TitleTesting excision models for responses of mismatch-repair systems to UV photoproducts in DNA.
Publication TypeJournal Article
Year of Publication2006
AuthorsWang H, Hoffman PD, Lawrence CW, Hays JB
JournalEnviron Mol Mutagen
Date Published2006 May
Animals, Base Pair Mismatch, CHO Cells, Cricetinae, Cricetulus, DNA, DNA Repair, HeLa Cells, Humans, Plasmids, Pyrimidine Dimers, Ultraviolet Rays

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.

Alternate JournalEnviron. Mol. Mutagen.
PubMed ID16493608
Grant ListES09848 / ES / NIEHS NIH HHS / United States