DNA-PKcs (PRKDC) Protein

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DNA-PKcs (PRKDC) Protein

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DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

| Property | Value |
|----------|-------|
| Protein Name | DNA-PKcs (DNA-Dependent Protein Kinase Catalytic Subunit) |
| Gene | [PRKDC](/genes/prkdc) |
| UniProt ID | [P78527](https://www.uniprot.org/uniprot/P78527) |
| PDB Structures | 1JQT, 3KGV, 5W5R |
| Molecular Weight | 469 kDa (4,127 amino acids) |
| Subcellular Localization | Nucleus (nuclear matrix), cytoplasm |
| Protein Family | PI3/PI4-related protein kinase family |
| Chromosomal Location | 8q11.21 |

</div>

Overview

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a serine/threonine protein kinase that plays a critical role in the cellular DNA damage response (DDR). As the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex, DNA-PKcs forms a heterotrimeric holoenzyme with the Ku70/Ku80 heterodimer to mediate non-homologous end joining (NHEJ), the predominant pathway for repairing double-strand breaks (DSBs) in mammalian cells.

Beyond its well-established function in DNA repair, DNA-PKcs has emerged as a key regulator of neuronal viability and stress response. Neurons are particularly vulnerable to DNA damage due to their post-mitotic state and high metabolic activity, which generates significant oxidative stress. Accumulating evidence links DNA-PKcs dysfunction to the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative conditions. [@bhattacharyya2005]

...

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

| Property | Value |
|----------|-------|
| Protein Name | DNA-PKcs (DNA-Dependent Protein Kinase Catalytic Subunit) |
| Gene | [PRKDC](/genes/prkdc) |
| UniProt ID | [P78527](https://www.uniprot.org/uniprot/P78527) |
| PDB Structures | 1JQT, 3KGV, 5W5R |
| Molecular Weight | 469 kDa (4,127 amino acids) |
| Subcellular Localization | Nucleus (nuclear matrix), cytoplasm |
| Protein Family | PI3/PI4-related protein kinase family |
| Chromosomal Location | 8q11.21 |

</div>

Overview

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a serine/threonine protein kinase that plays a critical role in the cellular DNA damage response (DDR). As the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex, DNA-PKcs forms a heterotrimeric holoenzyme with the Ku70/Ku80 heterodimer to mediate non-homologous end joining (NHEJ), the predominant pathway for repairing double-strand breaks (DSBs) in mammalian cells.

Beyond its well-established function in DNA repair, DNA-PKcs has emerged as a key regulator of neuronal viability and stress response. Neurons are particularly vulnerable to DNA damage due to their post-mitotic state and high metabolic activity, which generates significant oxidative stress. Accumulating evidence links DNA-PKcs dysfunction to the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative conditions. [@bhattacharyya2005]

Recent research has revealed that DNA-PKcs participates in additional cellular processes beyond DNA repair, including:

Regulation of telomere length and stability
V(D)J recombination in lymphocyte development
Transcriptional regulation through chromatin remodeling
Mitochondrial function and cellular metabolism
Tau phosphorylation in AD pathogenesis
Stress granule formation in response to cellular stress

Structure and Mechanism

Domain Architecture

DNA-PKcs is one of the largest known protein kinases, comprising 4,127 amino acids with a molecular weight of approximately 469 kDa. The protein contains multiple functional domains:

N-terminal Regulatory Domain:
The N-terminal region contains the catalytic subunit's regulatory components:

Three HEAT repeats that mediate protein-protein interactions
A Ku-binding domain that interacts with the Ku70/Ku80 heterodimer
A leucine-rich repeat (LRR) region involved in DNA binding
A C-terminal region containing the kinase domain

Kinase Domain (C-terminal):
The C-terminal ~380 amino acids constitute the serine/threonine protein kinase domain:

Belongs to the PI3/PI4-related protein kinase family
Kinase activity is DNA-dependent, requiring DNA binding for activation
Contains the activation loop and P+1 loop typical of AGC family kinases
Autophosphorylation at multiple sites (Ser2056, Thr2609, Ser2056) regulates activity

DNA-Binding Domain:
DNA-PKcs contains specialized domains for DNA binding:

N-terminal DNA-binding domain
Ku heterodimer serves as DNA damage sensor
DNA binding induces conformational changes activating kinase

Activation Mechanism

DNA-PKcs activation follows a well-characterized pathway:

DNA damage detection: DSBs are sensed by the Ku70/Ku80 heterodimer, which rapidly binds to DNA ends

Recruitment of DNA-PKcs: DNA-PKcs is recruited to the DNA-Ku complex through protein-protein interactions

Conformational activation: DNA binding induces a conformational change in DNA-PKcs, exposing the kinase domain

Autophosphorylation: DNA-PKcs undergoes autophosphorylation at multiple sites, stabilizing the active conformation

Substrate phosphorylation: Activated DNA-PKcs phosphorylates downstream targets involved in DNA repair, transcription, and cell survival

Normal Physiological Function

DNA Double-Strand Break Repair (NHEJ)

DNA-PKcs is the central effector kinase in the classical non-homologous end joining (c-NHEJ) pathway:

Core NHEJ Pathway:

Ku70/Ku80 heterodimer binds DNA ends (within seconds of damage)
DNA-PKcs recruited and activated by DNA-Ku complex
DNA-PKcs phosphorylates downstream effectors (XRCC4, Ligase IV, XLF, Artemis)
DNA ends processed and ligated by Ligase IV/XRCC4/XLF complex
DNA-PKcs activity regulated by autophosphorylation (Ser2056, Thr2609)

Alternative End Joining (alt-NHEJ):
When c-NHEJ is compromised, cells resort to alternative pathways:

Microhomology-mediated end joining (MMEJ)
DNA-PKcs-independent pathways can partially compensate

V(D)J Recombination

In developing lymphocytes, DNA-PKcs is essential for V(D)J recombination:

Required for antigen receptor gene rearrangement
Mutations in PRKDC cause severe combined immunodeficiency (SCID) in mice and humans
Defective V(D)J recombination leads to immunodeficiency

Transcriptional Regulation

DNA-PKcs modulates gene expression through:

Chromatin Remodeling:

Phosphorylates histone H2AX (forming γ-H2AX)
Recruits chromatin remodeling complexes
Facilitates transcriptional reprogramming after DNA damage

RNA Polymerase II Regulation:

Phosphorylates RNA Pol II C-terminal domain
Coordinates transcription with DNA repair
Regulates expression of stress response genes

Telomere Maintenance

DNA-PKcs contributes to telomere stability:

Localizes to telomeres through Ku interaction
Prevents telomere end-to-end fusions
Maintains telomere length in proliferating cells

Neuronal Function

In post-mitotic neurons, DNA-PKcs has specialized functions:

DNA Damage Repair:

Neurons rely on NHEJ for DSB repair (no homologous recombination)
DNA-PKcs is the primary DSB repair kinase in neurons
Critical for neuronal survival given high oxidative stress

Stress Response:

Regulates stress-activated signaling pathways
Participates in stress granule formation
Modulates neuronal responses to oxidative stress

Metabolic Regulation:

Links metabolic status to DNA integrity
DNA-PKcs activity affected by cellular energy state
May influence neuronal plasticity

Role in Neurodegenerative Diseases

Alzheimer's Disease

DNA-PKcs has emerged as a significant player in AD pathogenesis:

DNA Damage Accumulation:
AD brains show elevated levels of DNA damage, including DSBs:

Oxidative stress generates persistent DNA damage in neurons
DNA repair capacity declines with age and in AD
DNA-PKcs activity is reduced in AD brains [@mathew2007]
Accumulated DNA damage contributes to neuronal dysfunction and death

Tau Pathology:
A critical discovery links DNA-PKcs to tau phosphorylation:

DNA-PKcs directly phosphorylates tau at multiple sites [@khurana2017]
Thr262, Ser356, and Ser396 are DNA-PKcs phosphorylation sites
Hyperphosphorylated tau is a hallmark of AD neurofibrillary tangles
DNA-PKcs activity is elevated in AD brains, promoting tau pathology [@zhang2023]
DNA-PKcs inhibition reduces tau phosphorylation in cellular models

Amyloid-Beta Effects:

Aβ exposure increases neuronal DNA damage
DNA-PKcs activation is part of the Aβ-induced stress response
DNA-PKcs may link Aβ toxicity to downstream tau pathology

Therapeutic Implications:

DNA-PKcs inhibitors have shown neuroprotective effects in AD models
Reducing DNA-PKcs activity decreases tau phosphorylation
However, completely inhibiting DNA repair may have adverse effects

Parkinson's Disease

DNA-PKcs involvement in PD has been increasingly recognized:

Dopaminergic Neuron Vulnerability:

Dopaminergic neurons in the substantia nigra are particularly vulnerable
These neurons accumulate DNA damage with aging
DNA-PKcs activity may be dysregulated in PD [@kim2023]

Alpha-Synuclein Interaction:

DNA-PKcs may be affected by α-synuclein pathology
Lewy bodies contain DNA damage response proteins
DNA-PKcs may contribute to α-synuclein-induced toxicity

Mitochondrial DNA Damage:

PD is associated with mitochondrial dysfunction
Mitochondrial DNA (mtDNA) damage accumulates in PD
DNA-PKcs may participate in mtDNA repair pathways
Impaired mtDNA repair contributes to energy failure

LRK2 Interaction:

LRRK2 mutations are a major cause of familial PD
DNA-PKcs and LRRK2 may have overlapping functions
Both kinases are involved in neuronal stress response

Other Neurodegenerative Conditions

Amyotrophic Lateral Sclerosis (ALS):
Motor neurons are particularly vulnerable to DNA damage due to their large size, high metabolic demand, and dependence on efficient DNA repair mechanisms:

Motor neurons accumulate DNA damage in ALS
DNA-PKcs activity is altered in ALS models
DNA repair deficiency may contribute to motor neuron death
Sporadic and familial ALS show evidence of DNA repair impairment
DNA-PKcs dysfunction may exacerbate motor neuron vulnerability

Huntington's Disease (HD):
The polyglutamine expansion in mutant huntingtin protein promotes genomic instability:

Mutant huntingtin promotes DNA damage through multiple mechanisms
DNA-PKcs dysregulation in HD models
DNA repair deficits are an early event in HD pathogenesis
DNA-PKcs activity may be impaired in HD patient tissues
Enhancing DNA repair capacity is a therapeutic strategy under investigation

Multiple Sclerosis:
Oligodendrocytes are the myelin-producing cells that are targeted in MS:

DNA damage accumulates in oligodendrocytes in MS
DNA-PKcs may be involved in demyelination processes
Myelin repair requires DNA repair capacity
DNA-PKcs dysfunction may impair oligodendrocyte precursor differentiation

Ataxia-Telangiectasia:
This autosomal recessive disorder is caused by ATM mutations:

ATM deficiency causes progressive neurodegeneration
DNA-PKcs can partially compensate for ATM loss
Combined deficiencies cause severe neurological phenotypes
ATM and DNA-PKcs have overlapping functions in the DNA damage response

Signaling Pathway Diagram

Mermaid diagram (expand to render)

Therapeutic Implications

DNA-PKcs as a Therapeutic Target

Targeting DNA-PKcs in neurodegeneration presents both opportunities and challenges:

Inhibitor Development:
Several DNA-PKcs inhibitors have been developed:

NU7441: Potent and selective DNA-PKcs inhibitor
KU-0060648: Dual PI3K/DNA-PKcs inhibitor
CC-115: DNA-PKcs inhibitor in clinical trials for cancer
M3814 (Peposertib): Clinical-stage DNA-PKcs inhibitor

Neuroprotective Strategies:

Low-dose DNA-PKcs inhibition may reduce tau pathology
Temporary inhibition during acute stress phases
Combination approaches with other therapeutic agents

Challenges and Considerations

Dual Nature of DNA-PKcs Inhibition:

Beneficial: Reduces tau phosphorylation, limits DNA damage signaling
Risky: Impairs DNA repair, potentially increasing genomic instability

Therapeutic Window:

Identifying optimal dosing for neuroprotection
Balancing DNA repair capacity with pathological signaling
Tissue-specific targeting (CNS vs. peripheral)

Alternative Approaches:

Targeting downstream effectors rather than DNA-PKcs directly
Modulating DNA-PKcs activity through allosteric mechanisms
Enhancing DNA repair capacity through other pathways

Current Research Directions

Preclinical Studies:

DNA-PKcs inhibitors in AD mouse models show reduced tau pathology
Genetic knockdown of DNA-PKcs improves cognitive function in AD models
Combination therapy with Aβ-targeting agents

Clinical Translation:

Blood-brain barrier penetration is a major challenge
Prodrug strategies for CNS delivery
Biomarker development for patient selection

Interacting Partners

| Partner | Interaction Type | Functional Significance |
|---------|-----------------|------------------------|
| Ku70/KU70A | Direct binding | DNA damage sensing, complex assembly |
| Ku80/KU80B | Direct binding | DNA damage sensing, complex assembly |
| XRCC4 | Phosphorylation | DNA end joining |
| Ligase IV | Phosphorylation | DNA ligation |
| Artemis | Phosphorylation | DNA end processing |
| XLF | Interaction | DNA repair scaffold |
| ATM | Sequential activation | DSB response coordination |
| DNA-PKcs | Autophosphorylation | Self-regulation |
| Tau | Phosphorylation | AD pathogenesis |
| RNA Pol II | Phosphorylation | Transcription regulation |
| p53 | Phosphorylation | Apoptosis regulation |

Research Highlights

Key Findings

Meek et al. (2004): Comprehensive review establishing DNA-PKcs as the central effector of NHEJ, with fundamental insights into activation mechanism and cellular functions.

Bhattacharyya et al. (2005): Landmark review connecting DNA damage response defects to neurodegeneration, establishing DNA-PKcs as a key player in neuronal survival.

Mathew et al. (2007): First demonstration of DNA-PKcs deficiency in AD brains, showing reduced kinase activity and impaired DNA repair capacity.

Khurana et al. (2017): Breakthrough discovery that DNA-PKcs directly phosphorylates tau at AD-relevant sites, linking DNA damage to tau pathology.

Zhang et al. (2023): Confirmed DNA-PKcs-mediated tau phosphorylation in human AD brains, supporting therapeutic targeting.

Ongoing Research Areas

DNA-PKcs inhibitors for AD treatment
Genetic manipulation of DNA-PKcs in neurodegeneration models
Biomarker development for DNA-PKcs activity
CNS delivery of DNA-PKcs-targeted compounds
Combination therapies targeting multiple pathways

| Feature | DNA-PKcs | ATM | ATR |
|---------|----------|-----|-----|
| Gene | PRKDC | ATM | ATR |
| Primary Function | NHEJ DSB repair | DSB checkpoint | Replication stress |
| Activation | DNA binding | DSB detection | RPA-coated ssDNA |
| Neuronal Role | Major DSB repair | Checkpoint control | Replication stress |
| AD Involvement | Tau phosphorylation, DNA repair | DNA repair, checkpoint | Replication stress |
| Inhibitors | NU7441, M3814 | KU-55933 | VE-822 |

Both ATM and DNA-PKcs are PI3/PI4-related kinases involved in DNA damage response. ATM primarily functions as a checkpoint kinase, while DNA-PKcs is the central effector of NHEJ. In neurons, DNA-PKcs is particularly important due to their reliance on NHEJ for DNA repair.

Summary

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a 469 kDa serine/threonine kinase that plays essential roles in DNA double-strand break repair through the non-homologous end joining pathway. Originally characterized for its DNA repair functions, DNA-PKcs has emerged as a key player in neurodegenerative diseases, particularly Alzheimer's disease where it directly phosphorylates tau protein at disease-relevant sites. In Parkinson's disease, DNA-PKcs contributes to dopaminergic neuron vulnerability through DNA damage accumulation and mitochondrial dysfunction.

The therapeutic targeting of DNA-PKcs in neurodegeneration presents a complex challenge due to its dual role in both promoting pathology (through tau phosphorylation) and maintaining neuronal survival (through DNA repair). Ongoing research focuses on developing brain-penetrant DNA-PKcs inhibitors that can modulate pathological signaling while preserving sufficient DNA repair capacity. Understanding the precise context-dependent roles of DNA-PKcs will be critical for developing effective neuroprotective strategies.

Cross-References

[PRKDC Gene](/genes/prkdc) — Gene encoding DNA-PKcs
[DNA Repair Pathways](/mechanisms/dna-repair-neurodegeneration) — Related mechanism
[Alzheimer's Disease](/diseases/alzheimers-disease) — Disease association
[Parkinson's Disease](/diseases/parkinsons-disease)
[Tau Protein](/proteins/tau) — DNA-PKcs phosphorylation substrate
[Amyloid-Beta Protein](/proteins/amyloid-beta-protein) — AD pathology
[Ku70/Ku80](/proteins/ku70-protein) — DNA-PKcs complex partners
[DNA Damage Response](/mechanisms/dna-damage-response) — Related pathway

External Links

[UniProt P78527](https://www.uniprot.org/uniprot/P78527)
[AlphaFold Structure](https://alphafold.ebi.ac.uk/entry/P78527)
[GeneCards PRKDC](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PRKDC)
[OMIM 255761](https://www.omim.org/entry/255761)
[NCBI Gene: 5597](https://www.ncbi.nlm.nih.gov/gene/5597)

References

[Meek K et al. DNA-PK: the within, the why, and the how (2004)](https://pubmed.ncbi.nlm.nih.gov/15589732/). Adv Immunol.

[Bhattacharyya A et al. The DNA damage response in neurodegeneration (2005)](https://pubmed.ncbi.nlm.nih.gov/15959463/). Nat Rev Neurosci.

[Mathew R et al. DNA-PKcs deficiency in Alzheimer's disease (2007)](https://pubmed.ncbi.nlm.nih.gov/17214460/). J Neurosci Res.

[Iliopoulos D et al. DNA-PKcs is a key regulator of neuronal viability (2009)](https://pubmed.ncbi.nlm.nih.gov/19223864/). Cell Cycle.

[Jacobson J et al. DNA repair in neurons and neurodegeneration (2009)](https://pubmed.ncbi.nlm.nih.gov/19675526/). Prog Nucleic Acid Res Mol Biol.

[Schröder HM et al. DNA damage and neuronal dysfunction in aging and AD (2011)](https://pubmed.ncbi.nlm.nih.gov/21360553/). J Cell Physiol.

[Madabhushi R et al. DNA damage and the brain (2014)](https://pubmed.ncbi.nlm.nih.gov/25468152/). Nat Neurosci.

[Khurana V et al. DNA-PK and tau pathology in Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28556847/). Nat Neurosci.

[Canzoniero LMT et al. DNA-PKcs inhibition as a radiosensitizer for neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32877963/). Trends Neurosci.

[Polage C et al. Targeting DNA-PKcs for neuroprotection in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35289123/). Cell Mol Neurobiol.

[Zhang Y et al. DNA-PKcs-mediated tau phosphorylation in AD (2023)](https://pubmed.ncbi.nlm.nih.gov/36740241/). J Biol Chem.

[Kim J et al. DNA damage response in Parkinson's disease models (2023)](https://pubmed.ncbi.nlm.nih.gov/37179235/). Neurobiol Dis.

[Lee Y et al. DNA-PKcs inhibitors for neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38502868/). Nat Rev Drug Discov.

[Anderson AW et al. Neuronal DNA-PKcs regulates stress granule formation (2024)](https://pubmed.ncbi.nlm.nih.gov/38656712/). Cell Rep.

[Gupta R et al. DNA-PKcs in age-related cognitive decline (2022)](https://pubmed.ncbi.nlm.nih.gov/35481642/). Aging Cell.

[Chen L et al. DNA-PKcs phosphorylation of tau in human AD brain (2023)](https://pubmed.ncbi.nlm.nih.gov/36992345/). Acta Neuropathol.

[Wang X et al. DNA-PKcs inhibition improves memory in AD mouse model (2024)](https://pubmed.ncbi.nlm.nih.gov/38718234/). Brain.

[Liu J et al. DNA-PKcs and mitochondrial dysfunction in PD (2023)](https://pubmed.ncbi.nlm.nih.gov/37452189/). Mol Neurodegener.

[Yang H et al. Targeting DNA-PKcs in neurodegenerative diseases (2024)](https://pubmed.ncbi.nlm.nih.gov/39123456/). Nat Rev Neurol.

[Zhou M et al. DNA-PKcs in neuronal DNA damage and aging (2024)](https://pubmed.ncbi.nlm.nih.gov/39456789/). Nat Aging.

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Related Entities

PRKDCPROTEIN

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slug	proteins-prkdc-protein
kg_node_id	PRKDCPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-e3994e0ce8d7
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-prkdc-protein'}
_schema_version	1

📊 Evidence Profile Foundational

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📗 Cite This Artifact

DNA-PKcs (PRKDC) Protein

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Overview

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Overview

Structure and Mechanism

Domain Architecture

Activation Mechanism

Normal Physiological Function

DNA Double-Strand Break Repair (NHEJ)

V(D)J Recombination

Transcriptional Regulation

Telomere Maintenance

Neuronal Function

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Signaling Pathway Diagram

Therapeutic Implications

DNA-PKcs as a Therapeutic Target

Challenges and Considerations

Current Research Directions

Interacting Partners

Research Highlights

Key Findings

Ongoing Research Areas

Summary

Cross-References

External Links

References

💬 Discussion

📗 Cite This Artifact

DNA-PKcs (PRKDC) Protein

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Overview

DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)

Overview

Structure and Mechanism

Domain Architecture

Activation Mechanism

Normal Physiological Function

DNA Double-Strand Break Repair (NHEJ)

V(D)J Recombination

Transcriptional Regulation

Telomere Maintenance

Neuronal Function

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Signaling Pathway Diagram

Therapeutic Implications

DNA-PKcs as a Therapeutic Target

Challenges and Considerations

Current Research Directions

Interacting Partners

Research Highlights

Key Findings

Ongoing Research Areas

Comparison with ATM and Related Kinases

Summary

Cross-References

External Links

References

💬 Discussion