Mutagenic And Toxic Effects Of Base Analogs

Environmental Health Sciences

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Abstract

Summary of Work: Base analogs are derivatives of the normal DNA bases. As DNA polymerases often do not discriminate effectively against such analogs, they may be readily incorporated in the DNA and, due to the ambiguous base-pairing properties of the analogs, high levels of mutations may result. The study of base-analog induced mutagenesis is of interest because the analogs are helpful tools for investigating the precise mechanisms of DNA replication fidelity. These mechanisms include polymerase base selection, exonucleolytic proofreading and postreplicative DNA mismatch repair. In addition, cells may contain other defense systems against base analogs, that will be important to study. Recently it has also been recognized that naturally occurring base analogs exist, such as 8-oxo-guanine, and that, indeed, cells have developed exquisite defense mechanisms against such analogs. Analogs that we have investigated include P-nucleoside (a bicyclic cytosine derivative), 6-hydroxyaminopurine (HAP), and 8-oxoguanine. Our data suggest that, compared to normal bases, exonucleolytic proofreading and DNA mismatch repair do not operate efficiently against these analogs, leaving most of the discrimination up to the base selection step. We have also discovered a novel protection system against the adenine analog HAP, based on the hypersensitivity (for both cell killing and mutagenesis) of certain E. coli mutants lacking the molybdenum cofactor. Presumably, E. coli contains an enzymatic oxidation/reduction activity requiring the molybdenum cofactor and capable of inactivating HAP.