On the fidelity of DNA replication. Mechanisms of misincorporation by intercalating agents.
Two distinct mechanisms of action for intercalating agents have been delineated: one leading to the production of frameshift misincorporations and the other leading to the production of single-base substitutions. Addition misincorporations are competitive with respect to DNA template (a measure of classical intercalation) but are not competitive with respect to deoxynucleotide substrates. Single-base substitutions are not competitive with template, polymerase, or deoxynucleotide as tested individually, but are proportional to the absolute drug concentration, indicating a ternary complex involving intercalator, polymerase, and template. Increased frequencies of single-base substitutions have not been considered as a general property of intercalators. Using a mutant phi X174 DNA, we demonstrate that intercalators also induce single-base substitutions with natural DNA templates. Reversion of am3 phi X174 DNA occurs only by single-base substitutions at position 587; this is increased 8-fold when the DNA is copied in vitro in the presence of intercalators.
D000818:Animals; D004256:DNA Polymerase I / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D004279:DNA, Viral; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology; D007364:Intercalating Agents / Q000494:pharmacology*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D011089:Polydeoxyribonucleotides; D051381:Rats; D013698:Templates, Genetic
D004279:DNA, Viral; D007364:Intercalating Agents; D011089:Polydeoxyribonucleotides; D004256:DNA Polymerase I; D004259:DNA-Directed DNA Polymerase