PRKDC encodes the catalytic subunit of DNA-dependent protein kinase (DNA-PK), a crucial enzyme in the non-homologous end joining (NHEJ) pathway for DNA double-strand break (DSB) repair. DNA-PK is essential for maintaining genomic integrity in neurons, and its dysfunction has been implicated in neurodegeneration, aging, and various neurological disorders [1][2].
| DNA-Dependent Protein Kinase Catalytic Subunit |
|---|
| Gene Symbol | PRKDC |
| Full Name | DNA-Dependent Protein Kinase Catalytic Subunit |
| Chromosome | 8q13-q21 |
| NCBI Gene ID | [5597](https://www.ncbi.nlm.nih.gov/gene/5597) |
| OMIM | 300123 |
| Ensembl ID | ENSG00000151067 |
| UniProt ID | [P78527](https://www.uniprot.org/uniprot/P78527) |
| Protein Size | 4,128 amino acids |
| Protein Family | PI3/PI4-related kinase family |
¶ DNA Double-Strand Break Repair
DNA-PK is the central enzyme in the classical NHEJ (c-NHEJ) pathway:
- DNA damage detection: Ku70/Ku80 heterodimer binds DSB ends
- DNA-PK recruitment: DNA-PKcs (PRKDC) recruited to Ku-bound DNA
- Activation: DNA binding activates DNA-PKcs kinase activity
- End processing: Artemis nuclease processes DNA ends
- Ligation: XRCC4/DNA ligase IV seals the break
- V(D)J recombination: Essential for lymphocyte development
- Telomere maintenance: Protects chromosome ends
- Transcription regulation: Modulates RNA polymerase II activity
- Metabolic regulation: Links DNA damage response to cellular metabolism
DNA-PKcs is one of the largest known protein kinases (~469 kDa):
- N-terminal region: HEAT repeats involved in DNA binding
- Ku-binding domain: Interaction with Ku70/Ku80
- PI3-kinase domain: Kinase catalytic core
- C-terminal region: Regulatory FAT domain
The kinase domain contains the activation loop and is structurally related to ATR and ATM kinases.
PRKDC is expressed in neurons and glia throughout the CNS:
Neurons accumulate DNA damage with age due to:
- Oxidative metabolism (ROS)
- Environmental insults
- Impaired repair mechanisms
DNA-PK activity declines with age, contributing to genomic instability.
DNA-PK dysfunction in AD:
- Amyloid-beta toxicity: Aβ induces DNA damage, overwhelming repair
- Tau pathology: Phosphorylated tau impairs DNA repair
- Neuronal loss: DNA damage accumulation leads to apoptosis
- Therapeutic target: DNA-PK inhibitors under investigation
- Oxidative stress: PD substantia nigra neurons face high oxidative load
- Mitochondrial DNA: mtDNA damage accumulates
- α-Synuclein interaction: May interfere with DNA repair
While AT is caused by ATM mutations, there is overlap:
- Both ATM and DNA-PK participate in DSB repair
- ATM deficiency enhances sensitivity to DNA-PK inhibition
- Potential synthetic lethal approaches
- Huntington's Disease: DNA repair deficits contribute to neuronal death
- Amyotrophic Lateral Sclerosis (ALS): Oxidative DNA damage
- Stroke: Ischemia-reperfusion causes massive DNA damage
- Traumatic Brain Injury: Secondary DNA damage cascades
| Compound |
Development Stage |
Indication |
| VX-984 (M3814) |
Preclinical/Phase I |
Cancer, neurodegeneration |
| AZD7648 |
Preclinical |
Cancer |
| Nedisertib (M3541) |
Preclinical |
Radiation protection |
- Combination therapy: DNA-PK inhibitors + antioxidants
- Gene therapy: Enhance NHEJ components
- Lifestyle interventions: Reduce oxidative stress
- Balancing DNA repair inhibition with cancer risk
- Blood-brain barrier penetration
- Selectivity over related kinases (ATM, ATR)
- Meek K, et al. DNA-PK: the guardian of the genome. Ageing Res Rev. 2006
- Schiller MJ, et al. DNA-PK in neuronal development and disease. J Neurochem. 2020
- Shamim MS, et al. DNA damage and repair in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2020
- Katyal S, et al. DNA-PK deficiency in Alzheimer's disease. J Neurosci. 2014
- Gueven N, et al. DNA-PK and the repair of oxidative DNA damage. Antioxid Redox Signal. 2006