On its own, DNA-PKcs is inactive and relies on Ku to direct it to DNA ends and trigger its kinase activity.

[9] DNA-PKcs is required for the non-homologous end joining (NHEJ) pathway of DNA repair, which rejoins double-strand breaks.

[10] DNA-PK also cooperates with ATR and ATM to phosphorylate proteins involved in the DNA damage checkpoint.

[13] In response to ionizing radiation, DNA-PKcs can serve as an upstream effector for p53 protein activation, thus linking DNA damage to apoptosis.

[13] Both Repair of DNA damages and apoptosis are catalytic activities required for maintaining integrity of the human genome.

PRKDC (DNA-PKcs) mutations were found in 3 out of 10 of endometriosis-associated ovarian cancers, as well as in the field defects from which they arose.

HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations.

[36] The ATM protein is important in homologous recombinational repair (HRR) of DNA double strand breaks.

The elevation of DNA-PKcs is thought to reflect the induction of a compensatory DNA repair capability, due to the genome instability in these cancers.

Non-homologous end joining (NHEJ) is the principal DNA repair process used by mammalian somatic cells to cope with double-strand breaks that continually occur in the genome.

DNA-PKcs deficient mice have a shorter lifespan and show an earlier onset of numerous aging related pathologies than corresponding wild-type littermates.