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RONALD BREAKER

The Breaker laboratory uses a variety of approaches to explore the fundamental properties of nucleic acids. For example, the laboratory develops new techniques for in vitro selection to create new functional RNAs and DNAs. In vitro selection is patterned after natural Darwinian evolution, but where "survival-of-the-fittest" is played out at the molecular level in the absence of living cells. Up to 100 trillion different molecules can be subjected to this test-tube evolution process to isolate or engineer molecules that perform tasks such as catalysis and molecular sensing.

Previous molecular engineering projects have provided evidence that both RNA and DNA have substantial untapped potential for sophisticated biochemical function. For example, we have produced a variety of new DNA enzymes, some that operate under cell-like conditions and perform reactions that mimic important biochemical transformations. In addition, we have generated dozens of examples of RNAs that function as designer molecular switches that respond to specific small molecules. These findings demonstrate that the primary roles of RNA and DNA in nature might be greater than currently appreciated, and suggests that the function of nucleic acids could be expanded via molecular engineering.

Inspired by these molecular engineering demonstrations, we have more recently begun to search for novel types of non-coding RNAs that perform undiscovered catalytic or molecular sensing tasks in cells. We have identified numerous classes of "riboswitches", which are metabolite-binding mRNA domains that control genes responsible for biosynthesis of essential compounds. Among the first dozen riboswitches classes identified are representatives that sense coenzymes, nucleobases, amino acids or sugars. Some riboswitch classes exhibit complex biochemical behaviors including ribozyme activity, cooperative ligand binding, and logic gate function. In addition, we have identified other non-coding RNAs that are not riboswitches, but whose biological functions remain to be established. We will continue to use bioinformatics, genetics, and biochemistry techniques to discover new types of non-coding RNAs and to establish the functions of these complex-folded nucleic acids.

Publications
K. F. Blount, J. X. Wang, J. Lim, N. Sudarsan and R. R. Breaker. Antibacterial lysine analogs that target lysine riboswitches. Nature Chem. Biol. 3, 44-49 (2007).

E. Puerta-Fernandez, J. E. Barrick, A. Roth and R. R. Breaker. Identification of a large noncoding RNA in extremophilic eubacteria. Proc. Natl. Acad. Sci. USA 103, 19490-19495 (2006).

N. Sudarsan, M. C. Hammond, K. F. Block, R. Welz, J. E. Barrick, A. Roth and R. R. Breaker. Tandem riboswitch architectures exhibit complex gene control functions. Science 314, 300-304 (2006).

A. Serganov, A. Polonskaia, A. T. Phan, R. R. Breaker and D. Patel. Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch. Nature 441, 1167-1171 (2006).

K. H. link, L. Guo and R. R. Breaker. Examination of the structural and functional versatility of glmS ribozymes by using in vitro selection. Nucleic Acids Res. 34, 4968-4975 (2006).