DNA-dependent protein kinase catalytic subunit (DNA-PKcs) (DNA-PKcs)

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a large serine/threonine kinase (UniProt: P78527) essential for the non-homologous end joining (NHEJ) pathway of DNA repair (PubMed: 30305475). It is recruited to DNA double-strand breaks by the Ku70/Ku80 heterodimer, forming the active DNA-PK holoenzyme (NCBI Gene: 5591). In cancer, DNA-PKcs is often overexpressed, contributing to resistance against radiotherapy and chemotherapy (PubMed: 25100772). Therapeutic strategies involving Ku blockade utilize agents like the peptide Pep-pos to disrupt the Ku-DNA-PKcs interaction, thereby preventing DNA repair and sensitizing tumors to DNA-damaging agents (PubMed: 22499221). This mechanism of downstream functional inhibition is distinct from direct kinase domain inhibition and offers a targeted approach to disrupting the NHEJ machinery (PubMed: 28235109). By preventing the assembly of the functional repair complex, these inhibitors induce synthetic lethality or enhance the efficacy of ionizing radiation and topoisomerase inhibitors.

Other names

PRKDCDNA-PKp460HYRCHYRC1XRCC7Protein kinase, DNA-activated, catalytic polypeptide

The mechanism involves the disruption of the protein-protein interaction between the Ku70/Ku80 heterodimer and the DNA-PKcs protein. By blocking the C-terminal domain of Ku80 or the corresponding binding site on DNA-PKcs, these agents prevent the recruitment and subsequent activation of the catalytic subunit at the site of DNA double-strand breaks, effectively halting the non-homologous end joining (NHEJ) repair process (PubMed: 22499221, PubMed: 28235109).