Thomas C. Leeper

Research Interests

My group is interested in the atomic structures (interatomic distances, bond angles, and topology) of biomolecules associated with chromatin and chromatin modifying factors.  Some of these factors generate heritable epigenetic effects that are important to biological processes such as cellular development, tumorigenesis, and aging.

Recently, a number of non-coding ribonucleic acid molecules (RNAs) have been implicated in chromatin modification. We are particularly keen to study the modes of RNA recognition in these ribonucleoprotein (RNP) complexes. These RNPs are particularly exciting for the simple fact that RNA's role in epigenetic programming is still somewhat poorly understood.

As a general technique, nuclear magnetic resonance spectroscopy (NMR) is appealing because it permits structure determination under physiologically relevant solution conditions, and also because it is a powerful tool for probing biophysical phenomena at the atomic level. Small molecule drug-like fragment screens and second site equilibrium binding events can be easily observed via NMR and thus nicely complement the obvious structural biology applications.

Using both NMR and molecular genetics, we are investigating a number of specific factors: yeast and human telomerase RNA-protein interactions, centromeric histone variants, and RNA-polycomb protein complexes. We believe that a complete understanding of the biochemistry of RNA-protein interactions at atomic detail will be vital to understanding the biology of epigenetic change.

 

Selected Publications

Lunde BM, Reichow SL, Kim M, Suh H, TC Leeper, Yang F, Mutschler H, Buratowski S, Meinhart A, Varani G. “Cooperative interaction of transcription termination factors with the RNA polymerase II C-terminal domain.” Nature Structural and Molecular Biology (2010).

TC Leeper, Qu X, Lu C, Moore C, Varani G. “Novel protein-protein contacts facilitate mRNA 3'-processing signal recognition by Rna15 and Hrp1.” Journal of Molecular Biology 401, 334-49 (2010).

A Davidson, TC Leeper, Z Athanassiou, K Patora-Komisarska, J Karn, JA Robinson and G Varani, Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. PNAS, 106, 11931-11936 (2009).

TC Leeper, Z Athanassiou, RL Dias, JA Robinson, G Varani, TAR RNA recognition by a cyclic peptidomimetic of Tat protein. Biochemistry 44 12362-12372 (2005).

TC Leeper, G Varani, The structure of an enzyme activating fragment of human telomerase RNA. RNA 11 394-403 (2005).

G Varani, Y Chen and TC Leeper, NMR Studies of Protein-RNA Interactions, Methods in Molecular Biology 278 289-312 (2004).

N Leulliot, S Quevillon-Cheruel, M Graille, H van Tilbeurgh, TC Leeper, KS Godin, TE Edwards, STh Sigurdsson, N Rosenkrantz, RJ Nagel, M Ares and G Varani, A new alpha-helical extension promotes RNA binding by the dsRBD of Rnt1p RNAse III. EMBO J. 23 2468-2477 (2004).

TC Leeper, N Leulliot, and G Varani, , The solution structure of an essential stem-loop of human telomerase RNA. Nucleic Acids Research 31 2614-2621 (2003)

TC Leeper, MB Martin, H Kim, S Cox, V Semenchenko, FJ Schmidt, SR Van Doren. "Structure of the UGAGAU hexaloop that braces Bacillus RNase P for action." Nature Structural Biology 2002, 9(5):397-403.