PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

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](/entities/neurons), and its dysfunction has been implicated in neurodegeneration, aging, and various neurological disorders [1][2].

PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

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](/entities/neurons), and its dysfunction has been implicated in neurodegeneration, aging, and various neurological disorders [1][2].

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">DNA-Dependent Protein Kinase Catalytic Subunit</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>PRKDC</td></tr>
<tr><td><strong>Full Name</strong></td><td>DNA-Dependent Protein Kinase Catalytic Subunit</td></tr>
<tr><td><strong>Chromosome</strong></td><td>8q13-q21</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[5597](https://www.ncbi.nlm.nih.gov/gene/5597)</td></tr>
<tr><td><strong>OMIM</strong></td><td>300123</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000151067</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P78527](https://www.uniprot.org/uniprot/P78527)</td></tr>
<tr><td><strong>Protein Size</strong></td><td>4,128 amino acids</td></tr>
<tr><td><strong>Protein Family</strong></td><td>PI3/PI4-related kinase family</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/glioblastoma" style="color:#ef9a9a">Glioblastoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">23 edges</a></td>
</tr>
</table>
</div>

Function

DNA Double-Strand Break Repair

DNA-PK is the central enzyme in the classical NHEJ (c-NHEJ) pathway:

Additional Roles

• 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

Structure

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

Expression in the Brain

PRKDC is expressed in neurons and glia throughout the CNS:

• Neurons: High expression in [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), cerebellum
• [Astrocytes](/entities/astrocytes): Moderate expression
• [Microglia](/cell-types/microglia-neuroinflammation): Inducible expression upon activation
• Oligodendrocytes: Lower expression

Role in Neurodegeneration

DNA Damage in Aging Brain

Neurons accumulate DNA damage with age due to:

• Oxidative metabolism (ROS)
• Environmental insults
• Impaired repair mechanisms

Alzheimer's Disease

DNA-PK dysfunction in AD:

• [Amyloid-beta](/proteins/amyloid-beta) toxicity: Aβ induces DNA damage, overwhelming repair
• [Tau](/proteins/tau) pathology: Phosphorylated tau impairs DNA repair
• Neuronal loss: DNA damage accumulation leads to [apoptosis](/entities/apoptosis)
• Therapeutic target: DNA-PK inhibitors under investigation

Parkinson's Disease

• Oxidative stress: PD substantia nigra neurons face high oxidative load
• Mitochondrial DNA: mtDNA damage accumulates
• [α-Synuclein](/proteins/alpha-synuclein) interaction: May interfere with DNA repair

Ataxia-Telangiectasia (AT)

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

Other Neurodegenerative Conditions

• 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

Therapeutic Implications

DNA-PK Inhibitors

| Compound | Development Stage | Indication |
|----------|-------------------|------------|
| VX-984 (M3814) | Preclinical/Phase I | Cancer, neurodegeneration |
| AZD7648 | Preclinical | Cancer |
| Nedisertib (M3541) | Preclinical | Radiation protection |

Neuroprotective Strategies

• Combination therapy: DNA-PK inhibitors + antioxidants
• Gene therapy: Enhance NHEJ components
• Lifestyle interventions: Reduce oxidative stress

Challenges

• Balancing DNA repair inhibition with cancer risk
• [Blood-brain barrier](/entities/blood-brain-barrier) penetration
• Selectivity over related kinases (ATM, ATR)

Key Publications

See Also

• [DNA Repair](/mechanisms/dna-repair-neurodegeneration)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Ataxia-Telangiectasia](/diseases/ataxia-telangiectasia)
• [Huntington's Disease](/diseases/huntingtons)
• [Oxidative Stress](/mechanisms/oxidative-stress)
• [DNA Damage Response](/mechanisms/dna-damage-response)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit discovered through SciDEX knowledge graph analysis: