TREX1
Function
Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini (PubMed:10391904, PubMed:10393201, PubMed:17293595). Prevents cell-intrinsic initiation of autoimmunity (PubMed:10391904, PubMed:10393201, PubMed:17293595). Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements (PubMed:10391904, PubMed:10393201, PubMed:17293595). Plays a key role in degradation of DNA fragments at cytosolic micronuclei arising from genome instability: its association with the endoplasmic reticulum membrane directs TREX1 to ruptured micronuclei, leading to micronuclear DNA degradation (PubMed:33476576). Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation (PubMed:33476576). Unless degraded, these DNA fragments accumulate in the cytosol and activate the cGAS-STING innate immune signaling, leading to the production of type I interferon (PubMed:33476576). Prevents chronic ATM-dependent checkpoint activation, by processing ssDNA polynucleotide species arising from the processing of aberrant DNA replication intermediates (PubMed:18045533). Inefficiently degrades oxidized DNA, such as that generated upon antimicrobial reactive oxygen production or upon absorption of UV light (PubMed:23993650). During GZMA-mediated cell death, contributes to DNA damage in concert with NME1 (PubMed:16818237). NME1 nicks one strand of DNA and TREX1 removes bases from the free 3' end to enhance DNA damage and prevent DNA end reannealing and rapid repair (PubMed:16818237).
Involvement in disease
Aicardi-Goutieres syndrome 1
AGS1
A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
None
The disease is caused by variants affecting the gene represented in this entry.
Systemic lupus erythematosus
SLE
A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry. Enhanced immune sensing of oxidized DNA may be involved in the phototoxicity experienced by SLE patients. Exposure to UV-light produces DNA oxidative damage. Oxidized DNA being a poor TREX1 substrate, it accumulates in skin, leading to enhanced auto-immune reactivity and eventually skin lesions (PubMed:23993650).
Chilblain lupus 1
CHBL1
A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure.
None
The disease is caused by variants affecting the gene represented in this entry.
Vasculopathy, retinal, with cerebral leukoencephalopathy and systemic manifestations
RVCLS
An adult-onset, autosomal dominant endotheliopathy affecting the microvessels of the brain. It results in central nervous system degeneration and retinopathy, with progressive loss of vision, stroke, motor impairment, and cognitive decline. The ocular manifestations are characterized by telangiectasias, microaneurysms and retinal capillary obliteration starting in the macula. Diseased cerebral white matter has prominent small infarcts that often coalesce to pseudotumors. A subset of patients have systemic vascular involvement that can manifest as Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Ubiquitinated, but not targeted to proteasomal degradation. Ubiquitination may be important for interaction with UBQLN1.
Sequence Similarities
Belongs to the exonuclease superfamily. TREX family.
Tissue Specificity
Detected in thymus, spleen, liver, brain, heart, small intestine and colon.
Cellular localization
- Nucleus
- Cytoplasm
- Cytosol
- Endoplasmic reticulum membrane
- Peripheral membrane protein
- Retained in the cytoplasm through the C-terminal region (By similarity). Localization to the endoplasmic reticulum membrane is required to direct TREX1 to ruptured micronuclei (PubMed:33476576). In response to DNA damage, translocates to the nucleus where it is specifically recruited to replication foci (PubMed:16818237). Translocation to the nucleus also occurs during GZMA-mediated cell death (PubMed:16818237).
Alternative names
Three-prime repair exonuclease 1, 3'-5' exonuclease TREX1, Deoxyribonuclease III, DNase III, TREX1