Tankyrase 1 influences telomere recombination, stability of the NHEJ protein DNA-PKcs and genomic integrity
Date
2011
Authors
Dregalla, Ryan Christopher, author
Bailey, Susan M., advisor
Liber, Howard L., committee member
Weil, Michael M., committee member
Nyborg, Jennifer K., committee member
Laybourn, Paul J., committee member
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Abstract
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 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.
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Subject
DNA-PKcs
telomeres
tankyase
DNA-repair
cancer