%0 Journal Article %J Environ Mol Mutagen %D 2006 %T Testing excision models for responses of mismatch-repair systems to UV photoproducts in DNA. %A Wang, Huxian %A Peter D Hoffman %A Christopher W Lawrence %A John B Hays %K Animals %K Base Pair Mismatch %K CHO Cells %K Cricetinae %K Cricetulus %K DNA %K DNA Repair %K HeLa Cells %K Humans %K Plasmids %K Pyrimidine Dimers %K Ultraviolet Rays %X

Mismatch-repair (MMR) systems correct DNA replication errors and respond to a variety of DNA lesions. Previous observations that MMR antagonizes UV mutagenesis, and that the mismatch-recognition protein heterodimer MSH2*MSH6 (MutSalpha) selectively binds DNA containing "mismatched" photoproducts (T[CPD]T/AG, T[6-4]T/AG) but not "matched" photoproducts (T[CPD]T/AA, T[6-4]T/AA), suggested that mismatched photoproducts would provoke MMR excision similar to mismatched bases. Excision of incorrect nucleotides inserted opposite template photoproducts might then prevent UV-induced mutation. We tested T[CPD]T/AG DNA, in a sequence context in which it is bound substantially by hMutSalpha and in three other contexts, for stimulation of 3' MMR excision in mammalian nuclear extracts. T[CPD]T/AG was inactive in HeLa extracts, or in extracts deficient in the photoproduct-binding proteins DDB or XPC* hHR23B, arguing against interference from the nucleotide excision repair pathway. Prior incubation with hMutSalpha and MLH2.PMS2 (hMutLalpha) did not increase excision relative to homoduplex controls. T[6-4]T/AG also failed to provoke excision. T/G, C/A, and T/T substrates, even though bound by hMutSalpha no better than T[CPD]T/AG substrates, efficiently provoked excision. Even a substrate containing three T[CPD]T/AG photoproducts (in different contexts) did not significantly provoke excision. Thus, MMR may suppress UV mutagenesis by non-excisive mechanisms.

%B Environ Mol Mutagen %V 47 %P 296-306 %8 2006 May %G eng %N 4 %R 10.1002/em.20206