PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

📖 Wiki Page

gene710 wordssynced 2026-04-02

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

Mermaid diagram (expand to render)

<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:

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

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

The kinase domain contains the activation loop and is structurally related to ATR and ATM kinases.

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

DNA-PK activity declines with age, contributing to genomic instability.

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

[Meek K, et al. DNA-PK: the guardian of the genome. Ageing Res Rev. 2006](https://pubmed.ncbi.nlm.nih.gov/16890164/)

[Schiller MJ, et al. DNA-PK in neuronal development and disease. J Neurochem. 2020](https://pubmed.ncbi.nlm.nih.gov/32061147/)

[Shamim MS, et al. DNA damage and repair in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry. 2020](https://pubmed.ncbi.nlm.nih.gov/32147384/)

[Katyal S, et al. DNA-PK deficiency in Alzheimer's disease. J Neurosci. 2014](https://pubmed.ncbi.nlm.nih.gov/25471552/)

[Gueven N, et al. DNA-PK and the repair of oxidative DNA damage. Antioxid Redox Signal. 2006](https://pubmed.ncbi.nlm.nih.gov/16771878/)

References

[Unknown, Meek K, Dang V, Lees-Miller SP. DNA-PK: the guardian of the genome. Ageing Res Rev. 2006;5(3):283-294 (2006)](https://pubmed.ncbi.nlm.nih.gov/16890164/)

[Unknown, Schiller MJ, Chan M, Nikolova V, Silverman G, Shackelford D. DNA-PK in neuronal development and disease. J Neurochem. 2020;152(5):539-554 (2020)](https://pubmed.ncbi.nlm.nih.gov/32061147/)

[Shamim MS, et al., DNA damage and repair in neurodegenerative diseases: a potential therapeutic target. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109873 (2020)](https://pubmed.ncbi.nlm.nih.gov/32147384/)

[Katyal S, et al., DNA-PK deficiency in Alzheimer's disease. J Neurosci. 2014;34(24):7947-7957 (2014)](https://pubmed.ncbi.nlm.nih.gov/25471552/)

Pathway Diagram

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

Mermaid diagram (expand to render)

📖 View canonical wiki page →

PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

PRKDC — DNA-Dependent Protein Kinase Catalytic Subunit

Introduction

Function

DNA Double-Strand Break Repair

Additional Roles

Structure

Expression in the Brain

Role in Neurodegeneration

DNA Damage in Aging Brain

Alzheimer's Disease

Parkinson's Disease

Ataxia-Telangiectasia (AT)

Other Neurodegenerative Conditions

Therapeutic Implications

DNA-PK Inhibitors

Neuroprotective Strategies

Challenges

Key Publications

See Also

References

Pathway Diagram