ID TREX1_HUMAN Reviewed; 314 AA. AC Q9NSU2; B2RCN9; Q8TEU2; Q9BPW1; Q9Y4X2; DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot. DT 20-DEC-2017, sequence version 2. DT 24-JAN-2024, entry version 202. DE RecName: Full=Three-prime repair exonuclease 1 {ECO:0000305}; DE EC=3.1.11.2 {ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:33476576}; DE AltName: Full=3'-5' exonuclease TREX1 {ECO:0000303|PubMed:10391904}; DE AltName: Full=Deoxyribonuclease III {ECO:0000303|PubMed:10393201}; DE Short=DNase III {ECO:0000303|PubMed:10393201}; GN Name=TREX1 {ECO:0000303|PubMed:10391904, ECO:0000312|HGNC:HGNC:12269}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY, AND RP SUBCELLULAR LOCATION. RX PubMed=10393201; DOI=10.1093/emboj/18.13.3868; RA Hoess M., Robins P., Naven T.J.P., Pappin D.J.C., Sgouros J., Lindahl T.; RT "A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD RT protein."; RL EMBO J. 18:3868-3875(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=10391904; DOI=10.1074/jbc.274.28.19655; RA Mazur D.J., Perrino F.W.; RT "Identification and expression of the TREX1 and TREX2 cDNA sequences RT encoding mammalian 3'-->5' exonucleases."; RL J. Biol. Chem. 274:19655-19660(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND TISSUE SPECIFICITY. RX PubMed=11278605; DOI=10.1074/jbc.m010051200; RA Mazur D.J., Perrino F.W.; RT "Structure and expression of the TREX1 and TREX2 3'-->5' exonuclease RT genes."; RL J. Biol. Chem. 276:14718-14727(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION IN CELL DEATH, IDENTIFICATION IN THE SET COMPLEX, INTERACTION WITH RP NME1 AND SET, AND SUBCELLULAR LOCATION. RX PubMed=16818237; DOI=10.1016/j.molcel.2006.06.005; RA Chowdhury D., Beresford P.J., Zhu P., Zhang D., Sung J.S., Demple B., RA Perrino F.W., Lieberman J.; RT "The exonuclease TREX1 is in the SET complex and acts in concert with NM23- RT H1 to degrade DNA during granzyme A-mediated cell death."; RL Mol. Cell 23:133-142(2006). RN [10] RP FUNCTION IN CELL CYCLE REGULATION, AND CHARACTERIZATION OF VARIANT AGS1 RP HIS-114. RX PubMed=18045533; DOI=10.1016/j.cell.2007.10.017; RA Yang Y.G., Lindahl T., Barnes D.E.; RT "Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation RT and autoimmune disease."; RL Cell 131:873-886(2007). RN [11] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS AGS1 HIS-114; ASP-200 INS AND RP ASP-201. RX PubMed=17293595; DOI=10.1074/jbc.m700039200; RA de Silva U., Choudhury S., Bailey S.L., Harvey S., Perrino F.W., Hollis T.; RT "The crystal structure of TREX1 explains the 3' nucleotide specificity and RT reveals a polyproline II helix for protein partnering."; RL J. Biol. Chem. 282:10537-10543(2007). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-78 AND SER-261, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [13] RP FUNCTION IN OXIDIZED DNA DEGRADATION, AND POTENTIAL ROLE IN SLE SKIN RP LESIONS. RX PubMed=23993650; DOI=10.1016/j.immuni.2013.08.004; RA Gehrke N., Mertens C., Zillinger T., Wenzel J., Bald T., Zahn S., RA Tueting T., Hartmann G., Barchet W.; RT "Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 RT degradation and potentiates STING-dependent immune sensing."; RL Immunity 39:482-495(2013). RN [14] RP INTERACTION WITH UBQLN1, UBIQUITINATION, CHARACTERIZATION OF VARIANTS AGS1 RP ALA-122; LYS-198; ASN-200 AND PRO-303, CHARACTERIZATION OF VARIANTS SLE RP LEU-290 AND CYS-305, AND MUTAGENESIS OF LYS-30; LYS-66; LYS-75; LYS-160; RP LYS-175; LYS-242; LYS-271 AND LYS-277. RX PubMed=23979357; DOI=10.1074/jbc.m113.503391; RA Orebaugh C.D., Fye J.M., Harvey S., Hollis T., Wilkinson J.C., RA Perrino F.W.; RT "The TREX1 C-terminal region controls cellular localization through RT ubiquitination."; RL J. Biol. Chem. 288:28881-28892(2013). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-261, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-167, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT AGS1 RP ASN-18. RX PubMed=33476576; DOI=10.1016/j.molcel.2020.12.037; RA Mohr L., Toufektchan E., von Morgen P., Chu K., Kapoor A., Maciejowski J.; RT "ER-directed TREX1 limits cGAS activation at micronuclei."; RL Mol. Cell 81:724-738(2021). RN [19] RP VARIANTS AGS1 HIS-114; ASP-200 INS AND ASP-201. RX PubMed=16845398; DOI=10.1038/ng1845; RA Crow Y.J., Hayward B.E., Parmar R., Robins P., Leitch A., Ali M., RA Black D.N., van Bokhoven H., Brunner H.G., Hamel B.C.J., Corry P.C., RA Cowan F.M., Frints S.G., Klepper J., Livingston J.H., Lynch S.A., RA Massey R.F., Meritet J.F., Michaud J.L., Ponsot G., Voit T., Lebon P., RA Bonthron D.T., Jackson A.P., Barnes D.E., Lindahl T.; RT "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause RT Aicardi-Goutieres syndrome at the AGS1 locus."; RL Nat. Genet. 38:917-920(2006). RN [20] RP INVOLVEMENT IN CHBL1, VARIANT AGS1 ASN-200, AND CHARACTERIZATION OF VARIANT RP AGS1 ASN-200. RX PubMed=17357087; DOI=10.1086/513443; RA Rice G., Newman W.G., Dean J., Patrick T., Parmar R., Flintoff K., RA Robins P., Harvey S., Hollis T., O'Hara A., Herrick A.L., Bowden A.P., RA Perrino F.W., Lindahl T., Barnes D.E., Crow Y.J.; RT "Heterozygous mutations in TREX1 cause familial chilblain lupus and RT dominant Aicardi-Goutieres syndrome."; RL Am. J. Hum. Genet. 80:811-815(2007). RN [21] RP VARIANTS AGS1 HIS-114; ALA-122; ASN-200; ASP-201 AND PRO-303. RX PubMed=17846997; DOI=10.1086/521373; RA Rice G., Patrick T., Parmar R., Taylor C.F., Aeby A., Aicardi J., RA Artuch R., Montalto S.A., Bacino C.A., Barroso B., Baxter P., Benko W.S., RA Bergmann C., Bertini E., Biancheri R., Blair E.M., Blau N., Bonthron D.T., RA Briggs T., Brueton L.A., Brunner H.G., Burke C.J., Carr I.M., RA Carvalho D.R., Chandler K.E., Christen H.J., Corry P.C., Cowan F.M., RA Cox H., D'Arrigo S., Dean J., De Laet C., De Praeter C., Dery C., RA Ferrie C.D., Flintoff K., Frints S.G., Garcia-Cazorla A., Gener B., RA Goizet C., Goutieres F., Green A.J., Guet A., Hamel B.C., Hayward B.E., RA Heiberg A., Hennekam R.C., Husson M., Jackson A.P., Jayatunga R., RA Jiang Y.H., Kant S.G., Kao A., King M.D., Kingston H.M., Klepper J., RA van der Knaap M.S., Kornberg A.J., Kotzot D., Kratzer W., Lacombe D., RA Lagae L., Landrieu P.G., Lanzi G., Leitch A., Lim M.J., Livingston J.H., RA Lourenco C.M., Lyall E.G., Lynch S.A., Lyons M.J., Marom D., McClure J.P., RA McWilliam R., Melancon S.B., Mewasingh L.D., Moutard M.L., Nischal K.K., RA Ostergaard J.R., Prendiville J., Rasmussen M., Rogers R.C., Roland D., RA Rosser E.M., Rostasy K., Roubertie A., Sanchis A., Schiffmann R., RA Scholl-Burgi S., Seal S., Shalev S.A., Corcoles C.S., Sinha G.P., Soler D., RA Spiegel R., Stephenson J.B., Tacke U., Tan T.Y., Till M., Tolmie J.L., RA Tomlin P., Vagnarelli F., Valente E.M., Van Coster R.N., Van der Aa N., RA Vanderver A., Vles J.S., Voit T., Wassmer E., Weschke B., Whiteford M.L., RA Willemsen M.A., Zankl A., Zuberi S.M., Orcesi S., Fazzi E., Lebon P., RA Crow Y.J.; RT "Clinical and molecular phenotype of Aicardi-Goutieres syndrome."; RL Am. J. Hum. Genet. 81:713-725(2007). RN [22] RP VARIANT CHBL1 ASN-18, AND CHARACTERIZATION OF VARIANT CHBL1 ASN-18. RX PubMed=17440703; DOI=10.1007/s00109-007-0199-9; RA Lee-Kirsch M.A., Chowdhury D., Harvey S., Gong M., Senenko L., Engel K., RA Pfeiffer C., Hollis T., Gahr M., Perrino F.W., Lieberman J., Hubner N.; RT "A mutation in TREX1 that impairs susceptibility to granzyme A-mediated RT cell death underlies familial chilblain lupus."; RL J. Mol. Med. 85:531-537(2007). RN [23] RP VARIANTS SLE HIS-114; VAL-158; SER-227; SER-240; PRO-247; LEU-290; CYS-305 RP AND ALA-306, AND VARIANT GLY-266. RX PubMed=17660818; DOI=10.1038/ng2091; RA Lee-Kirsch M.A., Gong M., Chowdhury D., Senenko L., Engel K., Lee Y.A., RA de Silva U., Bailey S.L., Witte T., Vyse T.J., Kere J., Pfeiffer C., RA Harvey S., Wong A., Koskenmies S., Hummel O., Rohde K., Schmidt R.E., RA Dominiczak A.F., Gahr M., Hollis T., Perrino F.W., Lieberman J., RA Huebner N.; RT "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are RT associated with systemic lupus erythematosus."; RL Nat. Genet. 39:1065-1067(2007). RN [24] RP INVOLVEMENT IN RVCLS. RX PubMed=17660820; DOI=10.1038/ng2082; RA Richards A., van den Maagdenberg A.M.J.M., Jen J.C., Kavanagh D., RA Bertram P., Spitzer D., Liszewski M.K., Barilla-Labarca M.-L., RA Terwindt G.M., Kasai Y., McLellan M., Grand M.G., Vanmolkot K.R.J., RA de Vries B., Wan J., Kane M.J., Mamsa H., Schaefer R., Stam A.H., Haan J., RA de Jong P.T.V.M., Storimans C.W., van Schooneveld M.J., Oosterhuis J.A., RA Gschwendter A., Dichgans M., Kotschet K.E., Hodgkinson S., Hardy T.A., RA Delatycki M.B., Hajj-Ali R.A., Kothari P.H., Nelson S.F., Frants R.R., RA Baloh R.W., Ferrari M.D., Atkinson J.P.; RT "C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause RT autosomal dominant retinal vasculopathy with cerebral leukodystrophy."; RL Nat. Genet. 39:1068-1070(2007). RN [25] RP VARIANT AGS1 ASN-18. RX PubMed=20799324; DOI=10.1002/ajmg.a.33620; RA Haaxma C.A., Crow Y.J., van Steensel M.A., Lammens M.M., Rice G.I., RA Verbeek M.M., Willemsen M.A.; RT "A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres RT syndrome."; RL Am. J. Med. Genet. A 152:2612-2617(2010). RN [26] RP VARIANTS AGS1 HIS-114; LYS-198 AND HIS-200, AND VARIANT SLE HIS-200. RX PubMed=20131292; DOI=10.1002/art.27367; RA Ramantani G., Kohlhase J., Hertzberg C., Innes A.M., Engel K., Hunger S., RA Borozdin W., Mah J.K., Ungerath K., Walkenhorst H., Richardt H.H., RA Buckard J., Bevot A., Siegel C., von Stuelpnagel C., Ikonomidou C., RA Thomas K., Proud V., Niemann F., Wieczorek D., Haeusler M., Niggemann P., RA Baltaci V., Conrad K., Lebon P., Lee-Kirsch M.A.; RT "Expanding the phenotypic spectrum of lupus erythematosus in Aicardi- RT Goutieres syndrome."; RL Arthritis Rheum. 62:1469-1477(2010). CC -!- FUNCTION: Major cellular 3'-to-5' DNA exonuclease which digests single- CC stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' CC termini (PubMed:10391904, PubMed:10393201, PubMed:17293595). Prevents CC cell-intrinsic initiation of autoimmunity (PubMed:10391904, CC PubMed:10393201, PubMed:17293595). Acts by metabolizing DNA fragments CC from endogenous retroelements, including L1, LTR and SINE elements CC (PubMed:10391904, PubMed:10393201, PubMed:17293595). Plays a key role CC in degradation of DNA fragments at cytosolic micronuclei arising from CC genome instability: its association with the endoplasmic reticulum CC membrane directs TREX1 to ruptured micronuclei, leading to micronuclear CC DNA degradation (PubMed:33476576). Micronuclear DNA degradation is CC required to limit CGAS activation and subsequent inflammation CC (PubMed:33476576). Unless degraded, these DNA fragments accumulate in CC the cytosol and activate the cGAS-STING innate immune signaling, CC leading to the production of type I interferon (PubMed:33476576). CC Prevents chronic ATM-dependent checkpoint activation, by processing CC ssDNA polynucleotide species arising from the processing of aberrant CC DNA replication intermediates (PubMed:18045533). Inefficiently degrades CC oxidized DNA, such as that generated upon antimicrobial reactive oxygen CC production or upon absorption of UV light (PubMed:23993650). During CC GZMA-mediated cell death, contributes to DNA damage in concert with CC NME1 (PubMed:16818237). NME1 nicks one strand of DNA and TREX1 removes CC bases from the free 3' end to enhance DNA damage and prevent DNA end CC reannealing and rapid repair (PubMed:16818237). CC {ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:10393201, CC ECO:0000269|PubMed:16818237, ECO:0000269|PubMed:17293595, CC ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:23993650, CC ECO:0000269|PubMed:33476576}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Exonucleolytic cleavage in the 3'- to 5'-direction to yield CC nucleoside 5'-phosphates.; EC=3.1.11.2; CC Evidence={ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:33476576}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:Q91XB0}; CC Note=Binds 2 Mg(2+) per subunit. The second magnesium ion interacts CC with only one residue. Substitution with Mn(2+) results in partial CC activity. {ECO:0000250|UniProtKB:Q91XB0}; CC -!- SUBUNIT: Homodimer (By similarity). Interacts (via proline-rich region) CC with TCERG1/CA150 (via the second WW domain) (By similarity). Component CC of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, CC SET and TREX1 (PubMed:16818237). Within this complex, directly CC interacts with SET; this interaction does not result in TREX1 CC inhibition (PubMed:16818237). Also interacts with NME1, but only CC following translocation to the nucleus (PubMed:16818237). Directly CC interacts with UBQLN1 (via ubiquitin-like domain); the interaction may CC control TREX1 subcellular location (PubMed:23979357). CC {ECO:0000250|UniProtKB:Q91XB0, ECO:0000269|PubMed:16818237, CC ECO:0000269|PubMed:23979357}. CC -!- INTERACTION: CC Q9NSU2-1; Q13520: AQP6; NbExp=3; IntAct=EBI-16746122, EBI-13059134; CC Q9NSU2-1; P60033: CD81; NbExp=3; IntAct=EBI-16746122, EBI-712921; CC Q9NSU2-1; Q8N7P3: CLDN22; NbExp=3; IntAct=EBI-16746122, EBI-17766761; CC Q9NSU2-1; Q9BUF7-2: CRB3; NbExp=3; IntAct=EBI-16746122, EBI-17233035; CC Q9NSU2-1; P49447: CYB561; NbExp=3; IntAct=EBI-16746122, EBI-8646596; CC Q9NSU2-1; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-16746122, EBI-3867333; CC Q9NSU2-1; Q15125: EBP; NbExp=3; IntAct=EBI-16746122, EBI-3915253; CC Q9NSU2-1; Q9GZR5: ELOVL4; NbExp=3; IntAct=EBI-16746122, EBI-18535450; CC Q9NSU2-1; Q8TBP5: FAM174A; NbExp=3; IntAct=EBI-16746122, EBI-18636064; CC Q9NSU2-1; O14843: FFAR3; NbExp=3; IntAct=EBI-16746122, EBI-17762181; CC Q9NSU2-1; Q8TBE3: FNDC9; NbExp=3; IntAct=EBI-16746122, EBI-12142257; CC Q9NSU2-1; P36382: GJA5; NbExp=3; IntAct=EBI-16746122, EBI-750433; CC Q9NSU2-1; Q9NS71: GKN1; NbExp=3; IntAct=EBI-16746122, EBI-3933251; CC Q9NSU2-1; O15529: GPR42; NbExp=3; IntAct=EBI-16746122, EBI-18076404; CC Q9NSU2-1; Q7Z5P4: HSD17B13; NbExp=3; IntAct=EBI-16746122, EBI-18053395; CC Q9NSU2-1; P38484: IFNGR2; NbExp=3; IntAct=EBI-16746122, EBI-3905457; CC Q9NSU2-1; Q8N5M9: JAGN1; NbExp=3; IntAct=EBI-16746122, EBI-10266796; CC Q9NSU2-1; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-16746122, EBI-1055254; CC Q9NSU2-1; P60409: KRTAP10-7; NbExp=6; IntAct=EBI-16746122, EBI-10172290; CC Q9NSU2-1; Q5SR56: MFSD14B; NbExp=3; IntAct=EBI-16746122, EBI-373355; CC Q9NSU2-1; O00623: PEX12; NbExp=3; IntAct=EBI-16746122, EBI-594836; CC Q9NSU2-1; Q9UKY0: PRND; NbExp=3; IntAct=EBI-16746122, EBI-17783836; CC Q9NSU2-1; Q8IUW5: RELL1; NbExp=3; IntAct=EBI-16746122, EBI-11343385; CC Q9NSU2-1; Q6P5S7: RNASEK; NbExp=3; IntAct=EBI-16746122, EBI-18397230; CC Q9NSU2-1; Q9BY50: SEC11C; NbExp=3; IntAct=EBI-16746122, EBI-2855401; CC Q9NSU2-1; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-16746122, EBI-18159983; CC Q9NSU2-1; Q8TBB6: SLC7A14; NbExp=3; IntAct=EBI-16746122, EBI-5235586; CC Q9NSU2-1; Q96CE8: TM4SF18; NbExp=3; IntAct=EBI-16746122, EBI-13351685; CC Q9NSU2-1; Q6UW68: TMEM205; NbExp=3; IntAct=EBI-16746122, EBI-6269551; CC Q9NSU2-1; Q6UWW9: TMEM207; NbExp=3; IntAct=EBI-16746122, EBI-13301303; CC Q9NSU2-1; Q96B21: TMEM45B; NbExp=3; IntAct=EBI-16746122, EBI-3923061; CC Q9NSU2-1; Q8N661: TMEM86B; NbExp=3; IntAct=EBI-16746122, EBI-2548832; CC Q9NSU2-1; Q9Y320: TMX2; NbExp=3; IntAct=EBI-16746122, EBI-6447886; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:10393201}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:16818237}. Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:33476576}; Peripheral membrane protein CC {ECO:0000269|PubMed:33476576}. Note=Retained in the cytoplasm through CC the C-terminal region (By similarity). Localization to the endoplasmic CC reticulum membrane is required to direct TREX1 to ruptured micronuclei CC (PubMed:33476576). In response to DNA damage, translocates to the CC nucleus where it is specifically recruited to replication foci CC (PubMed:16818237). Translocation to the nucleus also occurs during CC GZMA-mediated cell death (PubMed:16818237). CC {ECO:0000250|UniProtKB:Q91XB0, ECO:0000269|PubMed:16818237, CC ECO:0000269|PubMed:33476576}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=3; CC IsoId=Q9NSU2-3; Sequence=Displayed; CC Name=1; CC IsoId=Q9NSU2-1; Sequence=VSP_059279; CC Name=2; CC IsoId=Q9NSU2-2; Sequence=VSP_010445; CC -!- TISSUE SPECIFICITY: Detected in thymus, spleen, liver, brain, heart, CC small intestine and colon. {ECO:0000269|PubMed:10393201, CC ECO:0000269|PubMed:11278605}. CC -!- PTM: Ubiquitinated, but not targeted to proteasomal degradation. CC Ubiquitination may be important for interaction with UBQLN1. CC {ECO:0000269|PubMed:23979357}. CC -!- DISEASE: Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750]: A form of CC Aicardi-Goutieres syndrome, a genetically heterogeneous disease CC characterized by cerebral atrophy, leukoencephalopathy, intracranial CC calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, CC increased CSF alpha-interferon, and negative serologic investigations CC for common prenatal infection. Clinical features as thrombocytopenia, CC hepatosplenomegaly and elevated hepatic transaminases along with CC intermittent fever may erroneously suggest an infective process. Severe CC neurological dysfunctions manifest in infancy as progressive CC microcephaly, spasticity, dystonic posturing and profound psychomotor CC retardation. Death often occurs in early childhood. CC {ECO:0000269|PubMed:16845398, ECO:0000269|PubMed:17293595, CC ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17846997, CC ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:20131292, CC ECO:0000269|PubMed:20799324, ECO:0000269|PubMed:23979357, CC ECO:0000269|PubMed:33476576}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, CC relapsing, inflammatory, and often febrile multisystemic disorder of CC connective tissue, characterized principally by involvement of the CC skin, joints, kidneys and serosal membranes. It is of unknown etiology, CC but is thought to represent a failure of the regulatory mechanisms of CC the autoimmune system. The disease is marked by a wide range of system CC dysfunctions, an elevated erythrocyte sedimentation rate, and the CC formation of LE cells in the blood or bone marrow. CC {ECO:0000269|PubMed:17660818, ECO:0000269|PubMed:20131292, CC ECO:0000269|PubMed:23979357}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. Enhanced CC immune sensing of oxidized DNA may be involved in the phototoxicity CC experienced by SLE patients. Exposure to UV-light produces DNA CC oxidative damage. Oxidized DNA being a poor TREX1 substrate, it CC accumulates in skin, leading to enhanced auto-immune reactivity and CC eventually skin lesions (PubMed:23993650). CC {ECO:0000269|PubMed:23993650}. CC -!- DISEASE: Chilblain lupus 1 (CHBL1) [MIM:610448]: A rare cutaneous form CC of lupus erythematosus. Affected individuals present with painful CC bluish-red papular or nodular lesions of the skin in acral locations CC precipitated by cold and wet exposure. {ECO:0000269|PubMed:17357087, CC ECO:0000269|PubMed:17440703}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Vasculopathy, retinal, with cerebral leukoencephalopathy and CC systemic manifestations (RVCLS) [MIM:192315]: An adult-onset, autosomal CC dominant endotheliopathy affecting the microvessels of the brain. It CC results in central nervous system degeneration and retinopathy, with CC progressive loss of vision, stroke, motor impairment, and cognitive CC decline. The ocular manifestations are characterized by CC telangiectasias, microaneurysms and retinal capillary obliteration CC starting in the macula. Diseased cerebral white matter has prominent CC small infarcts that often coalesce to pseudotumors. A subset of CC patients have systemic vascular involvement that can manifest as CC Raynaud phenomenon, micronodular cirrhosis, and glomerular dysfunction. CC {ECO:0000269|PubMed:17660820}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the exonuclease superfamily. TREX family. CC {ECO:0000305}. CC -!- CAUTION: The gene for this protein is either identical to or adjacent CC to that of ATRIP. Some of the mRNAs that encode ATRIP also encode TREX1 CC in another reading frame. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAD48774.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAL82504.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/trex1/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ243797; CAB50866.1; -; mRNA. DR EMBL; AF151105; AAD48774.2; ALT_INIT; mRNA. DR EMBL; AF319566; AAK07613.1; -; mRNA. DR EMBL; AF319567; AAK07614.1; -; mRNA. DR EMBL; AF319568; AAK07615.1; -; mRNA. DR EMBL; AF319569; AAK07616.1; -; mRNA. DR EMBL; AK315196; BAG37636.1; -; mRNA. DR EMBL; AL137745; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AF483777; AAL82504.1; ALT_INIT; Genomic_DNA. DR EMBL; BC023630; AAH23630.1; -; mRNA. DR CCDS; CCDS2769.1; -. [Q9NSU2-3] DR CCDS; CCDS59451.1; -. [Q9NSU2-2] DR PIR; T46299; T46299. DR RefSeq; NP_009179.2; NM_007248.3. [Q9NSU2-2] DR RefSeq; NP_057465.1; NM_016381.5. DR RefSeq; NP_338599.1; NM_033629.4. [Q9NSU2-3] DR PDB; 7TQN; X-ray; 1.80 A; A=1-242. DR PDB; 7TQO; X-ray; 1.25 A; A=1-242. DR PDB; 7TQP; X-ray; 1.95 A; A=1-242. DR PDB; 7TQQ; X-ray; 2.20 A; A/B/E/F=1-242. DR PDBsum; 7TQN; -. DR PDBsum; 7TQO; -. DR PDBsum; 7TQP; -. DR PDBsum; 7TQQ; -. DR AlphaFoldDB; Q9NSU2; -. DR SMR; Q9NSU2; -. DR BioGRID; 116433; 51. DR IntAct; Q9NSU2; 36. DR STRING; 9606.ENSP00000486676; -. DR BindingDB; Q9NSU2; -. DR iPTMnet; Q9NSU2; -. DR PhosphoSitePlus; Q9NSU2; -. DR BioMuta; TREX1; -. DR DMDM; 47606216; -. DR EPD; Q9NSU2; -. DR jPOST; Q9NSU2; -. DR MassIVE; Q9NSU2; -. DR MaxQB; Q9NSU2; -. DR PaxDb; 9606-ENSP00000296443; -. DR PeptideAtlas; Q9NSU2; -. DR ProteomicsDB; 82580; -. [Q9NSU2-1] DR ProteomicsDB; 82581; -. [Q9NSU2-2] DR ProteomicsDB; 82582; -. [Q9NSU2-3] DR Pumba; Q9NSU2; -. DR Antibodypedia; 30103; 323 antibodies from 35 providers. DR DNASU; 11277; -. DR Ensembl; ENST00000444177.1; ENSP00000415972.1; ENSG00000213689.14. [Q9NSU2-2] DR Ensembl; ENST00000625293.3; ENSP00000486676.2; ENSG00000213689.14. [Q9NSU2-3] DR GeneID; 11277; -. DR KEGG; hsa:11277; -. DR MANE-Select; ENST00000625293.3; ENSP00000486676.2; NM_033629.6; NP_338599.1. DR UCSC; uc031rzp.2; human. [Q9NSU2-3] DR AGR; HGNC:12269; -. DR CTD; 11277; -. DR DisGeNET; 11277; -. DR GeneCards; TREX1; -. DR GeneReviews; TREX1; -. DR HGNC; HGNC:12269; TREX1. DR HPA; ENSG00000213689; Tissue enhanced (choroid). DR MalaCards; TREX1; -. DR MIM; 152700; phenotype. DR MIM; 192315; phenotype. DR MIM; 225750; phenotype. DR MIM; 606609; gene. DR MIM; 610448; phenotype. DR neXtProt; NX_Q9NSU2; -. DR OpenTargets; ENSG00000213689; -. DR Orphanet; 51; Aicardi-Goutieres syndrome. DR Orphanet; 481662; Familial Chilblain lupus. DR Orphanet; 247691; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. DR Orphanet; 536; Systemic lupus erythematosus. DR PharmGKB; PA36949; -. DR VEuPathDB; HostDB:ENSG00000213689; -. DR eggNOG; KOG4793; Eukaryota. DR GeneTree; ENSGT00390000012715; -. DR HOGENOM; CLU_067419_1_0_1; -. DR InParanoid; Q9NSU2; -. DR OMA; ICQWRPR; -. DR OrthoDB; 2879091at2759; -. DR PhylomeDB; Q9NSU2; -. DR TreeFam; TF323333; -. DR BRENDA; 3.1.11.2; 2681. DR PathwayCommons; Q9NSU2; -. DR Reactome; R-HSA-3248023; Regulation by TREX1. DR Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN. DR SignaLink; Q9NSU2; -. DR BioGRID-ORCS; 11277; 9 hits in 1161 CRISPR screens. DR GeneWiki; TREX1; -. DR GenomeRNAi; 11277; -. DR Pharos; Q9NSU2; Tbio. DR PRO; PR:Q9NSU2; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q9NSU2; Protein. DR Bgee; ENSG00000213689; Expressed in olfactory segment of nasal mucosa and 96 other cell types or tissues. DR ExpressionAtlas; Q9NSU2; baseline. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0005635; C:nuclear envelope; NAS:UniProtKB. DR GO; GO:0043596; C:nuclear replication fork; IEA:Ensembl. DR GO; GO:0008250; C:oligosaccharyltransferase complex; IEA:Ensembl. DR GO; GO:0032993; C:protein-DNA complex; IEA:Ensembl. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB. DR GO; GO:0008296; F:3'-5'-DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0032558; F:adenyl deoxyribonucleotide binding; IEA:Ensembl. DR GO; GO:0008301; F:DNA binding, bending; IEA:Ensembl. DR GO; GO:0008311; F:double-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProt. DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Ensembl. DR GO; GO:0000287; F:magnesium ion binding; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; NAS:UniProtKB. DR GO; GO:0032405; F:MutLalpha complex binding; IDA:MGI. DR GO; GO:0032407; F:MutSalpha complex binding; IDA:MGI. DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl. DR GO; GO:0003697; F:single-stranded DNA binding; TAS:UniProtKB. DR GO; GO:0050699; F:WW domain binding; IEA:Ensembl. DR GO; GO:0002253; P:activation of immune response; IEA:Ensembl. DR GO; GO:0043277; P:apoptotic cell clearance; IEA:Ensembl. DR GO; GO:0003228; P:atrial cardiac muscle tissue development; IEA:Ensembl. DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl. DR GO; GO:0035781; P:CD86 biosynthetic process; IEA:Ensembl. DR GO; GO:0071480; P:cellular response to gamma radiation; IEA:Ensembl. DR GO; GO:0072711; P:cellular response to hydroxyurea; IEA:Ensembl. DR GO; GO:0035458; P:cellular response to interferon-beta; IEA:Ensembl. DR GO; GO:0034614; P:cellular response to reactive oxygen species; IEA:Ensembl. DR GO; GO:0051607; P:defense response to virus; IEA:Ensembl. DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl. DR GO; GO:0006308; P:DNA catabolic process; IEA:Ensembl. DR GO; GO:0032508; P:DNA duplex unwinding; IEA:Ensembl. DR GO; GO:0006259; P:DNA metabolic process; ISS:UniProtKB. DR GO; GO:0006304; P:DNA modification; IEA:Ensembl. DR GO; GO:0006310; P:DNA recombination; NAS:UniProtKB. DR GO; GO:0006281; P:DNA repair; TAS:ProtInc. DR GO; GO:0006260; P:DNA replication; NAS:UniProtKB. DR GO; GO:1904161; P:DNA synthesis involved in UV-damage excision repair; IEA:Ensembl. DR GO; GO:0045184; P:establishment of protein localization; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; IEA:Ensembl. DR GO; GO:0003007; P:heart morphogenesis; IEA:Ensembl. DR GO; GO:0003015; P:heart process; IEA:Ensembl. DR GO; GO:0097281; P:immune complex formation; IEA:Ensembl. DR GO; GO:0002383; P:immune response in brain or nervous system; IEA:Ensembl. DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0002320; P:lymphoid progenitor cell differentiation; IEA:Ensembl. DR GO; GO:0002281; P:macrophage activation involved in immune response; IEA:Ensembl. DR GO; GO:0006298; P:mismatch repair; NAS:UniProtKB. DR GO; GO:0031571; P:mitotic G1 DNA damage checkpoint signaling; IEA:Ensembl. DR GO; GO:0160049; P:negative regulation of cGAS/STING signaling pathway; IDA:UniProt. DR GO; GO:0045824; P:negative regulation of innate immune response; IDA:UniProtKB. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IEA:Ensembl. DR GO; GO:0050821; P:protein stabilization; IEA:Ensembl. DR GO; GO:0043457; P:regulation of cellular respiration; IEA:Ensembl. DR GO; GO:0019217; P:regulation of fatty acid metabolic process; IEA:Ensembl. DR GO; GO:0006110; P:regulation of glycolytic process; IEA:Ensembl. DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl. DR GO; GO:0050727; P:regulation of inflammatory response; IEA:Ensembl. DR GO; GO:0046890; P:regulation of lipid biosynthetic process; IEA:Ensembl. DR GO; GO:1905671; P:regulation of lysosome organization; IEA:Ensembl. DR GO; GO:0061635; P:regulation of protein complex stability; IEA:Ensembl. DR GO; GO:0050863; P:regulation of T cell activation; IEA:Ensembl. DR GO; GO:0032680; P:regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0032479; P:regulation of type I interferon production; IEA:Ensembl. DR GO; GO:0032197; P:retrotransposition; IEA:Ensembl. DR GO; GO:0002457; P:T cell antigen processing and presentation; IEA:Ensembl. DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; IEA:Ensembl. DR Gene3D; 3.30.420.10; Ribonuclease H-like superfamily/Ribonuclease H; 1. DR InterPro; IPR013520; Exonuclease_RNaseT/DNA_pol3. DR InterPro; IPR012337; RNaseH-like_sf. DR InterPro; IPR036397; RNaseH_sf. DR InterPro; IPR040393; TREX1/2. DR PANTHER; PTHR13058; THREE PRIME REPAIR EXONUCLEASE 1, 2; 1. DR PANTHER; PTHR13058:SF27; THREE-PRIME REPAIR EXONUCLEASE 1; 1. DR SMART; SM00479; EXOIII; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR Genevisible; Q9NSU2; HS. PE 1: Evidence at protein level; KW 3D-structure; Aicardi-Goutieres syndrome; Alternative splicing; Cytoplasm; KW Disease variant; Endoplasmic reticulum; Exonuclease; Hydrolase; Magnesium; KW Membrane; Metal-binding; Neurodegeneration; Nuclease; Nucleus; KW Phosphoprotein; Reference proteome; Systemic lupus erythematosus; KW Ubl conjugation. FT CHAIN 1..314 FT /note="Three-prime repair exonuclease 1" FT /id="PRO_0000109868" FT REGION 236..314 FT /note="Necessary for endoplasmic reticulum localization" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT REGION 240..278 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 243..314 FT /note="Interaction with UBQLN1" FT /evidence="ECO:0000269|PubMed:23979357" FT REGION 281..314 FT /note="Necessary for cytoplasmic retention" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT COMPBIAS 242..267 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 195 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 18 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 18 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 20..21 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 20 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 129 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 200 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT BINDING 200 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q91XB0" FT MOD_RES 78 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 167 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 261 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..10 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10393201" FT /id="VSP_010445" FT VAR_SEQ 1 FT /note="M -> MGPGARRQGRIVQGRPEMCFCPPPTPLPPLRILTLGTHTPTPCSSPG FT SAAGTYPTM (in isoform 1)" FT /evidence="ECO:0000303|PubMed:11278605" FT /id="VSP_059279" FT VARIANT 18 FT /note="D -> N (in CHBL1 and AGS1; autosomal dominant form; FT loss of 3'-to-5' DNA exonuclease activity; abolished FT ability to degrade micronuclear DNA and restrict activation FT of innate immune response; dbSNP:rs121908117)" FT /evidence="ECO:0000269|PubMed:17440703, FT ECO:0000269|PubMed:20799324, ECO:0000269|PubMed:33476576" FT /id="VAR_037948" FT VARIANT 114 FT /note="R -> H (in AGS1 and SLE; primary fibroblasts from an FT AGS1 patient carrying H-169 show defective G1/S transition FT and chronic G2/MDNA damage checkpoint activation; strongly FT reduces activity; dbSNP:rs72556554)" FT /evidence="ECO:0000269|PubMed:16845398, FT ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:17660818, FT ECO:0000269|PubMed:17846997, ECO:0000269|PubMed:18045533, FT ECO:0000269|PubMed:20131292" FT /id="VAR_028319" FT VARIANT 122 FT /note="V -> A (in AGS1; increases ubiquitination levels; no FT effect on exonuclease activity; dbSNP:rs79993407)" FT /evidence="ECO:0000269|PubMed:17846997, FT ECO:0000269|PubMed:23979357" FT /id="VAR_070899" FT VARIANT 158 FT /note="A -> V (in SLE; dbSNP:rs762011967)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037949" FT VARIANT 198 FT /note="E -> K (in AGS1; increases ubiquitination levels; no FT effect on exonuclease activity; dbSNP:rs1416519719)" FT /evidence="ECO:0000269|PubMed:20131292, FT ECO:0000269|PubMed:23979357" FT /id="VAR_070900" FT VARIANT 200 FT /note="D -> DD (in AGS1; heterozygous compound with H-169; FT loss of activity)" FT /evidence="ECO:0000269|PubMed:16845398, FT ECO:0000269|PubMed:17293595" FT /id="VAR_028320" FT VARIANT 200 FT /note="D -> H (in AGS1 and SLE)" FT /evidence="ECO:0000269|PubMed:20131292" FT /id="VAR_070901" FT VARIANT 200 FT /note="D -> N (in AGS1; autosomal dominant form; no effect FT on dsDNA exonuclease activity; abolishes ssDNA exonuclease FT activity; dbSNP:rs78846775)" FT /evidence="ECO:0000269|PubMed:17357087, FT ECO:0000269|PubMed:17846997, ECO:0000269|PubMed:23979357" FT /id="VAR_032940" FT VARIANT 201 FT /note="V -> D (in AGS1; reduces activity by 75%; FT dbSNP:rs78408272)" FT /evidence="ECO:0000269|PubMed:16845398, FT ECO:0000269|PubMed:17293595, ECO:0000269|PubMed:17846997" FT /id="VAR_028321" FT VARIANT 227 FT /note="G -> S (in SLE; associated in cis with P-302; FT dbSNP:rs113107733)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037950" FT VARIANT 240 FT /note="R -> S (in SLE; dbSNP:rs72556555)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037951" FT VARIANT 247 FT /note="A -> P (in SLE; associated in cis with S-282; FT dbSNP:rs112741962)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037952" FT VARIANT 266 FT /note="E -> G (in dbSNP:rs55999987)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037953" FT VARIANT 290 FT /note="P -> L (in SLE; increases ubiquitination levels; no FT effect on exonuclease activity; dbSNP:rs148833270)" FT /evidence="ECO:0000269|PubMed:17660818, FT ECO:0000269|PubMed:23979357" FT /id="VAR_037954" FT VARIANT 303 FT /note="T -> P (in AGS1; decreases ubiquitination levels; FT decreases colocalization with UBQLN1; no effect on FT exonuclease activity; dbSNP:rs76224909)" FT /evidence="ECO:0000269|PubMed:17846997, FT ECO:0000269|PubMed:23979357" FT /id="VAR_070902" FT VARIANT 305 FT /note="Y -> C (in SLE; decreases ubiquitination levels; FT decreases colocalization with UBQLN1; no effect on FT exonuclease activity; dbSNP:rs370504038)" FT /evidence="ECO:0000269|PubMed:17660818, FT ECO:0000269|PubMed:23979357" FT /id="VAR_037955" FT VARIANT 306 FT /note="G -> A (in SLE; dbSNP:rs780022923)" FT /evidence="ECO:0000269|PubMed:17660818" FT /id="VAR_037956" FT MUTAGEN 30 FT /note="K->R: Reduces ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 66 FT /note="K->R: No effect on ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 75 FT /note="K->R: Reduces ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 160 FT /note="K->R: Reduces ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 175 FT /note="K->R: Reduces ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 242 FT /note="K->R: Reduces ubiquitination." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 271 FT /note="K->R: Reduces ubiquitination. Strongly reduces FT ubiquitination; when associated with R-277." FT /evidence="ECO:0000269|PubMed:23979357" FT MUTAGEN 277 FT /note="K->R: Reduces ubiquitination. Strongly reduces FT ubiquitination; when associated with R-271." FT /evidence="ECO:0000269|PubMed:23979357" FT CONFLICT 265 FT /note="G -> R (in Ref. 1; CAB50866)" FT /evidence="ECO:0000305" FT STRAND 13..23 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 25..27 FT /evidence="ECO:0007829|PDB:7TQO" FT STRAND 31..40 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 41..44 FT /evidence="ECO:0007829|PDB:7TQO" FT STRAND 65..70 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 79..85 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 89..94 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 102..113 FT /evidence="ECO:0007829|PDB:7TQO" FT STRAND 117..123 FT /evidence="ECO:0007829|PDB:7TQO" FT TURN 124..129 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 130..140 FT /evidence="ECO:0007829|PDB:7TQO" FT TURN 144..149 FT /evidence="ECO:0007829|PDB:7TQO" FT STRAND 151..154 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 155..166 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 179..187 FT /evidence="ECO:0007829|PDB:7TQO" FT TURN 192..195 FT /evidence="ECO:0007829|PDB:7TQQ" FT HELIX 197..208 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 212..222 FT /evidence="ECO:0007829|PDB:7TQO" FT HELIX 226..228 FT /evidence="ECO:0007829|PDB:7TQO" FT STRAND 232..234 FT /evidence="ECO:0007829|PDB:7TQO" SQ SEQUENCE 314 AA; 33212 MW; EE8F63B6496D72F4 CRC64; MGSQALPPGP MQTLIFFDME ATGLPFSQPK VTELCLLAVH RCALESPPTS QGPPPTVPPP PRVVDKLSLC VAPGKACSPA ASEITGLSTA VLAAHGRQCF DDNLANLLLA FLRRQPQPWC LVAHNGDRYD FPLLQAELAM LGLTSALDGA FCVDSITALK ALERASSPSE HGPRKSYSLG SIYTRLYGQS PPDSHTAEGD VLALLSICQW RPQALLRWVD AHARPFGTIR PMYGVTASAR TKPRPSAVTT TAHLATTRNT SPSLGESRGT KDLPPVKDPG ALSREGLLAP LGLLAILTLA VATLYGLSLA TPGE //