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Title:Structural dynamics of telomeric overhang accessibility
Author(s):Hwang, Helen
Director of Research:Myong, Su-A
Doctoral Committee Chair(s):Myong, Su-A
Doctoral Committee Member(s):Cunningham, Brian T.; Freeman, Brian C.; Ma, Jian
Department / Program:Bioengineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
telomere-binding proteins
Protection of telomeres protein 1 (POT1)
Tripeptidyl-peptidase 1 (TPP1)
single molecule fluorescence
Abstract:Telomeres are dynamic nucleoprotein complexes that cap and protect chromosome ends from deleterious degradation and fusion events. In most eukaryotes, telomere length is regulated by a basal level of telomerase, a specialized reverse transcriptase, which can add telomeric repeats to the 3’ end of chromosomes. In normal cells, the telomere is shortened due to the end replication problem and DNA degradation, which sets the cell lifespan. 85% of cancer cells can escape this growth limitation by upregulating telomerase. The remaining cancer cells activate an alternative lengthening of telomere pathway (ALT). Therefore, treatments that target the telomere itself would potentially disrupt both mechanisms that cancer cells use to sustain unlimited proliferation. Hence, the telomere is an attractive target for anti-cancer drugs. Human telomeres terminate with an overhang repeat sequence that can self-fold into a G-quadruplex structure, allowing regulation of the telomere overhang. In addition, telomeric-binding proteins such as POT1 and TPP1 can sequester the overhang to regulate telomerase activity in vivo. Furthermore, existing small molecules that bind G-quadruplex have been shown to inhibit telomerase activity. However, there is little evidence on how the telomere-binding proteins impact the overhang structure. Previous structural studies have only provided snapshots of static telomere states, but have not provided any dynamics that may be exhibited. Bulk solution studies are unable to differentiate between the folded and the unfolded G-quadruplex states, as well as transient
Issue Date:2014-01-16
Rights Information:Copyright 2013 Helen Hwang. Chapter 4 is a reprint - reprinted from Structure, vol. 20, Hwang H, Buncher N, Opresko PL, Myong S, POT1TPP1 Regulates Telomeric Overhang Structural Dynamics, 1872-1880, 2012 with permission from Elsevier (license number: 3206221494025)
Date Available in IDEALS:2014-01-16
Date Deposited:2013-12

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