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Distinct Functions of POT1 in Telomere Protection and Length Regulation

dc.contributor.advisor Counter, Christopher M Barrientos, Katharine Specchio 2009-01-02T16:25:02Z 2011-07-26T04:30:03Z 2008-12-03
dc.description.abstract <p>Telomeres are DNA-protein structures that protect eukaryotic chromosome ends from illegitimate recombination and degradation. Telomeres become shortened with each cell division unless telomerase, a reverse transcriptase, is activated. In addition to playing a protective role of chromosome ends, telomeres and telomere binding proteins are also essential for regulating telomere length and telomerase access. The mammalian protein POT1 binds to telomeric single-stranded DNA (ssDNA), protecting chromosome ends from being detected as sites of DNA damage and negatively regulating telomere length. POT1 is composed of an N-terminal ssDNA-binding domain and a C-terminal protein-interaction domain. With regard to the latter, POT1 heterodimerizes with the protein TPP1 to foster binding to telomeric ssDNA in vitro and binds the telomeric double-stranded DNA (dsDNA) binding protein TRF2. I sought to determine which of these functions--ssDNA, TPP1, or TRF2 binding--was required for POT1-mediated telomere localization, protection, and length regulation. Using separation-of-function POT1 mutants deficient in one of POT1's three functions, I found that binding to TRF2 fosters robust loading of POT1 onto telomeric chromatin and regulates telomere length, but is dispensable in the protection of telomeres. Although it remains unclear what role TPP1 binding plays in telomere length regulation, I found that the telomeric ssDNA-binding activity and binding to TPP1 are required in cis for POT1-mediated protection of telomeres, possibly by excluding RPA from telomeres.</p>
dc.format.extent 10836610 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Biology, Molecular
dc.title Distinct Functions of POT1 in Telomere Protection and Length Regulation
dc.type Dissertation
dc.department Pharmacology
duke.embargo.months 24

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