Polymerase ζ and mismatch repair cooperatively determine the mutagenicity of a methylating agent. PolZeta/MMR MNNG

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 ζ catalytic subunit REV3L. Pol ζ deficiency was associated with an increase in MNNG-induced GC>AT mutations, suggesting that in vivo Pol ζ-dependent TLS of O6-medG lesions is relatively non-mutagenic. However, in the absence of the core mismatch repair (MMR) gene Msh2, both Pol ζ-dependent and -independent TLS at O6-medG became error-prone, which implicates that MMR corrects misincorporations by TLS.

本研究对缺失DNA聚合酶ζ（Pol ζ）催化亚基REV3L的小鼠胚胎成纤维细胞中，由O6-脱氧鸟苷甲基化试剂N-甲基-N'-硝基-N-亚硝基胍（N-methyl-N’-nitro-N-nitrosoguanidine，MNNG）诱导产生的全基因组突变进行了表征。Pol ζ缺陷与MNNG诱导的GC→AT碱基替换突变增多存在关联，这提示体内O6-甲基鸟嘌呤损伤的Pol ζ依赖性跨损伤DNA合成（Translesion Synthesis，TLS）相对不具备致突变性。然而，在核心错配修复（MMR）基因Msh2缺失的情况下，O6-甲基鸟嘌呤位点的Pol ζ依赖性与非依赖性跨损伤DNA合成均转变为易误过程，这表明错配修复可纠正跨损伤DNA合成导致的碱基掺入错误。