THE A-RULE OF MUTAGEN SPECIFICITY - A CONSEQUENCE OF DNA-POLYMERASE BYPASS OF NON-INSTRUCTIONAL LESIONS

The replicative bypass of lesions in DNA and the induction of mutations by agents which react with DNA to produce damaged bases can be understood on the basis of a simple kinetic model. Bypass can be analyzed by separately considering three processess: a) addition of a base opposite a lesion, b) a proofreading excision process, and c) a rate limiting elongation step. Adenine nucleotides are preferentially added opposite many lesions making it possible to predict mutational specificity. Replicative bypass (translesion synthesis) is dependent on modulation of proofreading exonuclease activity but loss of exonuclease activity alone is not sufficient to ensure bypass. Frameshift mutation is the result of the failure of translesion synthesis accompanied by rearrangement of the template, particularly at repetitive sites.