DNA PHOTOLESION STRUCTURE ACTIVITY RELATIONSHIPS

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Although many of the toxic, mutagenic and carcinogenic effects of sunlight can be attributed to DNA photoproducts, the biological activities of individual photoproducts are unknown. To determine the precise structure-activity relationships, we have determined the structure of DNA photoproducts and developed building blocks for the site-specific incorporation of DNA photoproducts into oligonucleotides by automated synthesis. These uniquely photodamaged oligonucleotides are then used to construct (a) short duplexes for high field 2D NMR and modeling studies, (b) polymers for DNA bending studies, (c) long DNA fragments for in vitro repair and replication studies, (d) viral DNA for in vitro mutation studies, and most recently (e) antigens for generating photoproduct-targeted catalytic antibodies, i.e., artificial repair enzymes. Currently underway are investigations of 4, 6, and 8 mer oligodeoxynucleotides that are enriched in T. We are evaluating the capability of tandem mass spectrometry to distinguish isomers, to analyze mixtures of isomers, and, in conjunction with HPLC introduction, to sequence oligomers, and to determine the structure of photodamaged oligomers