XRCC4

XRCC4 — X-Ray Repair Cross Complementing 4

Introduction

Xrcc4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@xrcc2020]
<table> [@dna2021]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">XRCC4</th></tr> [@nhej2022]
<tr><td><strong>Gene Symbol</strong></td><td>XRCC4</td></tr> [@xrcc2018]
<tr><td><strong>Full Name</strong></td><td>X-Ray Repair Cross Complementing 4</td></tr>
<tr><td><strong>Chromosome</strong></td><td>5q14.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[7518](https://www.ncbi.nlm.nih.gov/gene/7518)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[604432](https://www.omim.org/entry/604432)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000152457</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q01426](https://www.uniprot.org/uniprot/Q01426)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Cancer, Immunodeficiency, Neurodegeneration</td></tr>
</table>
</div>

Overview

...

XRCC4 — X-Ray Repair Cross Complementing 4

Introduction

Xrcc4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@xrcc2020]
<table> [@dna2021]
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">XRCC4</th></tr> [@nhej2022]
<tr><td><strong>Gene Symbol</strong></td><td>XRCC4</td></tr> [@xrcc2018]
<tr><td><strong>Full Name</strong></td><td>X-Ray Repair Cross Complementing 4</td></tr>
<tr><td><strong>Chromosome</strong></td><td>5q14.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[7518](https://www.ncbi.nlm.nih.gov/gene/7518)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[604432](https://www.omim.org/entry/604432)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000152457</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q01426](https://www.uniprot.org/uniprot/Q01426)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Cancer, Immunodeficiency, Neurodegeneration</td></tr>
</table>
</div>

Overview

X-Ray Repair Cross Complementing 4 (XRCC4) is a core component of the non-homologous end joining (NHEJ) DNA double-strand break repair pathway. As the essential binding partner of DNA Ligase IV (LIG4), XRCC4 plays a critical role in joining DNA ends during NHEJ and is absolutely required for V(D)J recombination in developing lymphocytes. XRCC4 deficiency in humans causes severe combined immunodeficiency (SCID) with microcephaly, while complete knockout in mice is embryonic lethal. Beyond its well-established role in DNA repair, XRCC4 has been implicated in neurodegeneration, with altered expression and function observed in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.

Function

NHEJ DNA Repair

XRCC4 functions as the essential co-factor for DNA Ligase IV in the NHEJ pathway. The XRCC4 protein forms a stable heterotetramer with LIG4, which is required for:

• Stabilizing LIG4 in the nucleus
• Enhancing LIG4's DNA binding affinity
• Facilitating the ligation reaction

The XRCC4-LIG4 complex is recruited to DNA double-strand breaks by the Ku70/Ku80 heterodimer, which binds to free DNA ends and initiates the NHEJ repair process. XRCC4 interacts directly with Ku and DNA-PKcs, positioning the ligase complex at the repair site. Additional processing by Artemis endonuclease and polymerases mu/lambda prepares the DNA ends, after which XRCC4-LIG4 catalyzes final ligation.

V(D)J Recombination

XRCC4 is absolutely essential for V(D)J recombination, the site-specific DNA rearrangement process that generates antibody and T-cell receptor diversity. During V(D)J recombination:

• RAG1/2 endonuclease introduces double-strand breaks at recombination signal sequences
• The DNA ends are protected and processed by the NHEJ machinery
• XRCC4-LIG4 joins the coding segments and signal sequences

Mutations in XRCC4 cause SCID with impaired V(D)J recombination, similar to LIG4 deficiency.

Alternative Functions

Beyond canonical NHEJ, XRCC4 has been implicated in:

• Telomere maintenance through alternative lengthening of telomeres (ALT)
• Transcription regulation through interactions with chromatin modifiers
• Mitochondrial DNA repair
• Neural development

Disease Associations

Immunodeficiency

Biallelic XRCC4 mutations cause a form of SCID characterized by:

• Severe T and B cell lymphopenia
• Combined immunodeficiency
• Microcephaly and developmental delay
• Growth retardation
• Increased cancer risk

This phenotype overlaps with LIG4 syndrome, reflecting their functional partnership.

Neurodegenerative Diseases

Alzheimer's Disease (AD):

• XRCC4 expression is altered in AD brain, particularly in vulnerable regions like [hippocampus](/brain-regions/hippocampus) and [entorhinal cortex](/brain-regions/entorhinal-cortex)
• NHEJ efficiency decreases with aging and in AD
• DNA damage accumulation in [neurons](/entities/neurons) may contribute to synaptic dysfunction and neuronal loss
• XRCC4 polymorphisms may modify AD risk

Parkinson's Disease (PD):

• Oxidative stress in PD substantia nigra increases DNA damage burden
• XRCC4 may be involved in repairing mitochondrial DNA damage
• Altered NHEJ capacity in PD patient fibroblasts
• XRCC4 variants may influence PD susceptibility

Amyotrophic Lateral Sclerosis (ALS):

• Motor neurons are particularly vulnerable to DNA damage due to high metabolic demand
• RNA processing defects may lead to increased R-loop formation and DNA damage
• XRCC4 dysfunction may exacerbate motor neuron degeneration

Ataxia-Telangiectasia (AT):

• AT cells have impaired NHEJ due to ATM deficiency
• XRCC4 compensation may be reduced
• Combined defects accelerate neurodegeneration

Cancer

XRCC4 polymorphisms have been associated with cancer risk:

• Reduced XRCC4 expression may allow survival of genetically damaged cells
• Single nucleotide polymorphisms (SNPs) in XRCC4 modify cancer susceptibility
• XRCC4 may be overexpressed in certain tumors as an adaptive response

Expression

XRCC4 is ubiquitously expressed with high levels in:

• Lymphoid tissues (thymus, spleen, bone marrow)
• Brain (neurons, glia)
• Testis
• Embryonic tissues

In the brain, XRCC4 is expressed in:

• Cerebral [cortex](/brain-regions/cortex) pyramidal neurons
• Hippocampal CA1-CA3 neurons
• Cerebellar Purkinje cells
• Dopaminergic neurons of substantia nigra
• Cortical interneurons

Expression is generally higher in proliferating cells but is maintained in post-mitotic neurons for ongoing DNA repair.

Therapeutic Implications

Neurodegeneration

Strategies targeting DNA repair in neurodegeneration include:

• Gene therapy to enhance XRCC4-LIG4 function
• Small molecule activators of NHEJ
• Antioxidants to reduce oxidative DNA damage
• Lifestyle interventions to reduce DNA damage burden

Cancer

XRCC4 is a potential therapeutic target:

• XRCC4 inhibition may sensitize tumors to radiation therapy
• Synthetic lethality with other DNA repair defects
• Biomarker for DNA repair capacity in tumors

Cross-links

• [DNA Repair in Neurodegeneration](/mechanisms/dna-repair-neurodegeneration)
• [LIG4](/genes/lig4)
• [XRCC1](/genes/xrcc1)
• [DNA-PKcs](/proteins/dna-pkcs-protein)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

Pathway & Interaction Diagram

Interactive diagram showing XRCC4's key relationships in the SciDEX knowledge graph (7 connections shown).

See Also

• [Genes Index](/genes)
• [DNA Repair Genes](/entities/dna-repair-genes)

Background

The study of Xrcc4 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Unknown, XRCC4 and LIG4 in NHEJ: structure and function (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31162845/)

[Unknown, XRCC4 deficiency causes immunodeficiency (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32197074/)

[Unknown, DNA damage in Alzheimer's disease brain (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34421076/)

[Unknown, NHEJ repair in neuronal survival (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35653892/)

[Unknown, XRCC4 polymorphisms and cancer risk (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29524689/)

Pathway Diagram

The following diagram shows the key molecular relationships involving XRCC4 discovered through SciDEX knowledge graph analysis: