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

DNA-dependent protein kinase catalytic subunit (PRKDC) is a massive serine/threonine protein kinase that serves as a central component of the non-homologous end joining (NHEJ) pathway, the primary mechanism for repairing DNA double-strand breaks in mammalian cells (UniProt P78527). Upon DNA damage, PRKDC is recruited to the break site by the Ku70/Ku80 heterodimer, forming the active DNA-PK holoenzyme which then phosphorylates downstream targets to coordinate DNA end processing and ligation (PubMed: 30356214). In the context of oncology, PRKDC is a high-priority therapeutic target because many cancer cells rely on NHEJ to survive the DNA damage induced by radiotherapy and conventional chemotherapies (PubMed: 31533926). Small-molecule inhibitors of PRKDC, such as peposertib and AZD7648, are being evaluated in clinical trials to enhance the efficacy of these treatments by preventing DNA repair and promoting apoptosis in tumor cells (ClinicalTrials.gov). Beyond its role in DNA repair, PRKDC is essential for V(D)J recombination in the immune system, a process necessary for the development of B and T cells (NCBI Gene: 5591). It also plays significant roles in telomere maintenance, transcriptional regulation, and the cellular response to metabolic stress (PubMed: 29153503). Mutations in the PRKDC gene are associated with severe combined immunodeficiency (SCID) due to the failure of V(D)J recombination (PubMed: 24939634). Therapeutic challenges include managing the potential for systemic toxicity, as PRKDC is also involved in maintaining the integrity of normal tissues (PubMed: 32165432).

Other names

DNA-PKcsDNA-PKHYRCHYRC1p460XRCC7DNPK1

Inhibition of the catalytic activity of DNA-dependent protein kinase, thereby blocking the non-homologous end joining (NHEJ) pathway of DNA double-strand break repair and sensitizing cells to DNA-damaging agents.