The structural biology of protein-DNA complexes found at the tips of telomeres from the ciliated protozoa Oxytricha nova and Euplotes crassus will be studied through X-ray crystallography and biochemical binding experiments. The long term goal of this research is to understand the structure and function of telomere ends in terms of the noncovalent interactions that lead to specificity of recognition and in terms of the evolution of these specialized structures.
Three specific aims will be addressed: (1) Create amino-acid substitution variants of the O. nova telomere end binding protein to test the effect that removing protein-DNA interactions has on binding specificity. (2) Construct simplified binary protein-protein and protein-DNA binding systems derived from the ternary O. nova telomere end complex to test hypotheses regarding subunit and domain architecture of the native complex. (3) Determine binding properties and X-ray crystal structures of related telomere end protein-DNA complexes from E. crassus to explore common themes, diversity, and evolution of telomere structure. Telomeres are essential for chromosome stability and telomere structure is important to cell senescence and proliferation. The ends of telomeres appear to be especially critical as these can act as substrates both for regeneration by telomerase and for destabilizing recombination events. Ciliated protozoa such as O. nova and E. crassus provide important biochemical model systems because their telomeres have a relatively simple and well defined structure. Database searches and structural studies have uncovered homologues of the O. nova telomere end binding protein in yeast and humans. Insights obtained from the proposed research will thus have significance for understanding human telomeres and the role that telomere structure plays in the biology of aging and cancer. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Lewis, Catherine D
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Woods, Ryan D; O'Shea, Valerie L; Chu, Aurea et al. (2016) Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases. Nucleic Acids Res 44:801-10
Horvath, Martin P (2011) Structural anatomy of telomere OB proteins. Crit Rev Biochem Mol Biol 46:409-35
Zakharova, Elena; Horvath, Martin P; Goldenberg, David P (2009) Structure of a serine protease poised to resynthesize a peptide bond. Proc Natl Acad Sci U S A 106:11034-9
Zakharova, Elena; Horvath, Martin P; Goldenberg, David P (2008) Functional and structural roles of the Cys14-Cys38 disulfide of bovine pancreatic trypsin inhibitor. J Mol Biol 382:998-1013
Hanson, W Miachel; Domek, Gretchen J; Horvath, Martin P et al. (2007) Rigidification of a flexible protease inhibitor variant upon binding to trypsin. J Mol Biol 366:230-43
Suzuki, Takahito; McKenzie, Margaret; Ott, Elizabeth et al. (2006) DNA binding affinity and sequence permutation preference of the telomere protein from Euplotes crassus. Biochemistry 45:8628-38
Buczek, Pawel; Horvath, Martin P (2006) Structural reorganization and the cooperative binding of single-stranded telomere DNA in Sterkiella nova. J Biol Chem 281:40124-34
Buczek, Pawel; Horvath, Martin P (2006) Thermodynamic characterization of binding Oxytricha nova single strand telomere DNA with the alpha protein N-terminal domain. J Mol Biol 359:1217-34
Buczek, Pawel; Orr, Rochelle S; Pyper, Sean R et al. (2005) Binding linkage in a telomere DNA-protein complex at the ends of Oxytricha nova chromosomes. J Mol Biol 350:938-52