The long-term goals of this project are to use the unusual properties of expanded-size nucleobases, nucleotides, and nucleic acids in the study of steric effects in biomolecular recognition, and in the development of useful tools for biomedical research. During the initial term of this project we completed the synthesis of the full benzo-homologated """"""""xDNA"""""""" genetic set, and delineated a number of unusual properties that arise from this molecular design. In addition, we conceived, synthesized and studied a new widened molecular design as well, termed """"""""yDNA"""""""". All the expanded nucleotides were found to be inherently fluorescent, leading to promising possibilities for applications in biological and biomedical reporting, and the compounds were found to form extraordinarily stable helices as well. Our expanded DNA genetic set is the only complete set of size-expanded nucleotides known. This work is important because the enlarged nucleobase designs now make possible a broad number of experiments and applications that were not previously possible. Expanded nucleotides and oligomers containing them are expected to be useful as tools for basic biophysical and biochemical research, and we propose to use them for this purpose here, applied to the fields of mutagenesis and DNA repair, which are directly relevant to oncogenesis and cancer treatment. We will study kinetics and structure of DNA polymerases interacting with these compounds, as a test of how important steric factors are in maintaining fidelity of replication, in bypassing DNA lesions by error-prone polymerases, and in editing of DNA mismatches during replication. We will also use the unique properties of these compounds in the development of new applied tools for postgenomics applications in probing, hybridization, labeling and imaging. Finally, we will study basic biophysical, structural and thermodynamic properties of these compounds, to better understand and delineate their utility as broadly applicable tools.
| Winnacker, Malte; Kool, Eric T (2013) Artificial genetic sets composed of size-expanded base pairs. Angew Chem Int Ed Engl 52:12498-508 |
| Teo, Yin Nah; Kool, Eric T (2012) DNA-multichromophore systems. Chem Rev 112:4221-45 |
| Hernandez, Armando R; Peterson, Larryn W; Kool, Eric T (2012) Steric restrictions of RISC in RNA interference identified with size-expanded RNA nucleobases. ACS Chem Biol 7:1454-61 |
| Krueger, Andrew T; Peterson, Larryn W; Chelliserry, Jijumon et al. (2011) Encoding phenotype in bacteria with an alternative genetic set. J Am Chem Soc 133:18447-51 |
| Hernandez, Armando R; Kool, Eric T (2011) The components of xRNA: synthesis and fluorescence of a full genetic set of size-expanded ribonucleosides. Org Lett 13:676-9 |
| Jarchow-Choy, Sarah K; Krueger, Andrew T; Liu, Haibo et al. (2011) Fluorescent xDNA nucleotides as efficient substrates for a template-independent polymerase. Nucleic Acids Res 39:1586-94 |
| Khakshoor, Omid; Kool, Eric T (2011) Chemistry of nucleic acids: impacts in multiple fields. Chem Commun (Camb) 47:7018-24 |
| Lu, Haige; Krueger, Andrew T; Gao, Jianmin et al. (2010) Toward a designed genetic system with biochemical function: polymerase synthesis of single and multiple size-expanded DNA base pairs. Org Biomol Chem 8:2704-10 |
| Delaney, James C; Gao, Jianmin; Liu, Haibo et al. (2009) Efficient replication bypass of size-expanded DNA base pairs in bacterial cells. Angew Chem Int Ed Engl 48:4524-7 |
| Loakes, David; Gallego, José; Pinheiro, Vitor B et al. (2009) Evolving a polymerase for hydrophobic base analogues. J Am Chem Soc 131:14827-37 |
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