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Testing excision models for responses of mismatch‐repair systems to UV photoproducts in DNA
Author(s) -
Wang Huxian,
Hoffman Peter D.,
Lawrence Christopher,
Hays John B.
Publication year - 2006
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20206
Subject(s) - nucleotide excision repair , dna mismatch repair , pyrimidine dimer , mutagenesis , dna repair , msh2 , dna , biology , microbiology and biotechnology , nucleotide , dna damage , mutation , msh6 , mutagen , genetics , gene
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 (MutSα) selectively binds DNA containing “mismatched” photoproducts (T[CPD] T /A G , T[6‐4] T /A G ) 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 /A G DNA, in a sequence context in which it is bound substantially by hMutSα and in three other contexts, for stimulation of 3′ MMR excision in mammalian nuclear extracts. T[CPD] T /A G 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 hMutSα and MLH2·PMS2 (hMutLα) did not increase excision relative to homoduplex controls. T[6‐4] T /A G also failed to provoke excision. T/G , C/A , and T/T substrates, even though bound by hMutSα no better than T[CPD] T /A G substrates, efficiently provoked excision. Even a substrate containing three T[CPD] T /A G photoproducts (in different contexts) did not significantly provoke excision. Thus, MMR may suppress UV mutagenesis by non‐excisive mechanisms. Environ. Mol. Mutagen., 2006. © 2006 Wiley‐Liss, Inc.