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Tankyrase 1 influences telomere recombination, stability of the NHEJ protein DNA-PKcs and genomic integrity

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dc.contributor.authorDregalla, Ryan Christopher, author
dc.contributor.authorBailey, Susan M., advisor
dc.contributor.authorLiber, Howard L., committee member
dc.contributor.authorWeil, Michael M., committee member
dc.contributor.authorNyborg, Jennifer K., committee member
dc.contributor.authorLaybourn, Paul J., committee member
dc.date.accessioned2007-01-03T05:15:53Z
dc.date.available2007-01-03T05:15:53Z
dc.date.issued2011
dc.description.abstractThe Poly(ADP-ribosyl)ating Polymerase (PARP) family of enzymes has gained considerable attention recently due to the success of inhibiting their activities in breast cancers with BRCA 1/2 deficient backgrounds. PARPs serve as key regulators of protein recruitment, stability and activity in specific intracellular pathways including DNA-repair, telomere stability, transcription factor regulation and mitotic integrity. The PARP family member, PARP-5a, otherwise known as tankyrase 1 is unique in that it lacks a DNA-binding domain and interacts with proteins specifically. First found to regulate telomere length by promoting access to telomerase, tankyrase 1 has since become associated with a multitude of critical cellular processes. In our studies investigating the role of DNA-dependent Protein Kinase catalytic subunit (DNA-PKcs) and tankyrase 1 at telomeres, we find that tankyrase 1 is required for the suppression of sister chromatid recombination events at the telomere and that the leucine zipper domain of DNA-PKcs is necessary for accurate end-capping function. Interestingly, during our investigation we also identified a link between the stability of the DNA-PKcs protein and tankyrase 1. We find that under conditions in which tankyrase 1 is depleted or catalytically inhibited, DNA-PKcs becomes a substrate for proteasome mediated degradation. The depletion of tankyrase 1 by siRNA-mediated knockdown or PARP inhibition resulted in the failure of DNA-PKcs function in both telomere end-capping and the DNA damage response following exposure to ionizing radiation; i.e., increased sensitivity to ionizing radiation-induced cell killing, mutagenesis, chromosome aberrations and telomere fusions. Further, we find that the loss of DNA-PKcs is not coupled with depletion of Ku70, Ku80 or the PI3-kinase ATM, illustrating that tankyrase 1 acts to regulate DNA-PKcs specifically. Taken together, we identify important and novel roles of tankyrase 1 with implications not only for DNA repair and telomere biology, but also for cancer and aging.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierDregalla_colostate_0053A_10440.pdf
dc.identifier.urihttp://hdl.handle.net/10217/47381
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.subjectDNA-PKcs
dc.subjecttelomeres
dc.subjecttankyase
dc.subjectDNA-repair
dc.subjectcancer
dc.titleTankyrase 1 influences telomere recombination, stability of the NHEJ protein DNA-PKcs and genomic integrity
dc.typeText
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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