Sunlight and Skin Cancer. Many of the toxic, mutagenic and carcinogenic effects of sunlight can be attributed to DNA photoproducts, but the precise biological activities of individual photoproducts are unknown. We have developed building blocks for the site-specific incorporation of photoproducts and analogs into oligodeoxynucleotides (ODNs) by automated synthesis. These uniquely photodamaged ODNs are used to construct: 1) short duplexes for 3D structure determination by high field 2D NMR and x-ray crystallography; 2) polymers for DNA bending studies; and, 3) long DNA fragments and viral DNA for in vitro repair, transcription and replication studies with purified prokaryotic and eukaryotic enzymes and human cell extracts. We are currently investigating the mechanism of deamination of methylC-containing thymine dimers when bound to methylC binding proteins and histones to explain C to T mutations caused by sunlight, and photodamage of human telomeric DNA.
Design and Synthesis of Antisense-Based Diagnostic and Therapeutic Agents. We are developing an approach for the design and synthesis of disease-specific chemotherapeutic agents that makes use of disease-specific mRNAs as a trigger to cause the catalytic release of cytotoxic agents. We are also working in collaboration with a number of researchers including Dr. Karen Wooley and Dr. Michael Welch to develop nanoparticles for PET and optical imaging of gene transcription in diseased cells, as well as gene therapy agents. In another collaborative project with Dr. Roti Roti and Dr. Clayton Hunt we are developing PNA and polyamide-based antigene agents to enhance the sensitizing effect of heat on ionizing radiation induced killing of tumors.

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