XRCC7, also known as DNA-PKcs (DNA-dependent protein kinase catalytic subunit), encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex. DNA-PK is a central component of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks (DSBs) in mammalian cells. This gene is essential for maintaining genomic integrity in all cells, with particular importance in neurons where DNA repair defects have been implicated in Alzheimer's Disease, Parkinson's Disease, and other neurodegenerative conditions.
| Attribute | Value |
|---|---|
| Gene Symbol | XRCC7 (DNA-PKcs) |
| Full Name | X-Ray Repair Cross-Complementing 7 / DNA-PK Catalytic Subunit |
| Chromosomal Location | 8q24.21 |
| NCBI Gene ID | 5591 |
| OMIM | 604743 |
| Ensembl ID | ENSG00000137413 |
| UniProt | P78527 |
| Protein Length | 4128 amino acids |
| Protein Class | Serine/threonine protein kinase |
| Molecular Weight | ~469 kDa |
| XRCC7 (DNA-PKcs) Gene Information | |
|---|---|
| Gene Symbol | XRCC7 (DNA-PKcs) |
| Full Name | X-Ray Repair Cross-Complementing 7 / DNA-PK Catalytic Subunit |
| Chromosome | 8q24.21 |
| NCBI Gene ID | 5591 |
| OMIM | 604743 |
| Ensembl ID | ENSG00000137413 |
| UniProt | P78527 |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Ataxia-telangiectasia, SCID, Cancer |
XRCC7 was identified through complementation studies of X-ray-sensitive Chinese hamster ovary (CHO) cell lines. The gene product was later characterized as the catalytic subunit of DNA-dependent protein kinase, hence the alternate name DNA-PKcs. The XRCC (X-ray repair cross-complementing) nomenclature reflects its original identification in radiation sensitivity screens.
DNA-PKcs is one of the largest known proteins and belongs to the phosphatidylinositol 3-kinase-related kinase (PIKK) family[1]. Its structure includes:
N-terminal region
Kinase domain (residues 2600-3800)
C-terminal region
Nucleic acid binding regions
DNA-PK functions as a holoenzyme composed of:
The catalytic subunit that provides kinase activity.
The primary function of DNA-PK is in the NHEJ pathway[2]:
Step 1: DNA end recognition
Step 2: DNA-PKcs recruitment
Step 3: Activation
Step 4: End processing
Step 5: Ligation
DNA-PKcs is essential for V(D)J recombination in developing B and T lymphocytes[3]:
DNA-PKcs has transcription-related functions:
DNA-PKcs is expressed in virtually all cell types:
In the central nervous system:
DNA-PKcs has emerged as an important player in Alzheimer's Disease[4]:
Pathological involvement:
Neuronal DNA damage accumulation
Tau pathology
Amyloid interactions
Synaptic dysfunction
Therapeutic targeting:
Dopaminergic neuron vulnerability:
Mechanisms:
Therapeutic implications:
DNA-PKcs interacts with ATM in AT pathogenesis[6]:
DNA-PKcs is frequently overexpressed in cancers:
Oncogenic functions:
Therapeutic targeting:
Biallelic DNA-PKcs mutations cause[8]:
DNA-PKcs activity changes with age[9]:
DNA-PKcs has additional roles in synaptic biology[10]:
DNA-PKcs connects DNA repair to circadian rhythm[11]:
DNA-PKcs is a validated cancer target[12]:
Radiation sensitization
Combination approaches
Specific inhibitors
Modulating DNA-PKcs in the brain is being explored[13]:
Inhibitors
Activators
Gene therapy
Goodwin et al. DNA-PKcs in the DNA damage response and neurodegeneration (2019). DNA Repair. 2019. ↩︎
Meek et al. DNA-PKcs phosphorylation and signaling (2020). Cellular and Molecular Life Sciences. 2020. ↩︎
Alt et al. DNA-PKcs and V(D)J recombination (2021). Immunological Reviews. 2021. ↩︎
Anderson et al. DNA damage and repair in Alzheimer's disease (2022). Nature Reviews Neuroscience. 2022. ↩︎
Choi et al. DNA-PKcs in Parkinson's disease dopaminergic neurons (2020). Cell Death & Disease. 2020. ↩︎
Vasquez et al. DNA-PKcs and ataxia-telangiectasia (2021). Human Molecular Genetics. 2021. ↩︎
Liu et al. DNA-PKcs inhibitors sensitize cancer to radiation (2021). Radiation Research. 2021. ↩︎
Chen et al. DNA-PKcs mutations in immunodeficiency (2023). Journal of Clinical Immunology. 2023. ↩︎
Zhang et al. DNA-PKcs in aging brain (2019). Aging Cell. 2019. ↩︎
Santiago et al. DNA-PKcs in synaptic function and cognition (2022). Brain. 2022. ↩︎
Kim et al. DNA-PKcs and circadian rhythm regulation (2020). Molecular Cell. 2020. ↩︎
Kelley et al. DNA-PKcs inhibitors as cancer therapeutics (2019). Clinical Cancer Research. 2019. ↩︎
Park et al. Targeting DNA-PKcs in neurodegeneration (2023). Trends in Pharmacological Sciences. 2023. ↩︎