Ribozymes and DNAzymes-- ancient catalytic activities for modern biomedical and other utility

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My laboratory conducts broad-ranging research on the fundamental properties of DNA and RNA, the shared genetic material of all living organisms. Particularly, we are interested in the catalytic properties of RNA/DNA. Defining the range of catalysis available to RNA and DNA enzymes (ribozymes and DNAzymes) is crucial for understanding how early bio-catalytic systems evolved on earth; how quite different biopolymers (DNA/RNA versus proteins) can meet specific catalytic challenges; and, for obtaining powerful new reagents that can be applied towards disease bio-sensing, therapeutics, as well as other, often unanticipated, uses. Two very interesting and unexpected catalytic properties of RNA/DNA have been discovered in my laboratory: (a) that certain catalytic DNAs (DNAzymes) are able to harness light (at wavelengths not harmful to human DNA) to repair cancer-causing thymine dimer lesions in DNA itself. We have recently succeeded in creating variant DNAzymes that are able to utilize visible rather than UV light for their DNA repair activity. And, (b) that large numbers of RNAs and DNAs are able to form tight complexes with heme, an important and versatile metabolic cofactor. These DNA/RNA-complexes then surprisingly catalyze key oxidative reactions, that are normally associated with highly specialized heme-utilizing protein enzymes. This proposal has two goals: The first will be to dissect the catalytic properties of guanine-rich RNAs & DNAs that form tight complexes with heme. We will determine precisely how heme-ribozymes structurally and mechanistically replicate the properties of heme proteins; and, how a heme-ribozyme could be designed to oxidize "difficult" substrates. Our second goal will be to conduct in vitro selection, characterization, and practical utilization of DNAzymes that use visible light to repair thymine dimer lesions in DNA. Specifically, we will determine whether a photolyase DNAzyme can ever be as efficient as its protein counterparts; also we will design medically relevant photolyase DNAzymes, that can be applied topically to human skin to offer protection against DNA damage by ultraviolet light.