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作者 Dregalla, Ryan Christopher
書名 Tankyrase 1 influences telomere recombination, stability of the NHEJ protein DNA-PKCs and genomic integrity
國際標準書號 9781124643816
book jacket
說明 192 p
附註 Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: 4391
Adviser: Susan M. Bailey
Thesis (Ph.D.)--Colorado State University, 2011
The 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 DNAPKcs 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
School code: 0053
Host Item Dissertation Abstracts International 72-08B
主題 Biology, Molecular
Biology, Genetics
Biology, Cell
0307
0369
0379
Alt Author Colorado State University. Cell and Molecular Biology (Graduate Degree Program)
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