Ultramutagenesis through combined Msh2 depletion and proofreading-deficient DNA polymerase ε expression enhances small molecule target identification in forward genetic screens
DNA mismatch repair (MMR) deficiency has been widely utilized in forward genetic screens to identify drug resistance mutations and elucidate the mechanisms of action of cytotoxic small molecules. However, MMR deficiency generates a characteristic mutational signature enriched for C>T transitions that precludes saturati...