Rational regulation of DNA polymerase-mediated mutagenesis and autonomous 3′-5′-exonucleases

New data are briefly reviewed on the antimutagenic role of bacterial and mammalian autonomous 3'-5'-exonucleases (those not bound covalently to DNA polymerases but often involved in replicative complexes). The intracellular overproduction of DNA polymerase III subunit epsilon, displaying the 3'-5'-exonuclease activity, in Escherichia coli is accompanied by marked attenuation of UV and SOS mutagenesis. Conversely, elimination of the exonuclease activity in the epsilon subunit results in an avalanche of mistakes incompatible with E. coli viability. In mammals (rat, human), the autonomous exonucleases largely account for the cell 3'-5'-exonuclease activity, mainly toward single-stranded DNA. The accuracy of reproduction of the bacteriophage Phi X174 amber3 DNA catalyzed by DNA polymerase a from calf thymus or rat liver rises substantially in the presence of the bacterial 3'-5'-exonuclease or autonomous 3'-5'-exonucleases from rat liver, as indicated by the antimutagenic effect after transfection of the phage DNA into E. coli spheroplasts. The mammalian exonucleases increase the DNA polymerase a fidelity in the cell by two to three orders of magnitude. Apparently, an increase in the gene dose of the mammalian autonomous 3'-5'-exonucleases should markedly diminish the intensity of mutagenesis and thus decrease the probability of carcinogenesis and new hereditary diseases.