Structural dynamics of telomeric overhang accessibility

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

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Bioengineering

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2014

Author dc:creator

• Hwang, Helen

Contributors dc:contributor

• Myong, Su-A
• Cunningham, Brian T.
• Freeman, Brian C.
• Ma, Jian

• telomerase
• telomere-binding proteins
• Protection of telomeres protein 1 (POT1)
• Tripeptidyl-peptidase 1 (TPP1)
• telomere
• single molecule fluorescence

Statement dc:rights

• 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)

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/46840

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/46840