Polymerase ? and mismatch repair cooperatively determine the mutagenicity of a methylating agent

We characterised genome-wide mutations induced by the O6-dG-methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in mouse embryonic fibroblasts, deficient for the Pol ? catalytic subunit REV3L. Pol ? deficiency was associated with an increase in MNNG-induced GC>AT mutations, suggesting that in vivo Pol ?-dependent TLS of O6-medG lesions is relatively non-mutagenic. However, in the absence of the core mismatch repair (MMR) gene Msh2, both Pol ?-dependent and -independent TLS at O6-medG became error-prone, which implicates that MMR corrects misincorporations by TLS.