Inappropriate activation of a single enzyme, telomerase, is associated with the uncontrolled proliferation of cells seen in as many as 90 percent of all human cancers. Since the mid-1990s, when telomerase was first identified in human tumors, scientists have eyed the enzyme as an ideal target for developing broadly effective anti-cancer drugs. The important role of telomerase in cancer makes this enzyme an important drug target. I propose a structural biology approach to examine the function of telomerase and its role in human disease. Structural data can prove invaluable in explaining, as well as designing, biochemical and biophysical experiments. It can also be a very powerful tool for drug discovery. The long-term goal of my research plan is to use structural biology, in conjunction with biochemistry to understand how telomerase replicates telomere ends, and to apply this information to the pursuit of anti-cancer therapies.

Public Health Relevance

Telomerase has been implicated in cancer, cardiovascular disease and aging. For this reason, our goal is to elucidate the biological function of this enzyme and use this information to combat cancer and age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088332-05
Application #
8664879
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Preusch, Peter
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$357,143
Indirect Cost
$164,093
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rice, Cory; Shastrula, Prashanth Krishna; Kossenkov, Andrew V et al. (2017) Structural and functional analysis of the human POT1-TPP1 telomeric complex. Nat Commun 8:14928
Rice, Cory; Skordalakes, Emmanuel (2016) Structure and function of the telomeric CST complex. Comput Struct Biotechnol J 14:161-7
Hoffman, H; Skordalakes, E (2016) Crystallographic Studies of Telomerase. Methods Enzymol 573:403-19
Iwasaki, Osamu; Tanizawa, Hideki; Kim, Kyoung-Dong et al. (2015) Interaction between TBP and Condensin Drives the Organization and Faithful Segregation of Mitotic Chromosomes. Mol Cell 59:755-67
Zhu, Hengrui; Ren, Shancheng; Bitler, Benjamin G et al. (2015) SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. Cell Rep 13:1183-1193
Greetham, Matthew; Skordalakes, Emmanuel; Lydall, David et al. (2015) The Telomere Binding Protein Cdc13 and the Single-Stranded DNA Binding Protein RPA Protect Telomeric DNA from Resection by Exonucleases. J Mol Biol 427:3023-30
Panneer Selvam, Shanmugam; De Palma, Ryan M; Oaks, Joshua J et al. (2015) Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci Signal 8:ra58
Bryan, Christopher; Rice, Cory; Hoffman, Hunter et al. (2015) Structural Basis of Telomerase Inhibition by the Highly Specific BIBR1532. Structure 23:1934-42
Peng, Hongzhuang; Talebzadeh-Farrooji, Mehdi; Osborne, Michael J et al. (2014) LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase. Cancer Res 74:1390-1403
Bryan, Christopher; Rice, Cory; Harkisheimer, Michael et al. (2013) Structure of the human telomeric Stn1-Ten1 capping complex. PLoS One 8:e66756

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