View source for TREX1

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Three prime repair exonuclease 1''' is an [[enzyme]] that in humans is encoded by the ''TREX1'' [[gene]].<ref name="pmid10391904">{{cite journal |vauthors=Mazur DJ, Perrino FW | title = Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'-->5' exonucleases | journal = J Biol Chem | volume = 274 | issue = 28 | pages = 19655–60 |date=Aug 1999 | pmid = 10391904 | doi =10.1074/jbc.274.28.19655  | doi-access = free }}</ref><ref name="pmid10393201">{{cite journal |vauthors=Hoss M, Robins P, Naven TJ, Pappin DJ, Sgouros J, Lindahl T | title = A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein | journal = EMBO J | volume = 18 | issue = 13 | pages = 3868–75 |date=Aug 1999 | pmid = 10393201 | pmc = 1171463 | doi = 10.1093/emboj/18.13.3868 }}</ref><ref name="pmid16845398">{{cite journal |vauthors=Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T | title = Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus | journal = Nat Genet | volume = 38 | issue = 8 | pages = 917–20 |date=Jul 2006 | pmid = 16845398 | doi = 10.1038/ng1845 | s2cid = 9069106 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TREX1 three prime repair exonuclease 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11277}}</ref>
== Function ==
This gene encodes the major 3'-&gt;5' DNA [[exonuclease]] in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in [[Aicardi-Goutieres syndrome]], chilblain lupus, [[Autosomal dominant retinal vasculopathy with cerebral leukodystrophy|RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy)]], and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez" />
== Clinical relevance ==
Mutations within the ''TREX1'' gene cause familial [[chilblain]] lupus. The ''TREX1'' polymorphisms confer susceptibility to [[systemic lupus erythematosus]]. Missense mutations of the ''TREX1'' gene significantly downregulate its exonucleolytic capacity and result in the accumulation of nucleic acids. The build-up of the nucleic acids within the cytoplasm stimulates type-I [[interferon]] responses that could trigger autoimmune responses.<ref name=Jabalameli21>{{cite journal |first1=Navid |last1=Jabalameli |title=Overlap between Genetic Susceptibility to COVID-19 and Skin Diseases |journal=Immunological Investigations |year=2021 |volume=51 |issue=4 |pages=1087–94 |doi=10.1080/08820139.2021.1876086 |pmid=33494631|doi-access=free }}</ref> The region containing the ''TREX1'' gene (3p21.31) has been linked to [[Coronavirus_disease_2019|COVID-19]] severity in a recent genome-wide association study.<ref>{{cite journal |last1=Ellinghaus |title=Genomewide Association Study of Severe Covid-19 with Respiratory Failure |journal=New England Journal of Medicine |year=2020 |volume=383 |issue=16 |pages=1522–34 |doi=10.1056/NEJMoa2020283 |pmid=32558485 |pmc=7315890 |doi-access=free }}</ref> This might explain the occurrence of chilblain like lesions in patients infected with SARS-CoV-2.<ref name=Jabalameli21/>
TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm<ref>{{cite journal|last1=Doyle|first1=Thomas|title=HIV-1 and interferons: who's interfering with whom?|journal=Nature Reviews Microbiology|date=27 April 2015|volume=13|issue=Nature Reviews Microbiology 13|pages=403–413|doi=10.1038/nrmicro3449|pmid=25915633|s2cid=205499122|pmc=7768976}}</ref>
[[Mutation]]s in TREX1 can give cause failure to appropriately remove [[ribonucleotide]]s misincorporated into [[DNA]].<ref name = McKinnon2017>{{cite journal |vauthors=McKinnon PJ |title=Genome integrity and disease prevention in the nervous system |journal=Genes Dev |volume=31 |issue=12 |pages=1180–94 |date=June 2017 |pmid=28765160 |pmc=5558921 |doi=10.1101/gad.301325.117 }}</ref>  The removal process is ordinary performed by ribo[[nucleotide excision repair]].  In humans, a defect in this process can give rise to [[Aicardi-Goutieres syndrome]] involving [[microcephaly]] and [[neuroinflammation]].<ref name = McKinnon2017/>
==References==
{{reflist}}
==Further reading==
{{refbegin | 2}}
*{{cite journal  |vauthors=Tolmie JL, Shillito P, Hughes-Benzie R, Stephenson JB |title=The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis) |journal=J. Med. Genet. |volume=32 |issue= 11 |pages= 881–4 |year= 1996 |pmid= 8592332 |doi=10.1136/jmg.32.11.881  | pmc=1051740  }}
*{{cite journal  | author=Black DN |title=Encephalitis among Cree children in northern Quebec |journal=Ann. Neurol. |volume=24 |issue= 4 |pages= 483–9 |year= 1989 |pmid= 3239950 |doi= 10.1002/ana.410240402  |name-list-style=vanc| author2=Watters GV  | author3=Andermann E  | display-authors=3  | last4=Dumont  | first4=Charles  | last5=Kabay  | first5=Michel E.  | last6=Kaplan  | first6=Paige  | last7=Meagher-Villemure  | first7=Kathleen  | last8=Michaud  | first8=Jean  | last9=O'Gorman  | first9=Gus |s2cid=32112982 }}
*{{cite journal  |vauthors=Perrino FW, Miller H, Ealey KA |title=Identification of a 3'-->5'-exonuclease that removes cytosine arabinoside monophosphate from 3' termini of DNA |journal=J. Biol. Chem. |volume=269 |issue= 23 |pages= 16357–63 |year= 1994 |doi=10.1016/S0021-9258(17)34015-2 |pmid= 8206943 |doi-access=free }}
*{{cite journal  |vauthors=Goutières F, Aicardi J, Barth PG, Lebon P |title=Aicardi-Goutières syndrome: an update and results of interferon-alpha studies |journal=Ann. Neurol. |volume=44 |issue= 6 |pages= 900–7 |year= 1999 |pmid= 9851434 |doi= 10.1002/ana.410440608 |s2cid=58224378 }}
*{{cite journal  | author=Crow YJ |title=Aicardi-Goutières Syndrome Displays Genetic Heterogeneity with One Locus (AGS1) on Chromosome 3p21 |journal=Am. J. Hum. Genet. |volume=67 |issue= 1 |pages= 213–21 |year= 2000 |pmid= 10827106 |doi=10.1086/302955  | pmc=1287108  |name-list-style=vanc| author2=Jackson AP  | author3=Roberts E  | display-authors=3  | last4=Vanbeusekom  | first4=E  | last5=Barth  | first5=P  | last6=Corry  | first6=P  | last7=Ferrie  | first7=C  | last8=Hamel  | first8=B  | last9=Jayatunga  | first9=R  }}
*{{cite journal  |vauthors=Mazur DJ, Perrino FW |title=Structure and expression of the TREX1 and TREX2 3' --> 5' exonuclease genes |journal=J. Biol. Chem. |volume=276 |issue= 18 |pages= 14718–27 |year= 2001 |pmid= 11278605 |doi= 10.1074/jbc.M010051200 |doi-access= free }}
*{{cite journal  | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241  |name-list-style=vanc| author2=Feingold EA  | author3=Grouse LH  | display-authors=3  | last4=Derge  | first4=JG  | last5=Klausner  | first5=RD  | last6=Collins  | first6=FS  | last7=Wagner  | first7=L  | last8=Shenmen  | first8=CM  | last9=Schuler  | first9=GD |bibcode=2002PNAS...9916899M |doi-access=free }}
*{{cite journal  | author=Crow YJ |title=Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism |journal=J. Med. Genet. |volume=40 |issue= 3 |pages= 183–7 |year= 2003 |pmid= 12624136 |doi=10.1136/jmg.40.3.183  | pmc=1735395  |name-list-style=vanc| author2=Black DN  | author3=Ali M  | display-authors=3  | last4=Bond  | first4=J  | last5=Jackson  | first5=AP  | last6=Lefson  | first6=M  | last7=Michaud  | first7=J  | last8=Roberts  | first8=E  | last9=Stephenson  | first9=JB  }}
*{{cite journal  | author=Ota T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285  |name-list-style=vanc| author2=Suzuki Y  | author3=Nishikawa T  | display-authors=3  | last4=Otsuki  | first4=Tetsuji  | last5=Sugiyama  | first5=Tomoyasu  | last6=Irie  | first6=Ryotaro  | last7=Wakamatsu  | first7=Ai  | last8=Hayashi  | first8=Koji  | last9=Sato  | first9=Hiroyuki | doi-access=free  }}
*{{cite journal  | author=Gerhard DS |title=The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928  |name-list-style=vanc| author2=Wagner L  | author3=Feingold EA  | display-authors=3  | last4=Shenmen  | first4=CM  | last5=Grouse  | first5=LH  | last6=Schuler  | first6=G  | last7=Klein  | first7=SL  | last8=Old  | first8=S  | last9=Rasooly  | first9=R }}
*{{cite journal  |vauthors=Unsal-Kaçmaz K, Mullen TE, Kaufmann WK, Sancar A |title=Coupling of Human Circadian and Cell Cycles by the Timeless Protein |journal=Mol. Cell. Biol. |volume=25 |issue= 8 |pages= 3109–16 |year= 2005 |pmid= 15798197 |doi= 10.1128/MCB.25.8.3109-3116.2005  | pmc=1069621 }}
*{{cite journal  | author=Rual JF |title=Towards a proteome-scale map of the human protein-protein interaction network |journal=Nature |volume=437 |issue= 7062 |pages= 1173–8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209  |name-list-style=vanc| author2=Venkatesan K  | author3=Hao T  | display-authors=3  | last4=Hirozane-Kishikawa  | first4=Tomoko  | last5=Dricot  | first5=Amélie  | last6=Li  | first6=Ning  | last7=Berriz  | first7=Gabriel F.  | last8=Gibbons  | first8=Francis D.  | last9=Dreze  | first9=Matija |bibcode=2005Natur.437.1173R |s2cid=4427026 }}
*{{cite journal  | author=Kimura K |title=Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406  | pmc=1356129  |name-list-style=vanc| author2=Wakamatsu A  | author3=Suzuki Y  | display-authors=3  | last4=Ota  | first4=T  | last5=Nishikawa  | first5=T  | last6=Yamashita  | first6=R  | last7=Yamamoto  | first7=J  | last8=Sekine  | first8=M  | last9=Tsuritani  | first9=K }}
*{{cite journal  |vauthors=Yoshioka K, Yoshioka Y, Hsieh P |title=ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts |journal=Mol. Cell |volume=22 |issue= 4 |pages= 501–10 |year= 2006 |pmid= 16713580 |doi= 10.1016/j.molcel.2006.04.023  | pmc=2423943 }}
*{{cite journal  | author=Chowdhury D |title=The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death |journal=Mol. Cell |volume=23 |issue= 1 |pages= 133–42 |year= 2006 |pmid= 16818237 |doi= 10.1016/j.molcel.2006.06.005  |name-list-style=vanc| author2=Beresford PJ  | author3=Zhu P  | display-authors=3  | last4=Zhang  | first4=Dong  | last5=Sung  | first5=Jung-Suk  | last6=Demple  | first6=Bruce  | last7=Perrino  | first7=Fred W.  | last8=Lieberman  | first8=Judy | doi-access=free  }}
*{{cite journal  | author=Olsen JV |title=Global, in vivo, and site-specific phosphorylation dynamics in signaling networks |journal=Cell |volume=127 |issue= 3 |pages= 635–48 |year= 2006 |pmid= 17081983 |doi= 10.1016/j.cell.2006.09.026  |name-list-style=vanc| author2=Blagoev B  | author3=Gnad F  | display-authors=3  | last4=Macek  | first4=Boris  | last5=Kumar  | first5=Chanchal  | last6=Mortensen  | first6=Peter  | last7=Mann  | first7=Matthias |s2cid=7827573 | doi-access=free}}
*{{cite book |vauthors=Crow YJ |title=Aicardi-Goutières Syndrome |publisher=University of Washington, Seattle |series=GeneReviews® [Internet] |date=November 2016 |id=NBK1475 |pmid=20301648 |url=https://www.ncbi.nlm.nih.gov/books/NBK1475/}}
{{refend}}
==External links==
* [https://www.ncbi.nlm.nih.gov/omim/225750,606034,606609,610181,610326,610329,610330,610333,225750,606034,606609,610181,610326,610329,610330,610333  OMIM entries on Aicardi-Goutieres syndrome]
{{Esterases}}
{{gene-3-stub}}