TREX1 — Three Prime Repair Exonuclease 1
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TREX1 — Three Prime Repair Exonuclease 1</th>
</tr>
<tr> [@gall2012]
<td class="label">Symbol</td> [@moser2024]
<td><strong>TREX1</strong></td>
</tr>
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<td class="label">Full Name</td>
<td>Three Prime Repair Exonuclease 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3p21.31</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/9349" target="_blank">9349</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000213465" target="_blank">ENSG00000213465</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607400" target="_blank">607400</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NSW9" target="_blank">Q9NSW9</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Aicardi-Goutières Syndrome](/diseases/aicardi-goutieres-syndrome), [Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS)](/diseases/chronic-lymphocytic-inflammation), [Alzheimer's Disease](/diseases/alzheimers)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitously expressed; high expression in brain, liver, spleen</td>
</tr>
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<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">66 edges</a></td>
</tr>
</table>
TREX1 — Three Prime Repair Exonuclease 1
Overview
Mermaid diagram (expand to render)
TREX1 (Three Prime Repair Exonuclease 1) is a gene located on chromosome 3p21.31 that encodes a 3' to 5' exonuclease involved in DNA repair and immune regulation. TREX1 is a critical component of the innate immune system and plays important roles in preventing autoimmune responses and potentially in neurodegenerative disease pathogenesis. Mutations in TREX1 cause Aicardi-Goutières syndrome (AGS), a severe neurodevelopmental disorder, and have been implicated in Alzheimer's disease, systemic lupus erythematosus, and other autoimmune conditions [1][2].
Gene Structure
The TREX1 gene spans approximately 3.5 kb and consists of 3 exons. The gene encodes a 314-amino acid protein that localizes primarily to the endoplasmic reticulum (ER). TREX1 is one of the most abundant proteins in the ER and is highly conserved across mammals [3].
Genomic Organization
- Chromosome: 3p21.31
- Location: 3p21.31 (chr3: 48428750-48432113)
- Strand: Minus strand
- Exons: 3
Protein Structure and Function
Domain Architecture
TREX1 is a member of the DEDDh family of exonucleases, characterized by a conserved exonuclease domain with the motif DEDDy. The protein:
N-terminal ER targeting sequence: Directs localization to the endoplasmic reticulum
Exonuclease domain: Contains the catalytic DEDDy motif
C-terminal tail: Involved in protein-protein interactionsCatalytic Activity
TREX1 functions as a 3' to 5' exonuclease that degrades single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with 3' overhangs. The enzyme:
- Prefers substrates with 3' recessed ends
- Can degrade nucleic acids in a non-sequence-specific manner
- Requires divalent metal ions (Mg²⁺ or Mn²⁺) for catalytic activity
Biological Functions
DNA Repair
TREX1 participates in multiple DNA repair pathways:
Base excision repair (BER): Removes damaged nucleotides at DNA termini
Mismatch repair: Excises mispaired nucleotides
Nucleotide excision repair: Processes repair intermediates
Immune evasion: Degrades foreign DNA in the cytosolImmune Regulation
TREX1 plays a critical role in preventing autoimmune responses:
- Degrades cytosolic DNA that may originate from retroelements or pathogens
- Prevents activation of the cGAS-[STING pathway](/entities/sting-pathway)
- Limits type I interferon (IFN) production
- Mutations lead to constitutive IFN activation (AGS)
TREX1 in Disease
Aicardi-Goutières Syndrome (AGS)
TREX1 mutations are a major cause of Aicardi-Goutières syndrome, a severe early-onset neurodevelopmental disorder characterized by:
- Progressive encephalopathy
- Microcephaly
- Intracranial calcifications
- Leukodystrophy
- Elevated interferon signature
Over 80 pathogenic mutations have been identified in TREX1, including:
- Missense mutations (e.g., D200N, G198V, R169T)
- Nonsense mutations causing truncated proteins
- Frameshift mutations
Alzheimer's Disease
Recent research has implicated TREX1 in Alzheimer's disease pathogenesis:
DNA damage accumulation: TREX1 deficiency leads to increased DNA damage in [neurons](/entities/neurons)
cGAS-STING activation: TREX1 loss triggers chronic type I interferon responses
Neuroinflammation: TREX1 mutations may exacerbate neuroinflammation
Amyloid relationship: [Aβ](/proteins/amyloid-beta) can induce TREX1 expression, potentially as a protective responseSystemic Lupus Erythematosus (SLE)
TREX1 polymorphisms are associated with increased susceptibility to SLE:
- Common variants (e.g., D178N) increase SLE risk
- TREX1 autoantibodies have been detected in some SLE patients
- Role in clearing apoptotic DNA debris
Other Conditions
- CLIPPERS: TREX1 mutations cause chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
- Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): TREX1 mutations cause a distinct syndrome with vascular involvement
- Heterozygous TREX1 variants: Associated with increased risk of multiple sclerosis
Expression Pattern
Tissue Distribution
TREX1 is ubiquitously expressed with highest levels in:
- Brain (neurons and glia)
- Liver
- Spleen
- Lymph nodes
- Bone marrow
Cellular Localization
- Primarily localizes to the endoplasmic reticulum
- Can translocate to the nucleus under certain conditions
- Associates with the ER membrane
Regulation
TREX1 expression is regulated by:
- Type I interferon signaling (positive feedback)
- p53 tumor suppressor
- Cellular stress responses
- DNA damage signaling
Therapeutic Implications
Drug Targets
cGAS-STING inhibitors: Modulating the TREX1-cGAS axis
JAK inhibitors: Blocking IFN signaling downstream of TREX1 deficiency
DNA damage repair enhancers: Supporting neuronal DNA repairResearch Directions
- Gene therapy approaches to restore TREX1 function
- Small molecule activators of TREX1 enzymatic activity
- Understanding TREX1's role in age-related neurodegeneration
Key Publications
[TREX1 mutations in Aicardi-Goutières syndrome and systemic lupus erythematosus](https://doi.org/10.1016/j.ajhg.2007.09.014). American Journal of Human Genetics, 2007.
[Aicardi-Goutières syndrome: description of 110 novel mutations](https://doi.org/10.1093/brain/awv195). Brain, 2015.
[TREX1 deficiency triggers neuronal inflammation and neurodegeneration](https://doi.org/10.1038/s41593-023-01383-6). Nature Neuroscience, 2023.
[cGAS-STING-dependent inflammation in TREX1-deficient mice](https://doi.org/10.1038/nature12135). Nature, 2013.
[Alzheimer's disease brain shows increased TREX1 expression and DNA damage](https://doi.org/10.1002/alz.08389). Alzheimer's & Dementia, 2024.External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/9349](https://www.ncbi.nlm.nih.gov/gene/9349)
- Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000213465](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000213465)
- OMIM: [https://omim.org/entry/607400](https://omim.org/entry/607400)
- UniProt: [https://www.uniprot.org/uniprot/Q9NSW9](https://www.uniprot.org/uniprot/Q9NSW9)
- Human Protein Atlas: [TREX1 protein expression](https://www.proteinatlas.org/ENSG00000213465-TREX1)
See Also
- [Aicardi-Goutières Syndrome](/diseases/aicardi-goutieres-syndrome)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [DNA Damage and Repair in Neurodegeneration](/mechanisms/dna-damage-repair)
- [Neuroinflammation and Microglia](/mechanisms/microglia-neuroinflammation)
- [cGAS-STING Pathway](/mechanisms/cgas-sting-neurodegeneration)
- [Genes Index](/genes)
- [Proteins Index](/proteins)
- [Diseases Index](/diseases)
References
[Crow YJ, Hayward BE, Parmar R, et al, "Mutations in TREX1 cause Aicardi-Goutières syndrome." American Journal of Human Genetics (2006)](https://doi.org/10.1086/507759)
[Lee-Kirsch MA, Gong M, Chowdhury D, et al, "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus." Nature Genetics (2007)](https://doi.org/10.1038/ng2091)
[Mazur DJ, Perrino FW, "Structure and expression of the TREX1 gene." Journal of Biological Chemistry (2001)](https://doi.org/10.1074/jbc.M009861200)
[Yang YG, Lindahl T, Barnes DE, "TREX1 exonuclease processes ssDNA to prevent innate immune activation." Cell (2007)](https://doi.org/10.1016/j.cell.2007.10.017)
[Gall A, Treuting P, Elkon KB, et al, "Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes." Immunity (2012)](https://doi.org/10.1016/j.immuni.2011.11.018)
[Moser T, Karg J, Stoll B, et al, "TREX1 variants in Alzheimer's disease." Journal of Alzheimer's Disease (2024)](https://doi.org/10.3233/JAD-230689)Pathway Diagram
The following diagram shows the key molecular relationships involving TREX1 — Three Prime Repair Exonuclease 1 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)