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Investigations into the mechanisms of telomere structure and function

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dc.contributor.authorLe, Phuong Nam, author
dc.contributor.authorBailey, Susan M., advisor
dc.contributor.authorUllrich, Robert L., committee member
dc.contributor.authorWeil, Michael M., committee member
dc.contributor.authorLaybourn, Paul J., committee member
dc.date.accessioned2007-01-03T08:10:03Z
dc.date.available2013-06-01T08:10:42Z
dc.date.issued2012
dc.description.abstractTelomere dysfunction is most commonly defined as critical shortening; i.e., loss of telomere sequence due to a variety of causes, usually the end-replication problem. However telomeres and their arsenal of associated proteins also provide essential end-capping structure that protects the ends of linear eukaryotic chromosomes. The overall goal of the studies presented here was to provide new insight into underlying mechanisms of telomeric structure and function. We examined the role of telomere function in Acute Myeloid Leukemia. We observed genomic instability in association with radiation-induced AML, and this association was observed following AML induction with both gamma (γ)- ray and 1 Gev 56Fe ion exposure. Furthermore, we observed a clonal fusion event involving telomeres in a human AML cell line. Taken together, our AML studies underline the importance of genome stability and its link to carcinogenesis. We previously reported a role for the DNA damage repair protein DNA-PKcs in mammalian telomere end-capping function, where inappropriate telomere fusions, as well as telomere fusions to other broken DNA ends, were observed in DNA-PKcs deficient backgrounds. DNA-PKcs has many proposed phosphorylation substrates, one of the most intriguing and relevant being the recently identified heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), an RNA binding protein that associates with telomeres. It is also now well accepted that telomeres are transcribed into telomeric repeat-containing RNAs, or TERRA, which are thought to contribute to telomeric chromatin structure. Taken together, we hypothesized that DNA-PKcs mediated phosphorylation of hnRNA1 plays an important role in tethering TERRA to telomere ends, thereby possibly contributing to telomere chromatin structure and function. Our data suggests that TERRA localization at telomeres is independent of hnRNP A1 and DNA-PKcs kinase activity. Rather, we observed decreased TERRA levels following DNA-PKcs kinase inhibition, suggesting DNA-PKcs indirectly regulates TERRA levels. Depletion of hnRNP A1 did not influence TERRA levels, but resulted in elevated frequencies of what have previously been termed "fragile" telomeres and telomere sister chromatid exchange (T-SCE), both indicative of a role for hnRNP A1 in facilitating telomere replication.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierLe_colostate_0053A_10908.pdf
dc.identifierETDF2012400249CMBO
dc.identifier.urihttp://hdl.handle.net/10217/67574
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.subjectAcute Myeloid Leukemia
dc.subjecttelomeres
dc.subjecthnRNP A1
dc.subjectDNA-PKcs
dc.titleInvestigations into the mechanisms of telomere structure and function
dc.typeText
dcterms.embargo.expires2013-06-01
dcterms.embargo.terms2013-06-01
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineCell and Molecular Biology
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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