We are interested in the chemistry and biochemistry of DNA and RNA, with special regard to novel structural and functional properties for these nucleic acids. Two major areas of interest are:
(1) New catalytic activities for DNA and RNA, and control of ribozyme
Recently, it has been established that specific DNA sequences are capable of catalyzing a variety of chemical/biochemical reactions, in a manner analogous to catalytic RNAs (ribozymes). We have used in vitro selection methods from random-sequence DNA and RNA libraries to define new catalytic DNAs ("DNAzymes"). Among these are a chelatase (which catalyzes the insertion of copper ions into porphyrins-- this is the only major nucleic acid enzyme selected using a 'transition-state analogue' technology, such as used for deriving catalytic antibodies); a peroxidase; and several DNAzymes for the sequence-specific cleavage of RNA, using either metal cofactors or no cofactor at all. Current efforts are towards deriving DNAzymes/ribozymes for photochemical reactions and for the hydrolytic cleavage of DNA.
We have also recently developed a general, ligand-dependent method for controlling the catalytic activities of DNAzymes and ribozymes. This approach, which we call "expansive control" differs from classical allostery in significant ways. A number of the above catalysts have the potential for use in biomedical applications.
(2) DNA nanotechnology and sensor development :
We and a number of other researchers have established that nucleic acids rich in the nucleoside guanosine form a family of stable higher-order structures under physiological conditions, called G-DNA and G-RNA, which are held together by "guanine quartets".
These structures can be formed by chromosomal telomeres as well as by other interesting genomic sequences. Recently, we have begun to utilize the unusual bonding characteristics of guanine quartets to design novel DNA nanostructures, which could find broad practical use in structural studies, separation and detection techniques, as well as in such fields as microelecronics. We use G-G mismatch-containing DNA duplexes, called "Synapsable DNA", which bind one another at "synaptic" sites, to self-assemble and disassemble on demand.
Another major approach in the lab is to make the electron-conduction properties of DNA responsive to conformational changes of the DNA brought about by ligand binding. Development of this approach should lead to the development of novel biosensors and DNA chips, suitable for use in the post-genomic era.