Antimutagenic Role of Autonomous 3′ → 5′-Exonucleases

ISSN： 0026-8933

Source： Molecular Biology, Vol.38, Iss.5, 2004-09, pp. : 696-705

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Abstract

Original and published data on the antimutagenic role of autonomous 3′ → 5′-exonucleases (AE) are analyzed. AE are not bound covalently to DNA polymerases but are often involved in replicative complexes. AE overproduction in bacterial cells is accompanied by a sharp suppression of mutagenesis, whereas AE inactivation in bacteria and higher fungi results in the increase in mutation rates by two to three orders of magnitude. The combined action of AE and DNA polymerases substantially improves the fidelity of their functioning in vitro. The fidelity of nuclease-free DNA polymerases α and β increases by two to three orders of magnitude in the presence of AE. The fidelity of moderately processive DNA polymerase I increases by two orders of magnitude, and that of highly processive DNA polymerase δ increases by a factor of 5–10, although both these polymerases possess their own 3′ → 5′-exonucleolytic activity. In biochemical experiments, AE was shown to participate directly in the correction of errors made by DNA polymerase I. The presence of AE in multienzyme DNA polymerase complexes increases their fidelity by a factor of 5–10. A model of “extrinsic” proofreading by AE in DNA biosynthesis is proposed. An investigation of thirty objects from all three kingdoms of life (from archaea and bacteria to mammals, including humans) has shown that AE account for 30–90% of the total cellular 3′ → 5′-exonucleolytic activity. Therefore, AE increase significantly the intracellular ratio of 3′ → 5′-exonuclease to DNA polymerase activities in a wide phylogenetic variety of species, which always leads to the increasing fidelity of DNA biosynthesis.