A chief focus of research in our laboratory is on design, synthesis, and study of molecules that mimic DNA and its functions in biological systems. The research can lead to basic understanding of biological mechanisms such as DNA replication and DNA repair, and to the development of molecules for detecting and treating disease.

One long-term goal of the group is to develop RNA-templated chemistries that can be used to diagnose human cancers and infections highly specifically and very early. Toward this goal, we have been pursuing the discovery of new chemical reactions that generate a fluorescence signal; we then modify DNAs to perform these reactions upon binding cellular RNA. Such molecules can detect a single base alteration in a DNA or RNA target, and since such mutations are causative in many diseases, we are developing these molecules for use in identifying pathogenic bacteria and cancer-related sequences in human cells.

A different project involves the development of new fluorescent molecular assemblies built on a DNA scaffold. We synthesize new fluorescent molecules that resemble, but are quite distinct from, DNA nucleosides. These are assembled into DNA-like combinatorial libraries and are being evaluated for unusual fluorescence and sensing properties. The resulting molecules are under development as new tools for biological reporting in cells.

A third research goal involves the design of new bases for DNA and RNA. Our group was the first to show that DNA base pairs could be replicated very efficiently by polymerase enzymes even when they lack Watson-Crick hydrogen bonds. As a result, we are now developing new DNA bases with varied structures, sizes, and shapes. New bases and base pairs could be used to expand nature's genetic system, or to develop entirely new genetic systems. Such molecules are also used as tools in the study of protein-DNA recognition, and they are being developed as possible tumor imaging agents.

1) "A Four-base Paired Genetic Helix with Expanded Size," H. Liu, J. Gao, S. Lynch, L. Maynard, D. Saito, E.T. Kool, Science, 302, 868-871 (2003).

2) "Quenched Autoligating DNAs: Multicolor Identification of Nucleic Acids at Single Nucleotide Resolution," S. Sando, H. Abe, E.T. Kool, J. Am. Chem. Soc., 126, 1081-1087 (2004).

3) "Selective Pairing Between Polyfluorinated DNA Bases," J. Lai, J. Qu, E.T. Kool, J. Am. Chem. Soc., 126, 3040-3041 (2004).

4) "Modified DNA Analogues That Sense Light Exposure With Color Changes," J. Gao, S. Watanabe, E.T. Kool, J. Am. Chem. Soc., 126, 12748-12749 (2004).

5) "Assembly of the Complete Eight-Base Artifical Genetic Helix, xDNA, and Its Interaction With the Natural Genetic System," J. Gao, H. Liu, E.T. Kool, Angew. Chem Int. Ed., 44, 3118-3122 (2005).

6) "Probing the Active Site Tightness of DNA Polymerase in Sub-Angstrom Increments," T.W. Kim, J.C. Delaney, J.M. Essigmann, E.T. Kool, Proc. Natl. Acad. Sci. USA, 102, 15803-15808 (2005).

7) "Sensing Metal Ions with DNA Building Blocks: Fluorescent Pyridobenzimidazole Nucleosides," S.J. Kim, E.T. Kool, J. Am Chem. Soc., 128, 6164-6171 (2006).