DNA-dependent protein kinase catalytic subunit

DNA-dependent protein kinase catalytic subunit (DNA-PKcs), encoded by PRKDC, is a serine/threonine kinase that functions as a molecular sensor for DNA damage (UniProt: P78527). It plays a central role in non-homologous end joining (NHEJ), the primary pathway for double-strand break repair, and is essential for V(D)J recombination. The protein also acts as a scaffold at DNA damage sites, facilitates telomeric stability, modulates transcription, and participates in ribosome assembly by promoting precursor rRNA processing (UniProt: P78527).

DNA-PKcs is expressed broadly across tissues and interacts with the Ku complex (XRCC5/XRCC6) to protect and align broken DNA ends. Beyond DNA repair, it phosphorylates numerous substrates including p53, H2AX, AKT isoforms, and PARP1, thereby influencing DNA damage responses, signaling pathways, and innate immunity (UniProt: P78527). Biallelic PRKDC mutations cause immunodeficiency 26 with or without neurologic abnormalities, characterized by severe combined immunodeficiency and potential neurological complications (UniProt: P78527).

In Alzheimer's disease, DNA-PKcs shows an ambiguous directional change: across four subcellular fractions (P2, P3, S2, S3) in human post-mortem AD brain versus controls, the mean log2 fold-change is −0.13 (Chaparral AD proteomics), indicating minimal overall change with inconsistent direction across fractions. This subtle dysregulation may reflect compartment-specific alterations in DNA damage response or neuroinflammatory signaling in AD pathology.