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Frederick S Gimble

Biochemistry 

  • Associate Professor of Biochemistry
765.494.1653
765.494.7897
BCHM Room 315

 Lab Members

Area of Expertise: Protein-DNA interactions and protein engineering of homing endonucleases

The sequence of the human genome will help identify genetic mutations that cause disease, and a central goal in the post-genomic era will be to develop tools to correct these errors. The repair of complex genomes requires having reagents available that 1) are capable of locating a specific sequence from among several hundred megabases of non-specific DNA and 2) are able to catalyze specific molecular modifications of the DNA that either initiate an endogenous repair pathway or effect repair directly.

Our laboratory has focused on designing and engineering homing endonucleases with novel functions that have the potential to facilitate DNA repair and other molecular processes. Homing endonucleases are encoded by mobile DNA elements that propagate between individuals within a population by “homing,” and between species through lateral transmission. These enzymes initiate homing by introducing a double-strand break at a single genomic target sequence situated within a cognate allele that lacks the mobile element. A long term goal of our group is to harness the extreme DNA sequence specificity of homing endonucleases to catalyze specified events at targeted genomic loci.

Our laboratory applies directed evolution and rational design strategies that are based on structural and phylogenetic information in order to design homing endonucleases with novel functions.

Selected Publications

Joshi, R., & Gimble, F. S. (2014). A bacterial one-hybrid system to isolate homing endonuclease variants with altered DNA target specificities. Methods Mol. Biol., 1114, 221-236.

Katz, S. S., Gimble, F. S., & Storici, F. (2014). To nick or not to nick: comparison of I-SceI single- and double-strand break-induced recombination in yeast and human cells. PloS ONE, 9, e88840. Retrieved from http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0088840&representation=PDF

Joshi, R., Ho, K. K., Tenney, K., Chen, J. H., Golden, B. L., & Gimble, F. S. (2011). Evolution of I-Scel homing endonucleases with increased DNA recognition site specificity. J. Mol. Biol., 405, 185-200. Retrieved from http://www.sciencedirect.com/science/article/pii/S0022283610011460

Niu, Y., Tenney, K., Li, H., & Gimble, F. S. (2008). Engineering variants of the I-SceI homing endonuclease with strand-specific and site-specific DNA-nicking activity. Journal of Molecular BIology, 382, 188-202.

Moure, C. M., Gimble, F. S., & Quiocho, F. A. (2008). Crystal structures of I-Scel homing nicked DNA substrates: snapshots of intermediates along the DNA cleavage reaction pathway. Nucleic Acids, 36, 3287-3296. Retrieved from http://nar.oxfordjournals.org/cgi/content/full/36/10/3287

Gimble, F. S. (2007). Engineering homing endonucleases to modify complex genomes. Gene Therapy & Regulation, 3(1), 33-50.

Gimble, F. S. (2006). Broken Symmetry in Homing Endonucleases. Structure, 14, 804-806. Retrieved from www.sciencedirect.com/science/article/pii/S0969212606001821

Gimble, F. S. (2005). Engineering homing endonucleases for genomic applications (Vol. 16).

Posey, K., Koufopanou, V., Burt, A., & Gimble, F. S. (2004). Evolution of divergent DNA recognition specificities in VDE homing endonucleases from two yeast strains. Nucleic Acid Res., 32, 3947-3956. Retrieved from http://nar.oxfordjournals.org/cgi/content/full/32/13/3947

Gimble, F. S., Moure, C. M., & Posey, K. (2003). Assessing the plasticity of DNA target site recognition of the PI-Sce I homing endonucleases using a bacterial two-hybrid selection system. J. Mol. Biol., 334, 993-1008.