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Ming Lei, Ph.D.

Associate Professor, Biological Chemistry


Early Career Scientist with the Howard Hughes Medical Institute

B.S. Tsinghua University
M.Sc. McGill University
Ph.D. Harvard University
Postdoctoral, University of Colorado at Boulder

Research Profile

The goal of our laboratory is to understand the organization and dynamics of macromolecular assemblies important for genome 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 includes:
(1). 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 associated chromosomal abnormalities have been implicated in human aging and cancer. Work from our group is revealing important information about the mechanisms of telomere organization and telomere end protection by a group of specialized telomeric proteins. We are now biochemically and structurally characterizing the interactions of these telomeric proteins, both individually and complexed with various targets, to better model their molecular activity.

(2). We are searching small molecular inhibitors of the interaction between the single-stranded telomeric DNA and its binding protein POT1 using 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.

(3). 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 with H3 peptide substrate and with small molecular inhibitors.

Awards

1990 – 1994 Guanghua Scholarship – Tsinghua University
1994 – Max Stern Scholarship – McGill University
2001 Paul Sigler/Agouron Institute Fellow, Helen Hay Whitney
2004 Biological Science Scholar – UM
2006 American Cancer Society Scholar (ACS)
2006 Sidney Kimmel Scholar

Publications

Yu, E.Y., Wang, F., Lei, M., and Lue, N.F. (2008) Analysis of Candida albicans telomerase protein Est3: evidence for an OB-fold structure with a novel protein interaction surface. Nat Struct Mol Biol., 24 August 2008 | doi:10.1038/nsmb.1471.

Sowd, G., Lei, M., and Opresko, P.L. (2008) Mechanism and substrate specificity of telomeric protein POT1 stimulation of the Werner Syndrome helicase. Nucleic Acids Research, 36(13):4242-56. PMID: 18583366

Chen, Y., Yang, Y., van Overbeek, M., Donigian, J.R., Baciu, P., de Lange, T., and Lei, M. (2008) A shared docking motif in TRF1 and TRF2 used for differential recruitment of telomeric proteins. Science 319:1092-6. PMID: 18202258

Wang, F., Podell, E.R., Zaug, A.J., Yang, Y., Baciu, P., Cech, T.R., and Lei, M. (2007) The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445: 506-510. PMID: 17237768

Chen, Y., Yang, Y., Wang, F., Wan, K., Yamane, K., Zhang, Y., and Lei, M. (2006) Crystal structure of human lysince-specific demethylase 1 (LSD1). PNAS 103(38): 13956-61.

Opresko, P.L., Mason, P.A., Podell, E.R., Lei, M., Hickson, I.D., Cech, T.R., and Bohr, V.A. (2006) POT1 stimulates RecQ helicases WRN and BLM to unwind DNA substrates. J. Biol. Chem. 280(37):32069-80.

Lei, M., Robinson, M.A. and Harrison, S.C. (2005) The active conformation of the PAK1 kinase domain. Structure. 13: 769-778

Lei, M., Zaug, A.J., Podell, E.R. and Cech, T.R. (2005) Switching human telomerase on and off with hPOT1 protein in vitro. J. Biol. Chem. 280(21):20449-56. PMID: 15792951

Lei, M., Podell, E.R. and Cech, T.R. (2004) Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat. Struct. Mol. Biol. 11(12):1223-1229. PMID: 15558049

Lei, M., Podell, E.R., Baumann, P. and Cech, T.R. 2003, DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature, 426:198-203. PMID: 14614509

Lei, M., Baumann, P. and Cech, T.R. 2002. Cooperative binding of single-stranded telomeric DNA by the Pot1 protein of Schizosaccharomyces pombe. Biochemistry. 41(49):14560-14568.

Parrini, M.C., Lei, M., Harrison, S.C. and Mayer, B.J. 2002. Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. Molecular Cell, 9(1):73-83.

Lowry, W.E., Huang, J., Lei, M., Rawlings, D. and Huang, X.Y. 2001. Role of the PHTH module in protein substrate recognition by Bruton's agammaglobulinemia tyrosine kinase. J. Biol. Chem. 276(48):45276-45281.

Lei, M., Lu, W., Meng, W., Parrini, M.C., Eck, M., Mayer, B.J. and Harrison, S.C. 2000. Structure of PAK1 in an Autoinhibited Conformation Reveals a Multi-stage Activation Switch. Cell, 102(3):387-397.

Xu, W., Doshi, A., Lei, M., Eck, M. and Harrison, S.C. 1999. Crystal Structures of c-Src Reveals Features of Its Autoinhibitory Mechanism. Molecular Cell, 3(5):629-638.

leim@umich.edu


Office: 5301D MSRB3, Box 5606
PH: (734)647-5839

PubMed: lei+m[au]+telomere

Laboratory Members:

Postdoctoral Fellows
Yong Chen
Zhixiong Zeng