The polymerase eta translesion synthesis DNA polymerase acts independently of the mismatch repair system to limit mutagenesis caused by 7,8-dihydro-8-oxoguanine in yeast.

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 (Poleta) translesion synthesis DNA polymerase additionally promotes error-free bypass of GO lesions. It has been suggested that Poleta 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 --> TA mutation rates in strains defective in MMR (Msh2 or Msh6) and/or in Poleta activity. The results clearly demonstrate that Poleta 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 Poleta-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.
Mesh Terms:
Alleles, DNA Mismatch Repair, DNA Replication, DNA, Fungal, DNA-Directed DNA Polymerase, Genome, Fungal, Guanine, Mutagenesis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Mol. Cell. Biol.
Date: Oct. 01, 2009
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