Research Paper Volume 2, Issue 10 pp 691—708

Figure 10. Model of DNA-PKcs existence in three dynamic pools;. unmodified (blue), PARsylated (green), and marked for proteasome-mediated degradation (red). Unmodified pools of DNA-PKcs are PARsylated in a tankyrase 1 catalytic activity dependent manner (green arrow), a modification that can be reversed via PARG activity, resulting in unmodified DNA-PKcs (blue arrow). Once tankyrase 1 has PARsylated DNA-PKcs, tankyrase 1 auto-PARsylates (red) to dissociate from the multimerized-tankyrase complex. Tankyrase 1 relies on PARG activity to remove the auto-pADPr group and remain in an active state (green), otherwise, tankyrase 1 is ubiquitinated and targeted for degradation. The unmodified pool of DNA-PKcs is subject to being marked with a proteasome tag and subsequent degradation if not PARsylated by tankyrase 1. In conjunction with translation of new DNA-PKcs mRNA, there is a dynamic for DNA-PKcs PARsylation that shields a subpopulation of DNA-PKcs from degradation and perhaps represents the pool of kinase active DNA-PKcs. If this dynamic is disrupted by tankyrase 1 depletion or inhibition of its PARP catalytic activity, DNA-PKcs accumulates in the unmodified form and is forced to the right (degradation) resulting in depletion of DNA-PKcs protein.