TREX1 (original) (raw)

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Protein-coding gene in the species Homo sapiens

TREX1
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes2IOC, 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)Chromosome 3 (human)Chr.Chromosome 3 (human)[1]Chromosome 3 (human)Genomic location for TREX1Genomic location for TREX1Band3p21.31Start48,465,811 bp[1]End48,467,645 bp[1]
Gene location (Mouse)Chromosome 9 (mouse)Chr.Chromosome 9 (mouse)[2]Chromosome 9 (mouse)Genomic location for TREX1Genomic location for TREX1Band9|9 F2Start108,887,001 bp[2]End108,888,802 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed inolfactory zone of nasal mucosagranulocytemonocytespleenskin of abdomenskin of leganterior pituitarybloodsalivary glandminor salivary glandsTop expressed inlensspleenurinary bladderquadriceps femoris muscleadrenal glandbone marrowgranulocytemuscle tissuemuscle of thighwhite adipose tissueMore reference expression dataBioGPSMore reference expression data
Gene ontologyMolecular 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
OrthologsSpeciesHuman MouseEntrez1127722040EnsemblENSG00000213689ENSMUSG00000049734UniProtQ9NSU2Q91XB0RefSeq (mRNA)NM_033629NM_007248NM_016381NM_033627NM_033628NM_001012236NM_011637RefSeq (protein)NP_009179NP_338599NP_001012236NP_035767Location (UCSC)Chr 3: 48.47 – 48.47 MbChr 9: 108.89 – 108.89 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Three prime repair exonuclease 1 is an enzyme that in humans is encoded by the TREX1 gene.[5][6][7][8]

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.[8]

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.[9] The region containing the TREX1 gene (3p21.31) has been linked to COVID-19 severity in a recent genome-wide association study.[10] This might explain the occurrence of chilblain like lesions in patients infected with SARS-CoV-2.[9]

TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm[11]

Mutations in TREX1 can give cause failure to appropriately remove ribonucleotides misincorporated into DNA.[12] 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.[12]

Homology directed DNA repair

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TREX1 is the most abundant 3’-5’ DNA exonuclease in mammals.[13] 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.[13] Such TREX1 variants can also cause adult onset small vessel disease known as vasculopathy with cerebral leukoencephalopathy.[13]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000213689 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049734 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Mazur DJ, Perrino FW (Aug 1999). "Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'-->5' exonucleases". J Biol Chem. 274 (28): 19655–60. doi:10.1074/jbc.274.28.19655. PMID 10391904.
  6. ^ Hoss M, Robins P, Naven TJ, Pappin DJ, Sgouros J, Lindahl T (Aug 1999). "A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein". EMBO J. 18 (13): 3868–75. doi:10.1093/emboj/18.13.3868. PMC 1171463. PMID 10393201.
  7. ^ Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T (Jul 2006). "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus". Nat Genet. 38 (8): 917–20. doi:10.1038/ng1845. PMID 16845398. S2CID 9069106.
  8. ^ a b "Entrez Gene: TREX1 three prime repair exonuclease 1".
  9. ^ a b Jabalameli, Navid (2021). "Overlap between Genetic Susceptibility to COVID-19 and Skin Diseases". Immunological Investigations. 51 (4): 1087–94. doi:10.1080/08820139.2021.1876086. PMID 33494631.
  10. ^ Ellinghaus (2020). "Genomewide Association Study of Severe Covid-19 with Respiratory Failure". New England Journal of Medicine. 383 (16): 1522–34. doi:10.1056/NEJMoa2020283. PMC 7315890. PMID 32558485.
  11. ^ Doyle, Thomas (27 April 2015). "HIV-1 and interferons: who's interfering with whom?". Nature Reviews Microbiology. 13 (Nature Reviews Microbiology 13): 403–413. doi:10.1038/nrmicro3449. PMC 7768976. PMID 25915633. S2CID 205499122.
  12. ^ a b McKinnon PJ (June 2017). "Genome integrity and disease prevention in the nervous system". Genes Dev. 31 (12): 1180–94. doi:10.1101/gad.301325.117. PMC 5558921. PMID 28765160.
  13. ^ a b c Chauvin SD, Ando S, Holley JA, Sugie A, Zhao FR, Poddar S, Kato R, Miner CA, Nitta Y, Krishnamurthy SR, Saito R, Ning Y, Hatano Y, Kitahara S, Koide S, Stinson WA, Fu J, Surve N, Kumble L, Qian W, Polishchuk O, Andhey PS, Chiang C, Liu G, Colombeau L, Rodriguez R, Manel N, Kakita A, Artyomov MN, Schultz DC, Coates PT, Roberson ED, Belkaid Y, Greenberg RA, Cherry S, Gack MU, Hardy T, Onodera O, Kato T, Miner JJ (June 2024). "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans". Nat Commun. 15 (1): 4696. doi:10.1038/s41467-024-49066-7. PMC 11144269. PMID 38824133.