PRKDC encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine/threonine kinase that serves as a critical molecular sensor for DNA damage and orchestrates DNA double-strand break repair. The protein functions primarily through non-homologous end joining (NHEJ), where it must bind to DNA to express its catalytic activity and works with XRCC5/XRCC6 to protect and align broken DNA ends 1. PRKDC phosphorylates numerous substrates including histone H2AX at Ser-139, regulating DNA damage response mechanisms 2. Beyond DNA repair, PRKDC exhibits diverse cellular functions including regulation of autophagy through AMPK complex phosphorylation and lysosomal localization 3, and modulation of immune responses by phosphorylating PD-L1 to prevent its degradation, contributing to tumor immune escape 4. The protein also plays roles in chemotherapy resistance, particularly in osteosarcoma, by activating AKT signaling through the PRKDC-GDE2-GNAS axis 5. PRKDC expression correlates with tumor progression and poor prognosis across various cancers 6. Therapeutically, PRKDC inhibition with compounds like AZD7648 shows promise for improving homology-directed repair in genome editing 7 and enhancing chemotherapy sensitivity. The protein is also implicated in premature aging syndromes, where its nuclear absence correlates with aging phenotypes 8.