Increased Mutagenesis and Unique Mutation Signature Associated with Mitotic Gene Conversion

To examine the fidelity of DNA synthesis during double-strand break (DSB) repair in Saccharomyces cerevisiae we studied gene conversion in which both strands of DNA are newly synthesized. The mutation rate increases up to 1400 times over spontaneous events, with a significantly different mutation signature. Especially prominent are microhomology-mediated template switches. Recombination-induced mutations are largely independent of mismatch repair, by DNA polymerases Pol zeta, Pol eta, and Pol32, but result from errors made by Pol delta and Pol epsilon. These observations suggest that increased DSB frequencies in oncogene-activated mammalian cells may also increase the probability of acquiring mutations required for transition to a cancerous state.