DNA-PKcs post-translational modifications and associated diseases

Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) forms DNA-PK holoenzyme with Ku70/Ku80 heterodimer, which initiates the (non-homologous end-joining) NHEJ repair upon double-strand breaks (DSBs). Besides function in NHEJ, DNA-PKcs also plays multiple roles in other biological processes including transcription, telomere maintenance, autophagy, cell cycle checkpoint, and lymphocyte development. Dysregulation of DNA-PKcs associates with various diseases such as genome instability and cancer, immunological deficiency, and neurological disorders. DNA-PKcs function is strictly controlled by post-translational modifications, especially phosphorylation. DNA-PKcs phosphorylation affects either the end-processing or the end-joining in DSB repair or Variable (V) Diversity (D) and Joining (J)/Class switch recombination in lymphocytes development. With increasing evidence of proteomic advances in DNA-PKcs study, other PTMs have been added including ubiquitination, neddylation, acetylation, and PARylation. Different DNA-PKcs PTMs may be involved different pathophysiological activities. Moreover, complexed crosstalk between DNA-PKcs phosphorylation and other PTMs will further aid the understanding of DNA-PKcs biology.