for hypermutable), also changes the specificity of EPR, preferentially increasing the frequency of base pair substitution mutations. Although the hm mutation is difficult to map by conventional crosses or by DNA sequencing, we now have data placing it roughly in the middle of the polymerase gene and are performing complementation tests to confirm its assignment. We plan next to ascertain the effect on EPR of some previously described mutator and antimutator DNA polymerase mutations and then to characterize the more interesting of these mutations by determining whether the mutant polymerases express altered fidelity in the insertional or proofreading steps of DNA synthesis.
