TREX1_HUMAN
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 03-AUG-2022, entry version 194.
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 AlphaFoldDB; Q9NSU2; -.
DR SMR; Q9NSU2; -.
DR BioGRID; 116433; 48.
DR IntAct; Q9NSU2; 36.
DR STRING; 9606.ENSP00000296443; -.
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; Q9NSU2; -.
DR PeptideAtlas; Q9NSU2; -.
DR PRIDE; Q9NSU2; -.
DR ProteomicsDB; 82580; -. [Q9NSU2-1]
DR ProteomicsDB; 82581; -. [Q9NSU2-2]
DR ProteomicsDB; 82582; -. [Q9NSU2-3]
DR Antibodypedia; 30103; 296 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 CTD; 11277; -.
DR DisGeNET; 11277; -.
DR GeneCards; TREX1; -.
DR GeneReviews; TREX1; -.
DR HGNC; HGNC:12269; TREX1.
DR HPA; ENSG00000213689; Low tissue specificity.
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; 1365966at2759; -.
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; 7 hits in 1082 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 94 other tissues.
DR ExpressionAtlas; Q9NSU2; baseline and differential.
DR Genevisible; Q9NSU2; HS.
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'-exodeoxyribonuclease activity; ISS:UniProtKB.
DR GO; GO:0032558; F:adenyl deoxyribonucleotide binding; IEA:Ensembl.
DR GO; GO:0008301; F:DNA binding, bending; IEA:Ensembl.
DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0008853; F:exodeoxyribonuclease III activity; IDA:UniProtKB.
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:0000738; P:DNA catabolic process, exonucleolytic; IBA:GO_Central.
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: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:0050790; P:regulation of catalytic activity; 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:0002457; P:T cell antigen processing and presentation; IEA:Ensembl.
DR GO; GO:0032197; P:transposition, RNA-mediated; IEA:Ensembl.
DR GO; GO:0060337; P:type I interferon signaling pathway; IEA:Ensembl.
DR Gene3D; 3.30.420.10; -; 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; PTHR13058; 1.
DR SMART; SM00479; EXOIII; 1.
DR SUPFAM; SSF53098; SSF53098; 1.
PE 1: Evidence at protein level;
KW 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/M DNA 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"
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
