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Three-prime repair exonuclease 1 (EC 3.1.11.2) (3'-5' exonuclease TREX1) (DNase III)

 TREX1_HUMAN             Reviewed;         369 AA.
Q9NSU2; B2RCN9; Q8TEU2; Q9BPW1; Q9Y4X2;
24-MAY-2004, integrated into UniProtKB/Swiss-Prot.
01-OCT-2000, sequence version 1.
25-OCT-2017, entry version 163.
RecName: Full=Three-prime repair exonuclease 1;
EC=3.1.11.2;
AltName: Full=3'-5' exonuclease TREX1;
AltName: Full=DNase III;
Name=TREX1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, TISSUE SPECIFICITY,
AND SUBCELLULAR LOCATION.
PubMed=10393201; DOI=10.1093/emboj/18.13.3868;
Hoess M., Robins P., Naven T.J.P., Pappin D.J.C., Sgouros J.,
Lindahl T.;
"A human DNA editing enzyme homologous to the Escherichia coli
DnaQ/MutD protein.";
EMBO J. 18:3868-3875(1999).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3), AND FUNCTION.
PubMed=10391904; DOI=10.1074/jbc.274.28.19655;
Mazur D.J., Perrino F.W.;
"Identification and expression of the TREX1 and TREX2 cDNA sequences
encoding mammalian 3'-->5' exonucleases.";
J. Biol. Chem. 274:19655-19660(1999).
[3]
NUCLEOTIDE SEQUENCE [MRNA], ALTERNATIVE SPLICING, AND TISSUE
SPECIFICITY.
PubMed=11278605; DOI=10.1074/jbc.M010051200;
Mazur D.J., Perrino F.W.;
"Structure and expression of the TREX1 and TREX2 3'-->5' exonuclease
genes.";
J. Biol. Chem. 276:14718-14727(2001).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Thymus;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Testis;
PubMed=17974005; DOI=10.1186/1471-2164-8-399;
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
"The full-ORF clone resource of the German cDNA consortium.";
BMC Genomics 8:399-399(2007).
[6]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
NIEHS SNPs program;
Submitted (FEB-2002) to the EMBL/GenBank/DDBJ databases.
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Eye;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[8]
FUNCTION IN CELL DEATH, IDENTIFICATION IN THE SET COMPLEX, INTERACTION
WITH NME1 AND SET, AND SUBCELLULAR LOCATION.
PubMed=16818237; DOI=10.1016/j.molcel.2006.06.005;
Chowdhury D., Beresford P.J., Zhu P., Zhang D., Sung J.S., Demple B.,
Perrino F.W., Lieberman J.;
"The exonuclease TREX1 is in the SET complex and acts in concert with
NM23-H1 to degrade DNA during granzyme A-mediated cell death.";
Mol. Cell 23:133-142(2006).
[9]
FUNCTION IN CELL CYCLE REGULATION, AND CHARACTERIZATION OF VARIANT
AGS1 HIS-169.
PubMed=18045533; DOI=10.1016/j.cell.2007.10.017;
Yang Y.G., Lindahl T., Barnes D.E.;
"Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint
activation and autoimmune disease.";
Cell 131:873-886(2007).
[10]
FUNCTION, AND CHARACTERIZATION OF VARIANTS AGS1 HIS-169; ASP-255 INS
AND ASP-256.
PubMed=17293595; DOI=10.1074/jbc.M700039200;
de Silva U., Choudhury S., Bailey S.L., Harvey S., Perrino F.W.,
Hollis T.;
"The crystal structure of TREX1 explains the 3' nucleotide specificity
and reveals a polyproline II helix for protein partnering.";
J. Biol. Chem. 282:10537-10543(2007).
[11]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-133 AND SER-316, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[12]
FUNCTION IN OXIDIZED DNA DEGRADATION, AND POTENTIAL ROLE IN SLE SKIN
LESIONS.
PubMed=23993650; DOI=10.1016/j.immuni.2013.08.004;
Gehrke N., Mertens C., Zillinger T., Wenzel J., Bald T., Zahn S.,
Tueting T., Hartmann G., Barchet W.;
"Oxidative damage of DNA confers resistance to cytosolic nuclease
TREX1 degradation and potentiates STING-dependent immune sensing.";
Immunity 39:482-495(2013).
[13]
INTERACTION WITH UBQLN1, UBIQUITINATION, CHARACTERIZATION OF VARIANTS
AGS1 ALA-177; LYS-253; ASN-255 AND PRO-358, CHARACTERIZATION OF
VARIANTS SLE LEU-345 AND CYS-360, AND MUTAGENESIS OF LYS-85; LYS-121;
LYS-130; LYS-215; LYS-230; LYS-297; LYS-326 AND LYS-332.
PubMed=23979357; DOI=10.1074/jbc.M113.503391;
Orebaugh C.D., Fye J.M., Harvey S., Hollis T., Wilkinson J.C.,
Perrino F.W.;
"The TREX1 C-terminal region controls cellular localization through
ubiquitination.";
J. Biol. Chem. 288:28881-28892(2013).
[14]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[15]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-222, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Liver;
PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
Wang L., Ye M., Zou H.;
"An enzyme assisted RP-RPLC approach for in-depth analysis of human
liver phosphoproteome.";
J. Proteomics 96:253-262(2014).
[16]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=25944712; DOI=10.1002/pmic.201400617;
Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M.,
Ayoub D., Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
"N-terminome analysis of the human mitochondrial proteome.";
Proteomics 15:2519-2524(2015).
[17]
VARIANTS AGS1 HIS-169; ASP-255 INS AND ASP-256.
PubMed=16845398; DOI=10.1038/ng1845;
Crow Y.J., Hayward B.E., Parmar R., Robins P., Leitch A., Ali M.,
Black D.N., van Bokhoven H., Brunner H.G., Hamel B.C.J., Corry P.C.,
Cowan F.M., Frints S.G., Klepper J., Livingston J.H., Lynch S.A.,
Massey R.F., Meritet J.F., Michaud J.L., Ponsot G., Voit T., Lebon P.,
Bonthron D.T., Jackson A.P., Barnes D.E., Lindahl T.;
"Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause
Aicardi-Goutieres syndrome at the AGS1 locus.";
Nat. Genet. 38:917-920(2006).
[18]
INVOLVEMENT IN CHBL1, VARIANT AGS1 ASN-255, AND CHARACTERIZATION OF
VARIANT AGS1 ASN-255.
PubMed=17357087; DOI=10.1086/513443;
Rice G., Newman W.G., Dean J., Patrick T., Parmar R., Flintoff K.,
Robins P., Harvey S., Hollis T., O'Hara A., Herrick A.L., Bowden A.P.,
Perrino F.W., Lindahl T., Barnes D.E., Crow Y.J.;
"Heterozygous mutations in TREX1 cause familial chilblain lupus and
dominant Aicardi-Goutieres syndrome.";
Am. J. Hum. Genet. 80:811-815(2007).
[19]
VARIANTS AGS1 HIS-169; ALA-177; ASN-255; ASP-256 AND PRO-358.
PubMed=17846997; DOI=10.1086/521373;
Rice G., Patrick T., Parmar R., Taylor C.F., Aeby A., Aicardi J.,
Artuch R., Montalto S.A., Bacino C.A., Barroso B., Baxter P.,
Benko W.S., Bergmann C., Bertini E., Biancheri R., Blair E.M.,
Blau N., Bonthron D.T., Briggs T., Brueton L.A., Brunner H.G.,
Burke C.J., Carr I.M., Carvalho D.R., Chandler K.E., Christen H.J.,
Corry P.C., Cowan F.M., Cox H., D'Arrigo S., Dean J., De Laet C.,
De Praeter C., Dery C., Ferrie C.D., Flintoff K., Frints S.G.,
Garcia-Cazorla A., Gener B., Goizet C., Goutieres F., Green A.J.,
Guet A., Hamel B.C., Hayward B.E., Heiberg A., Hennekam R.C.,
Husson M., Jackson A.P., Jayatunga R., Jiang Y.H., Kant S.G., Kao A.,
King M.D., Kingston H.M., Klepper J., van der Knaap M.S.,
Kornberg A.J., Kotzot D., Kratzer W., Lacombe D., Lagae L.,
Landrieu P.G., Lanzi G., Leitch A., Lim M.J., Livingston J.H.,
Lourenco C.M., Lyall E.G., Lynch S.A., Lyons M.J., Marom D.,
McClure J.P., McWilliam R., Melancon S.B., Mewasingh L.D.,
Moutard M.L., Nischal K.K., Ostergaard J.R., Prendiville J.,
Rasmussen M., Rogers R.C., Roland D., Rosser E.M., Rostasy K.,
Roubertie A., Sanchis A., Schiffmann R., Scholl-Burgi S., Seal S.,
Shalev S.A., Corcoles C.S., Sinha G.P., Soler D., Spiegel R.,
Stephenson J.B., Tacke U., Tan T.Y., Till M., Tolmie J.L., Tomlin P.,
Vagnarelli F., Valente E.M., Van Coster R.N., Van der Aa N.,
Vanderver A., Vles J.S., Voit T., Wassmer E., Weschke B.,
Whiteford M.L., Willemsen M.A., Zankl A., Zuberi S.M., Orcesi S.,
Fazzi E., Lebon P., Crow Y.J.;
"Clinical and molecular phenotype of Aicardi-Goutieres syndrome.";
Am. J. Hum. Genet. 81:713-725(2007).
[20]
VARIANT CHBL1 ASN-73, AND CHARACTERIZATION OF VARIANT CHBL1 ASN-73.
PubMed=17440703; DOI=10.1007/s00109-007-0199-9;
Lee-Kirsch M.A., Chowdhury D., Harvey S., Gong M., Senenko L.,
Engel K., Pfeiffer C., Hollis T., Gahr M., Perrino F.W., Lieberman J.,
Hubner N.;
"A mutation in TREX1 that impairs susceptibility to granzyme A-
mediated cell death underlies familial chilblain lupus.";
J. Mol. Med. 85:531-537(2007).
[21]
VARIANTS SLE HIS-169; VAL-213; SER-282; SER-295; PRO-302; LEU-345;
CYS-360 AND ALA-361, AND VARIANT GLY-321.
PubMed=17660818; DOI=10.1038/ng2091;
Lee-Kirsch M.A., Gong M., Chowdhury D., Senenko L., Engel K.,
Lee Y.A., de Silva U., Bailey S.L., Witte T., Vyse T.J., Kere J.,
Pfeiffer C., Harvey S., Wong A., Koskenmies S., Hummel O., Rohde K.,
Schmidt R.E., Dominiczak A.F., Gahr M., Hollis T., Perrino F.W.,
Lieberman J., Huebner N.;
"Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are
associated with systemic lupus erythematosus.";
Nat. Genet. 39:1065-1067(2007).
[22]
INVOLVEMENT IN RVCL.
PubMed=17660820; DOI=10.1038/ng2082;
Richards A., van den Maagdenberg A.M.J.M., Jen J.C., Kavanagh D.,
Bertram P., Spitzer D., Liszewski M.K., Barilla-Labarca M.-L.,
Terwindt G.M., Kasai Y., McLellan M., Grand M.G., Vanmolkot K.R.J.,
de Vries B., Wan J., Kane M.J., Mamsa H., Schaefer R., Stam A.H.,
Haan J., de Jong P.T.V.M., Storimans C.W., van Schooneveld M.J.,
Oosterhuis J.A., Gschwendter A., Dichgans M., Kotschet K.E.,
Hodgkinson S., Hardy T.A., Delatycki M.B., Hajj-Ali R.A.,
Kothari P.H., Nelson S.F., Frants R.R., Baloh R.W., Ferrari M.D.,
Atkinson J.P.;
"C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause
autosomal dominant retinal vasculopathy with cerebral
leukodystrophy.";
Nat. Genet. 39:1068-1070(2007).
[23]
VARIANT AGS1 ASN-73.
PubMed=20799324; DOI=10.1002/ajmg.a.33620;
Haaxma C.A., Crow Y.J., van Steensel M.A., Lammens M.M., Rice G.I.,
Verbeek M.M., Willemsen M.A.;
"A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-
Goutieres syndrome.";
Am. J. Med. Genet. A 152:2612-2617(2010).
[24]
VARIANTS AGS1 HIS-169; LYS-253 AND HIS-255, AND VARIANT SLE HIS-255.
PubMed=20131292; DOI=10.1002/art.27367;
Ramantani G., Kohlhase J., Hertzberg C., Innes A.M., Engel K.,
Hunger S., Borozdin W., Mah J.K., Ungerath K., Walkenhorst H.,
Richardt H.H., Buckard J., Bevot A., Siegel C., von Stuelpnagel C.,
Ikonomidou C., Thomas K., Proud V., Niemann F., Wieczorek D.,
Haeusler M., Niggemann P., Baltaci V., Conrad K., Lebon P.,
Lee-Kirsch M.A.;
"Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-
Goutieres syndrome.";
Arthritis Rheum. 62:1469-1477(2010).
-!- FUNCTION: Major cellular 3'-to-5' DNA exonuclease which digests
single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with
mismatched 3' termini. Prevents cell-intrinsic initiation of
autoimmunity. Acts by metabolizing DNA fragments from endogenous
retroelements, including L1, LTR and SINE elements. Unless
degraded, these DNA fragments accumulate in the cytosol and
activate the IFN-stimulatory DNA (ISD) response and innate immune
signaling. Prevents chronic ATM-dependent checkpoint activation,
by processing ssDNA polynucleotide species arising from the
processing of aberrant DNA replication intermediates.
Inefficiently degrades oxidized DNA, such as that generated upon
antimicrobial reactive oxygen production or upon absorption of UV
light. During GZMA-mediated cell death, contributes to DNA damage
in concert with NME1. NME1 nicks one strand of DNA and TREX1
removes bases from the free 3' end to enhance DNA damage and
prevent DNA end reannealing and rapid repair.
{ECO:0000269|PubMed:10391904, ECO:0000269|PubMed:10393201,
ECO:0000269|PubMed:16818237, ECO:0000269|PubMed:17293595,
ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:23993650}.
-!- CATALYTIC ACTIVITY: Exonucleolytic cleavage in the 3'- to 5'-
direction to yield nucleoside 5'-phosphates.
-!- COFACTOR:
Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
Note=Binds 2 Mg(2+) per subunit. The second magnesium ion
interacts with only one residue. Substitution with Mn(2+) results
in partial activity. {ECO:0000250};
-!- SUBUNIT: Homodimer. Interacts (via proline-rich region) with
TCERG1/CA150 (via the second WW domain). Component of the SET
complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and
TREX1. Within this complex, directly interacts with SET; this
interaction does not result in TREX1 inhibition. Also interacts
with NME1, but only following translocation to the nucleus.
Directly interacts with UBQLN1 (via ubiquitin-like domain); the
interaction may control TREX1 subcellular location.
{ECO:0000269|PubMed:16818237, ECO:0000269|PubMed:23979357}.
-!- INTERACTION:
P60409:KRTAP10-7; NbExp=3; IntAct=EBI-10313481, EBI-10172290;
P60409-2:KRTAP10-7; NbExp=3; IntAct=EBI-10313481, EBI-10695388;
-!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm, cytosol. Endoplasmic
reticulum membrane; Peripheral membrane protein. Note=Retained in
the cytoplasm through the C-terminal region (By similarity). In
response to DNA damage, translocates to the nucleus where it is
specifically recruited to replication foci. Translocation to the
nucleus also occurs during GZMA-mediated cell death.
{ECO:0000250}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=Q9NSU2-1; Sequence=Displayed;
Name=2;
IsoId=Q9NSU2-2; Sequence=VSP_010445;
Name=3;
IsoId=Q9NSU2-3; Sequence=VSP_010446;
-!- TISSUE SPECIFICITY: Detected in thymus, spleen, liver, brain,
heart, small intestine and colon. {ECO:0000269|PubMed:10393201,
ECO:0000269|PubMed:11278605}.
-!- INDUCTION: Induced by cytosolic DNA. Induced by inflammatory
stimuli such as IFN-alpha and IFN-gamma in B cells and also by LPS
and viral and bacterial DNA (via TLR9) in dendritic cells and
macrophages (By similarity). {ECO:0000250}.
-!- PTM: Ubiquitinated, but not targeted to proteasomal degradation.
Ubiquitination may be important for interaction with UBQLN1.
{ECO:0000269|PubMed:23979357}.
-!- DISEASE: Aicardi-Goutieres syndrome 1 (AGS1) [MIM:225750]: A form
of Aicardi-Goutieres syndrome, a genetically heterogeneous disease
characterized by cerebral atrophy, leukoencephalopathy,
intracranial calcifications, chronic cerebrospinal fluid (CSF)
lymphocytosis, increased CSF alpha-interferon, and negative
serologic investigations for common prenatal infection. Clinical
features as thrombocytopenia, hepatosplenomegaly and elevated
hepatic transaminases along with intermittent fever may
erroneously suggest an infective process. Severe neurological
dysfunctions manifest in infancy as progressive microcephaly,
spasticity, dystonic posturing and profound psychomotor
retardation. Death often occurs in early childhood.
{ECO:0000269|PubMed:16845398, ECO:0000269|PubMed:17293595,
ECO:0000269|PubMed:17357087, ECO:0000269|PubMed:17846997,
ECO:0000269|PubMed:18045533, ECO:0000269|PubMed:20131292,
ECO:0000269|PubMed:20799324, ECO:0000269|PubMed:23979357}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A
chronic, relapsing, inflammatory, and often febrile multisystemic
disorder of connective tissue, characterized principally by
involvement of the skin, joints, kidneys and serosal membranes. It
is of unknown etiology, but is thought to represent a failure of
the regulatory mechanisms of the autoimmune system. The disease is
marked by a wide range of system dysfunctions, an elevated
erythrocyte sedimentation rate, and the formation of LE cells in
the blood or bone marrow. {ECO:0000269|PubMed:17660818,
ECO:0000269|PubMed:20131292, ECO:0000269|PubMed:23979357}.
Note=Disease susceptibility is associated with variations
affecting the gene represented in this entry. Enhanced immune
sensing of oxidized DNA may be involved in the phototoxicity
experienced by SLE patients. Exposure to UV-light produces DNA
oxidative damage. Oxidized DNA being a poor TREX1 substrate, it
accumulates in skin, leading to enhanced auto-immune reactivity
and eventually skin lesions (PubMed:23993650).
{ECO:0000269|PubMed:23993650}.
-!- DISEASE: Chilblain lupus 1 (CHBL1) [MIM:610448]: A rare cutaneous
form of lupus erythematosus. Affected individuals present with
painful bluish-red papular or nodular lesions of the skin in acral
locations precipitated by cold and wet exposure at temperatures
less than 10 degrees centigrade. {ECO:0000269|PubMed:17357087,
ECO:0000269|PubMed:17440703}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- DISEASE: Vasculopathy, retinal, with cerebral leukodystrophy
(RVCL) [MIM:192315]: A microvascular endotheliopathy resulting in
central nervous system degeneration and retinopathy, with
progressive loss of vision, stroke, motor impairment, and
cognitive decline. The ocular manifestations are characterized by
telangiectasias, microaneurysms and retinal capillary obliteration
starting in the macula. Diseased cerebral white matter has
prominent small infarcts that often coalesce to pseudotumors.
{ECO:0000269|PubMed:17660820}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the exonuclease superfamily. TREX family.
{ECO:0000305}.
-!- CAUTION: The gene for this protein is either identical to or
adjacent to that of ATRIP. Some of the mRNAs that encode ATRIP
also encode TREX1 in another reading frame. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=AAD48774.2; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/trex1/";
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EMBL; AJ243797; CAB50866.1; -; mRNA.
EMBL; AF319566; AAK07613.1; -; mRNA.
EMBL; AF319567; AAK07614.1; -; mRNA.
EMBL; AF319568; AAK07615.1; -; mRNA.
EMBL; AF319569; AAK07616.1; -; mRNA.
EMBL; AF151105; AAD48774.2; ALT_INIT; mRNA.
EMBL; AK315196; BAG37636.1; -; mRNA.
EMBL; AL137745; -; NOT_ANNOTATED_CDS; mRNA.
EMBL; AF483777; AAL82504.1; -; Genomic_DNA.
EMBL; BC023630; AAH23630.1; -; mRNA.
CCDS; CCDS2769.1; -. [Q9NSU2-3]
CCDS; CCDS43086.1; -. [Q9NSU2-1]
CCDS; CCDS59451.1; -. [Q9NSU2-2]
PIR; T46299; T46299.
RefSeq; NP_009179.2; NM_007248.3. [Q9NSU2-2]
RefSeq; NP_057465.1; NM_016381.5. [Q9NSU2-1]
RefSeq; NP_338599.1; NM_033629.4. [Q9NSU2-3]
UniGene; Hs.707026; -.
UniGene; Hs.713742; -.
UniGene; Hs.744646; -.
ProteinModelPortal; Q9NSU2; -.
SMR; Q9NSU2; -.
BioGrid; 116433; 12.
IntAct; Q9NSU2; 5.
MINT; MINT-1466830; -.
STRING; 9606.ENSP00000390478; -.
iPTMnet; Q9NSU2; -.
PhosphoSitePlus; Q9NSU2; -.
DMDM; 47606216; -.
EPD; Q9NSU2; -.
MaxQB; Q9NSU2; -.
PaxDb; Q9NSU2; -.
PeptideAtlas; Q9NSU2; -.
PRIDE; Q9NSU2; -.
DNASU; 11277; -.
Ensembl; ENST00000444177; ENSP00000415972; ENSG00000213689. [Q9NSU2-2]
Ensembl; ENST00000625293; ENSP00000486676; ENSG00000213689. [Q9NSU2-1]
Ensembl; ENST00000629913; ENSP00000486444; ENSG00000213689. [Q9NSU2-3]
GeneID; 11277; -.
KEGG; hsa:11277; -.
UCSC; uc031rzp.2; human. [Q9NSU2-1]
CTD; 11277; -.
DisGeNET; 11277; -.
EuPathDB; HostDB:ENSG00000213689.10; -.
EuPathDB; HostDB:ENSG00000282827.1; -.
GeneCards; TREX1; -.
GeneReviews; TREX1; -.
HGNC; HGNC:12269; TREX1.
HPA; HPA035437; -.
MalaCards; TREX1; -.
MIM; 152700; phenotype.
MIM; 192315; phenotype.
MIM; 225750; phenotype.
MIM; 606609; gene.
MIM; 610448; phenotype.
neXtProt; NX_Q9NSU2; -.
OpenTargets; ENSG00000213689; -.
Orphanet; 51; Aicardi-Goutieres syndrome.
Orphanet; 3421; Cerebroretinal vasculopathy.
Orphanet; 90280; Chilblain lupus.
Orphanet; 71291; Hereditary vascular retinopathy.
Orphanet; 63261; HERNS syndrome.
Orphanet; 536; Systemic lupus erythematosus.
PharmGKB; PA36949; -.
eggNOG; KOG4793; Eukaryota.
eggNOG; ENOG4111YSP; LUCA.
GeneTree; ENSGT00390000012715; -.
HOGENOM; HOG000118119; -.
HOVERGEN; HBG079278; -.
InParanoid; Q9NSU2; -.
KO; K10790; -.
OMA; LLSICQW; -.
OrthoDB; EOG091G0LSM; -.
PhylomeDB; Q9NSU2; -.
TreeFam; TF323333; -.
Reactome; R-HSA-3248023; Regulation by TREX1.
Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
ChiTaRS; TREX1; human.
GeneWiki; TREX1; -.
GenomeRNAi; 11277; -.
PRO; PR:Q9NSU2; -.
Proteomes; UP000005640; Chromosome 3.
Bgee; ENSG00000213689; -.
CleanEx; HS_TREX1; -.
ExpressionAtlas; Q9NSU2; baseline.
Genevisible; Q9NSU2; HS.
GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
GO; GO:0005635; C:nuclear envelope; NAS:UniProtKB.
GO; GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB.
GO; GO:0008296; F:3'-5'-exodeoxyribonuclease activity; ISS:UniProtKB.
GO; GO:0008853; F:exodeoxyribonuclease III activity; IEA:UniProtKB-EC.
GO; GO:0046872; F:metal ion binding; TAS:UniProtKB.
GO; GO:0032405; F:MutLalpha complex binding; IDA:MGI.
GO; GO:0032407; F:MutSalpha complex binding; IDA:MGI.
GO; GO:0042803; F:protein homodimerization activity; TAS:UniProtKB.
GO; GO:0003697; F:single-stranded DNA binding; TAS:UniProtKB.
GO; GO:0006259; P:DNA metabolic process; ISS:UniProtKB.
GO; GO:0006310; P:DNA recombination; NAS:UniProtKB.
GO; GO:0006281; P:DNA repair; TAS:ProtInc.
GO; GO:0006260; P:DNA replication; NAS:UniProtKB.
GO; GO:0006298; P:mismatch repair; NAS:UniProtKB.
GO; GO:0032479; P:regulation of type I interferon production; TAS:Reactome.
Gene3D; 3.30.420.10; -; 1.
InterPro; IPR013520; Exonuclease_RNaseT/DNA_pol3.
InterPro; IPR012337; RNaseH-like_sf.
InterPro; IPR036397; RNaseH_sf.
SMART; SM00479; EXOIII; 1.
SUPFAM; SSF53098; SSF53098; 1.
1: Evidence at protein level;
Aicardi-Goutieres syndrome; Alternative splicing; Complete proteome;
Cytoplasm; Disease mutation; Endoplasmic reticulum; Exonuclease;
Hydrolase; Magnesium; Membrane; Metal-binding; Neurodegeneration;
Nuclease; Nucleus; Phosphoprotein; Reference proteome;
Systemic lupus erythematosus; Ubl conjugation.
CHAIN 1 369 Three-prime repair exonuclease 1.
/FTId=PRO_0000109868.
REGION 75 76 Substrate binding. {ECO:0000250}.
REGION 109 118 Proline-rich region. {ECO:0000250}.
REGION 291 369 Necessary for endoplasmic reticulum
localization. {ECO:0000250}.
REGION 298 369 Interaction with UBQLN1.
{ECO:0000269|PubMed:23979357}.
REGION 336 369 Necessary for cytoplasmic retention.
{ECO:0000250}.
ACT_SITE 250 250 Proton donor/acceptor. {ECO:0000250}.
METAL 73 73 Magnesium 1. {ECO:0000250}.
METAL 73 73 Magnesium 2. {ECO:0000250}.
METAL 75 75 Magnesium 1. {ECO:0000250}.
METAL 255 255 Magnesium 1. {ECO:0000250}.
BINDING 184 184 Substrate. {ECO:0000250}.
BINDING 255 255 Substrate. {ECO:0000250}.
MOD_RES 133 133 Phosphoserine.
{ECO:0000244|PubMed:18669648}.
MOD_RES 222 222 Phosphoserine.
{ECO:0000244|PubMed:24275569}.
MOD_RES 316 316 Phosphoserine.
{ECO:0000244|PubMed:18669648,
ECO:0000244|PubMed:23186163}.
VAR_SEQ 1 65 Missing (in isoform 2).
{ECO:0000303|PubMed:10393201}.
/FTId=VSP_010445.
VAR_SEQ 1 55 Missing (in isoform 3).
{ECO:0000303|PubMed:10391904}.
/FTId=VSP_010446.
VARIANT 73 73 D -> N (in CHBL1 and AGS1; loss of
function; dbSNP:rs121908117).
{ECO:0000269|PubMed:17440703,
ECO:0000269|PubMed:20799324}.
/FTId=VAR_037948.
VARIANT 169 169 R -> H (in AGS1 and SLE; primary
fibroblasts from an AGS1 patient carrying
H-169 show defective G1/S transition and
chronic G2/M DNA damage checkpoint
activation; strongly reduces activity;
dbSNP:rs72556554).
{ECO:0000269|PubMed:16845398,
ECO:0000269|PubMed:17293595,
ECO:0000269|PubMed:17660818,
ECO:0000269|PubMed:17846997,
ECO:0000269|PubMed:18045533,
ECO:0000269|PubMed:20131292}.
/FTId=VAR_028319.
VARIANT 177 177 V -> A (in AGS1; increases ubiquitination
levels; no effect on exonuclease
activity; dbSNP:rs79993407).
{ECO:0000269|PubMed:17846997,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_070899.
VARIANT 213 213 A -> V (in SLE; dbSNP:rs762011967).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037949.
VARIANT 253 253 E -> K (in AGS1; increases ubiquitination
levels; no effect on exonuclease
activity). {ECO:0000269|PubMed:20131292,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_070900.
VARIANT 255 255 D -> DD (in AGS1; heterozygous compound
with H-169; loss of activity).
{ECO:0000269|PubMed:16845398,
ECO:0000269|PubMed:17293595}.
/FTId=VAR_028320.
VARIANT 255 255 D -> H (in AGS1 and SLE).
{ECO:0000269|PubMed:20131292}.
/FTId=VAR_070901.
VARIANT 255 255 D -> N (in AGS1; autosomal dominant form;
no effect on dsDNA exonuclease activity;
abolishes ssDNA exonuclease activity;
dbSNP:rs78846775).
{ECO:0000269|PubMed:17357087,
ECO:0000269|PubMed:17846997,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_032940.
VARIANT 256 256 V -> D (in AGS1; reduces activity by 75%;
dbSNP:rs78408272).
{ECO:0000269|PubMed:16845398,
ECO:0000269|PubMed:17293595,
ECO:0000269|PubMed:17846997}.
/FTId=VAR_028321.
VARIANT 282 282 G -> S (in SLE; associated in cis with P-
302; dbSNP:rs113107733).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037950.
VARIANT 295 295 R -> S (in SLE; dbSNP:rs72556555).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037951.
VARIANT 302 302 A -> P (in SLE; associated in cis with S-
282; dbSNP:rs112741962).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037952.
VARIANT 321 321 E -> G (in dbSNP:rs55999987).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037953.
VARIANT 345 345 P -> L (in SLE; increases ubiquitination
levels; no effect on exonuclease
activity; dbSNP:rs148833270).
{ECO:0000269|PubMed:17660818,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_037954.
VARIANT 358 358 T -> P (in AGS1; decreases ubiquitination
levels; decreases colocalization with
UBQLN1; no effect on exonuclease
activity; dbSNP:rs76224909).
{ECO:0000269|PubMed:17846997,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_070902.
VARIANT 360 360 Y -> C (in SLE; decreases ubiquitination
levels; decreases colocalization with
UBQLN1; no effect on exonuclease
activity; dbSNP:rs370504038).
{ECO:0000269|PubMed:17660818,
ECO:0000269|PubMed:23979357}.
/FTId=VAR_037955.
VARIANT 361 361 G -> A (in SLE; dbSNP:rs780022923).
{ECO:0000269|PubMed:17660818}.
/FTId=VAR_037956.
MUTAGEN 85 85 K->R: Reduces ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 121 121 K->R: No effect on ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 130 130 K->R: Reduces ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 215 215 K->R: Reduces ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 230 230 K->R: Reduces ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 297 297 K->R: Reduces ubiquitination.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 326 326 K->R: Reduces ubiquitination. Strongly
reduces ubiquitination; when associated
with R-332.
{ECO:0000269|PubMed:23979357}.
MUTAGEN 332 332 K->R: Reduces ubiquitination. Strongly
reduces ubiquitination; when associated
with R-326.
{ECO:0000269|PubMed:23979357}.
CONFLICT 320 320 G -> R (in Ref. 1; CAB50866).
{ECO:0000305}.
SEQUENCE 369 AA; 38923 MW; 42B79047A9AD9837 CRC64;
MGPGARRQGR IVQGRPEMCF CPPPTPLPPL RILTLGTHTP TPCSSPGSAA GTYPTMGSQA
LPPGPMQTLI FFDMEATGLP FSQPKVTELC LLAVHRCALE SPPTSQGPPP TVPPPPRVVD
KLSLCVAPGK ACSPAASEIT GLSTAVLAAH GRQCFDDNLA NLLLAFLRRQ PQPWCLVAHN
GDRYDFPLLQ AELAMLGLTS ALDGAFCVDS ITALKALERA SSPSEHGPRK SYSLGSIYTR
LYGQSPPDSH TAEGDVLALL SICQWRPQAL LRWVDAHARP FGTIRPMYGV TASARTKPRP
SAVTTTAHLA TTRNTSPSLG ESRGTKDLPP VKDPGALSRE GLLAPLGLLA ILTLAVATLY
GLSLATPGE


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