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[摘要]：Reactive oxygen species are ubiquitous mutagens that have been linked to both disease and aging. The most studied oxidative lesion is 7,8-dihydro-8-oxoguanine (GO), which is often miscoded during DNA replication, resulting specifically in GC -> TA transversions. In yeast, the mismatch repair (MMR) system repairs GO (.) A mismatches generated during DNA replication, and the polymerase eta (Pol eta) translesion synthesis DNA polymerase additionally promotes error-free bypass of GO lesions. It has been suggested that Pol eta limits GO-associated mutagenesis exclusively through its participation in the filling of MMR-generated gaps that contain GO lesions. In the experiments reported here, the SUP4-o forward-mutation assay was used to monitor GC 3 TA mutation rates in strains defective in MMR (Msh2 or Msh6) and/or in Pol eta activity. The results clearly demonstrate that Pol eta can function independently of the MMR system to prevent GO-associated mutations, presumably through preferential insertion of cytosine opposite replication-blocking GO lesions. Furthermore, the Pol eta-dependent bypass of GO lesions is more efficient on the lagging strand of replication and requires an interaction with proliferating cell nuclear antigen. These studies establish a new paradigm for the prevention of GO-associated mutagenesis in eukaryotes. |
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