Faculty

The goal of our laboratory is to understand the organization and dynamics of macromolecular assemblies important for gemone regulation and stability. A combination of structural analyses, such as X-ray crystallography and electron microscopy, coupled with biophysical and biochemical experimentation, forms the core of our methodological approach. Active areas of investigation include:

Telomere protection and regulation. Telomeres are higher order nucleoprotein complexes that cap the ends of chromosomes and play essential roles in conferring genome stability and cell proliferation capacity in all eukaryotes. Changes in telomere functions and the asociated chromosomal abnormalities have been implicated in human aging and cancer. Work from our group is revealing important information about the mechanisms of telomeric proteins, both individually and complexed with various targets, to better model their molecular activity.

We are searching small molecular inhibitors of the interaction between the single-stranded telomeric DNA and its binding protein POT1 using a high-throughput chemical genomics approach. These small molecular inhibitors will provide insights into the interaction between POT1 and the telomeric ssDNA and address the feasibility of the POT1-ssDNA complex as a therapeutic target. We will biochemically characterize the interactions between the identified inhibitors and POT1. Using X-ray crystallography, we aim to understand how the inhibitors bind specifically to POT1 and to guide improvements in their binding affinity and specificity.

Molecular mechanism of histone dymethylase. Histone modifications mediate changes in gene expression by altering the chromatin structure or by serving as a binding platform to recruit other proteins. One such modification, histone methylation, was thought to be irreversible until recently when a new class of enzymes, lysine-specific histone demethylase (LSD1), was identified. LSD1 is a bona fide histone H3 lysine 4 and lysine 9 demethylase. Its activity and specificity is regulated by associated protein factors. In order to understand the molecular mechanisms of LSD1 enzymatic activity and regulation, we are determining the structures of LSD1 in complex wtih H3 peptide substrate and with small molecular inhibitors.

Awards

Biological Science Scholar, University of Michigan
Paul Sigler / Agouron Institute Postdoctoral Fellow, Helen Hay Whitney Foundation

Representative Publications

1. Lei, M., Zaug, A.J., Podell, E.R. and Cech, T.R., "Switching human telomerase on and off wtih hPOT1 protein in vitro", J. Biol. Chem., 2005, 281(21), 20449.

2. Lei, M., Podell, E.R. and Cech, T.R., "Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-production", Nat. Struc. Mol. Biol., 2004, 11(12), 1223.

3. Lei, M., Podell, E.R., Baumann, P. and Cech, T.R., "DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA", Nature, 426, 198.

4. Lei, M., Baumann, P. and Cech, T.R., "Cooperative binding of single-stranded telomeric DNA by the Pot1 protein of Schizosaccharomyces pombe", 2002, Biochem., 41(49), 14560.

5. Lei, M., Lu, W., Meng, W., Parrini, M.C., Eck, M., Mayer, B.J. and Harrison, S.C., "Structure of PAK1 in an Autoinhibited Conformation Reveals a Multi-stage Activation Switch", Cell, 2000, 102(3), 387.