Abstract
UV light forms three types of DNA damage, cyclobutane pyrimidine dimers (CPD), pyrimidine(6-4)pyrimidone photoproducts (64PP) and Dewar valence isomers at dipyrimidine sites in DNA and induces specific types of mutations at those damaged sites in mammalian genome, finally leading to skin cancer. Triplet mutations, which are characterized by multiple base substitutions or frameshifts within a three-nucleotide sequence including a dipyrimidine, have been identified recently as a new type of UV-specific mutation and found to occur preferably in nucleotide excision repair (NER)-deficient genetic backgrounds. However, the mechanism of formation of the triplet mutation is unknown. Here, we show that 64PP as well as CPD (and probably Dewar isomers) contribute to the triplet mutagenesis, depending on the types of the triplet mutations. We further propose several models of error-prone translesional DNA synthesis (TLS) on those lesions as underlying mechanisms for triplet mutagenesis. These models would promote the study of TLS mechanisms by providing a number of concrete molecular objects to analyze.
