TREX1

Three prime repair exonuclease 1 is an enzyme that in humans is encoded by the TREX1 gene.

TREX1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2IOC, 2O4G, 2O4I, 2OA8, 3B6O, 3B6P, 3MXI, 3MXJ, 3MXM, 3U3Y, 3U6F, 4YNQ
Identifiers
Aliases	TREX1, AGS1, CRV, DRN3, HERNS, three prime repair exonuclease 1, RVCLS
External IDs	OMIM: 606609; MGI: 1328317; HomoloGene: 7982; GeneCards: TREX1; OMA:TREX1 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3p21.31 Start 48,465,811 bp End 48,467,645 bp
Gene location (Mouse) Chr. Chromosome 9 (mouse) Band 9|9 F2 Start 108,887,001 bp End 108,888,802 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in olfactory zone of nasal mucosa granulocyte monocyte spleen skin of abdomen skin of leg anterior pituitary blood salivary gland minor salivary glands Top expressed in lens spleen urinary bladder quadriceps femoris muscle adrenal gland bone marrow granulocyte muscle tissue muscle of thigh white adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity metal ion binding single-stranded DNA binding exodeoxyribonuclease III activity MutSalpha complex binding protein binding 3'-5'-exodeoxyribonuclease activity MutLalpha complex binding nucleic acid binding nuclease activity exonuclease activity hydrolase activity 3'-5' exonuclease activity double-stranded DNA binding adenyl deoxyribonucleotide binding magnesium ion binding DNA binding DNA binding, bending WW domain binding Cellular component cytoplasm nuclear envelope endoplasmic reticulum membrane membrane endoplasmic reticulum nucleus cytosol oligosaccharyltransferase complex protein-DNA complex nuclear replication fork Biological process DNA recombination regulation of type I interferon production DNA replication DNA mismatch repair nucleic acid phosphodiester bond hydrolysis DNA metabolic process DNA repair cellular response to interferon-beta blood vessel development kidney development adaptive immune response organ or tissue specific immune response activation of immune response macrophage activation involved in immune response lymphoid progenitor cell differentiation immune response in brain or nervous system inflammatory response to antigenic stimulus T cell antigen processing and presentation regulation of immunoglobulin production heart morphogenesis heart process atrial cardiac muscle tissue development generation of precursor metabolites and energy regulation of glycolytic process DNA modification DNA catabolic process inflammatory response immune response cellular response to DNA damage stimulus determination of adult lifespan response to UV regulation of gene expression regulation of fatty acid metabolic process regulation of cellular metabolic process transposition, RNA-mediated DNA duplex unwinding interferon-alpha production regulation of tumor necrosis factor production cellular response to oxidative stress cellular response to reactive oxygen species cellular response to UV CD86 biosynthetic process apoptotic cell clearance regulation of cellular respiration innate immune response regulation of innate immune response establishment of protein localization regulation of lipid biosynthetic process regulation of inflammatory response regulation of catalytic activity protein stabilization regulation of T cell activation defense response to virus type I interferon signaling pathway negative regulation of type I interferon-mediated signaling pathway regulation of protein complex stability cellular response to organic substance cellular response to type I interferon cellular response to gamma radiation cellular response to hydroxyurea immune complex formation DNA synthesis involved in UV-damage excision repair regulation of lysosome organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11277 22040 Ensembl ENSG00000213689 ENSMUSG00000049734 UniProt Q9NSU2 Q91XB0 RefSeq (mRNA) NM_033629 NM_007248 NM_016381 NM_033627 NM_033628 NM_001012236 NM_011637 RefSeq (protein) NP_009179 NP_338599 NP_001012236 NP_035767 Location (UCSC) Chr 3: 48.47 – 48.47 Mb Chr 9: 108.89 – 108.89 Mb PubMed search
Wikidata
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Function

This gene encodes the major 3'->5' DNA exonuclease in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.

Clinical relevance

Mutations within the TREX1 gene cause familial chilblain lupus. The TREX1 polymorphisms confer susceptibility to systemic lupus erythematosus. Missense mutations of the TREX1 gene significantly downregulate its exonucleolytic capacity and result in the accumulation of nucleic acids. The build-up of the nucleic acids within the cytoplasm stimulates type-I interferon responses that could trigger autoimmune responses. The region containing the TREX1 gene (3p21.31) has been linked to COVID-19 severity in a recent genome-wide association study. This might explain the occurrence of chilblain like lesions in patients infected with SARS-CoV-2.

TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm

Mutations in TREX1 can give cause failure to appropriately remove ribonucleotides misincorporated into DNA. The removal process is ordinary performed by ribonucleotide excision repair. In humans, a defect in this process can give rise to Aicardi-Goutieres syndrome involving microcephaly and neuroinflammation.

Homology directed DNA repair

TREX1 is the most abundant 3’-5’ DNA exonuclease in mammals. Dominant C-terminal TREX1 genetic variants can disrupt homology-directed DNA repair and thus can trigger DNA damage and premature senescence phenotypes in humans, mice and Drosophila. Such TREX1 variants can also cause adult onset small vessel disease known as vasculopathy with cerebral leukoencephalopathy.

Further reading

• Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JB (1996). "The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis)". J. Med. Genet. 32 (11): 881–4. doi:10.1136/jmg.32.11.881. PMC 1051740. PMID 8592332.
• Black DN, Watters GV, Andermann E, et al. (1989). "Encephalitis among Cree children in northern Quebec". Ann. Neurol. 24 (4): 483–9. doi:10.1002/ana.410240402. PMID 3239950. S2CID 32112982.
• Perrino FW, Miller H, Ealey KA (1994). "Identification of a 3'-->5'-exonuclease that removes cytosine arabinoside monophosphate from 3' termini of DNA". J. Biol. Chem. 269 (23): 16357–63. doi:10.1016/S0021-9258(17)34015-2. PMID 8206943.
• Goutières F, Aicardi J, Barth PG, Lebon P (1999). "Aicardi-Goutières syndrome: an update and results of interferon-alpha studies". Ann. Neurol. 44 (6): 900–7. doi:10.1002/ana.410440608. PMID 9851434. S2CID 58224378.
• Crow YJ, Jackson AP, Roberts E, et al. (2000). "Aicardi-Goutières Syndrome Displays Genetic Heterogeneity with One Locus (AGS1) on Chromosome 3p21". Am. J. Hum. Genet. 67 (1): 213–21. doi:10.1086/302955. PMC 1287108. PMID 10827106.
• Mazur DJ, Perrino FW (2001). "Structure and expression of the TREX1 and TREX2 3' --> 5' exonuclease genes". J. Biol. Chem. 276 (18): 14718–27. doi:10.1074/jbc.M010051200. PMID 11278605.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Crow YJ, Black DN, Ali M, et al. (2003). "Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism". J. Med. Genet. 40 (3): 183–7. doi:10.1136/jmg.40.3.183. PMC 1735395. PMID 12624136.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Unsal-Kaçmaz K, Mullen TE, Kaufmann WK, Sancar A (2005). "Coupling of Human Circadian and Cell Cycles by the Timeless Protein". Mol. Cell. Biol. 25 (8): 3109–16. doi:10.1128/MCB.25.8.3109-3116.2005. PMC 1069621. PMID 15798197.
• Rual JF, Venkatesan K, Hao T, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Yoshioka K, Yoshioka Y, Hsieh P (2006). "ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts". Mol. Cell. 22 (4): 501–10. doi:10.1016/j.molcel.2006.04.023. PMC 2423943. PMID 16713580.
• Chowdhury D, Beresford PJ, Zhu P, et al. (2006). "The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death". Mol. Cell. 23 (1): 133–42. doi:10.1016/j.molcel.2006.06.005. PMID 16818237.
• Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.
• Crow YJ (November 2016). Aicardi-Goutières Syndrome. GeneReviews® [Internet]. University of Washington, Seattle. PMID 20301648. NBK1475.

External links

• OMIM entries on Aicardi-Goutieres syndrome