Stochastic repair-misrepair model

The potential to quantitate both damage and mutation at the molecular level opens the possibility for stochastic simulation of mutation induction. The model described in this paper is based on the hypothesis that mutations induced by physical and chemical mutagens result from errors in DNA replication because of damage in the parental template. In bacteria it is meaningful to distinguish direct and indirect effects of DNA damage. Miscoding due to distortion in the DNA helix near a covalently bound adduct is an example of a direct effect. However, DNA damage may also induce responses (e.g., SOS repair) that involve mutator genes. At present, there is no evidence for an SOS-type response in mammalian cells. Nevertheless, mammalian cells do tolerate DNA damage and it is frequently speculated that the process by which the replication complex replitase) bypasses DNA damage is error-prone. In this model the consequences of replication on damaged templates are treated stochastically (i.e., by random variables). The probability distributions that govern the possible outcomes of damage-replitase interactions are the primary input to the model. This information is far from complete; however, formulation of the model will serve to focus on the data needs and perhaps will stimulate new experiments