Title | Testing excision models for responses of mismatch-repair systems to UV photoproducts in DNA. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Wang H, Hoffman PD, Lawrence CW, Hays JB |
Journal | Environ Mol Mutagen |
Volume | 47 |
Issue | 4 |
Pagination | 296-306 |
Date Published | 2006 May |
ISSN | 0893-6692 |
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. | |
10.1002/em.20206 | |
Alternate Journal | Environ. Mol. Mutagen. |
PubMed ID | 16493608 |
Grant List | ES09848 / ES / NIEHS NIH HHS / United States |