Structural dynamics of telomeric overhang accessibility

Hwang, Helen

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https://hdl.handle.net/2142/46840 Copy

Description

Title

Structural dynamics of telomeric overhang accessibility

Author(s)

Hwang, Helen

Issue Date

2014-01-16T18:17:58Z

Director of Research (if dissertation) or Advisor (if thesis)

Myong, Su-A

Doctoral Committee Chair(s)

Myong, Su-A

Committee Member(s)

• Cunningham, Brian T.
• Freeman, Brian C.
• Ma, Jian

Department of Study

Bioengineering

Discipline

Bioengineering

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

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

Graduation Semester

2013-12

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

Copyright and License 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)

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