Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQG7K12)

• DOT Name: Three-prime repair exonuclease 1 (TREX1)
• Synonyms: EC 3.1.11.2; 3'-5' exonuclease TREX1; Deoxyribonuclease III; DNase III
• Gene Name: TREX1
• Related Disease:
  Aicardi-Goutieres syndrome 1
  Pseudo-TORCH syndrome
  Adult lymphoma
  Aicardi-Goutieres syndrome 2
  Aicardi-Goutieres syndrome 3
  Aicardi-Goutieres syndrome 4
  Aicardi-Goutieres syndrome 5
  Aicardi-Goutieres syndrome 6
  Aicardi-Goutieres syndrome 7
  Alzheimer disease
  Anemia
  Ataxia-telangiectasia
  Barrett esophagus
  Brain disease
  Breast cancer
  Breast carcinoma
  Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy
  Chilblain lupus 1
  Cutaneous lupus erythematosus
  HIV infectious disease
  Influenza
  Intellectual disability
  Leukodystrophy
  Lupus
  Lymphoma
  Migraine disorder
  Nephropathy
  Osteoarthritis
  Pediatric lymphoma
  Psoriasis
  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
  Retinopathy
  Rheumatoid arthritis
  Stroke
  Systemic sclerosis
  Trichohepatoenteric syndrome
  Vascular disease
  Advanced cancer
  Breast neoplasm
  Glioma
  Immune system disorder
  Malignant glioma
  Aicardi-Goutieres syndrome
  Familial chilblain lupus
  Chilblain lupus
  Dystonia
  Inflammation
  Neoplasm
  Neuroblastoma
  Sjogren syndrome
• UniProt ID: TREX1_HUMAN
• PDB ID: 7TQN; 7TQO; 7TQP; 7TQQ
• EC Number: 3.1.11.2
• Sequence:
  MGSQALPPGPMQTLIFFDMEATGLPFSQPKVTELCLLAVHRCALESPPTSQGPPPTVPPP
  PRVVDKLSLCVAPGKACSPAASEITGLSTAVLAAHGRQCFDDNLANLLLAFLRRQPQPWC
  LVAHNGDRYDFPLLQAELAMLGLTSALDGAFCVDSITALKALERASSPSEHGPRKSYSLG
  SIYTRLYGQSPPDSHTAEGDVLALLSICQWRPQALLRWVDAHARPFGTIRPMYGVTASAR
  TKPRPSAVTTTAHLATTRNTSPSLGESRGTKDLPPVKDPGALSREGLLAPLGLLAILTLA
  VATLYGLSLATPGE
• 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. Plays a key role in degradation of DNA fragments at cytosolic micronuclei arising from genome instability: its association with the endoplasmic reticulum membrane directs TREX1 to ruptured micronuclei, leading to micronuclear DNA degradation. Micronuclear DNA degradation is required to limit CGAS activation and subsequent inflammation. Unless degraded, these DNA fragments accumulate in the cytosol and activate the cGAS-STING innate immune signaling, leading to the production of type I interferon. 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.
• Tissue Specificity: Detected in thymus, spleen, liver, brain, heart, small intestine and colon.
• KEGG Pathway: Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Regulation by TREX1 (R-HSA-3248023)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome 1	DISPAXC2	Definitive	Autosomal recessive	[1]
Pseudo-TORCH syndrome	DISM9N8Y	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[2]
Aicardi-Goutieres syndrome 2	DISOL1R1	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome 3	DIS16XSH	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome 4	DIS5GQQ1	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome 5	DISU0BME	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome 6	DIS9TLMY	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome 7	DIS89BRW	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Anemia	DISTVL0C	Strong	Genetic Variation	[5]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[6]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[7]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy	DIS93Z3E	Strong	Genetic Variation	[10]
Chilblain lupus 1	DISEBS1O	Strong	Autosomal dominant	[11]
Cutaneous lupus erythematosus	DISOIX6L	Strong	Genetic Variation	[12]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[13]
Influenza	DIS3PNU3	Strong	Biomarker	[14]
Intellectual disability	DISMBNXP	Strong	Biomarker	[15]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[16]
Lupus	DISOKJWA	Strong	Genetic Variation	[17]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[2]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[18]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[19]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[20]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[2]
Psoriasis	DIS59VMN	Strong	Altered Expression	[21]
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations	DISI621C	Strong	Autosomal dominant	[22]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[23]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[20]
Stroke	DISX6UHX	Strong	Biomarker	[24]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[25]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[26]
Vascular disease	DISVS67S	Strong	Biomarker	[27]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[28]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[29]
Glioma	DIS5RPEH	moderate	Altered Expression	[30]
Immune system disorder	DISAEGPH	moderate	Biomarker	[31]
Malignant glioma	DISFXKOV	moderate	Altered Expression	[30]
Aicardi-Goutieres syndrome	DIS1NH4X	Supportive	Autosomal dominant	[32]
Familial chilblain lupus	DISOSPDL	Supportive	Autosomal dominant	[33]
Chilblain lupus	DIS5792K	Limited	Genetic Variation	[34]
Dystonia	DISJLFGW	Limited	Biomarker	[35]
Inflammation	DISJUQ5T	Limited	Biomarker	[19]
Neoplasm	DISZKGEW	Limited	Biomarker	[36]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[37]
Sjogren syndrome	DISUBX7H	Limited	Genetic Variation	[2]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Three-prime repair exonuclease 1 (TREX1).	[38]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Three-prime repair exonuclease 1 (TREX1).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Three-prime repair exonuclease 1 (TREX1).	[40]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Three-prime repair exonuclease 1 (TREX1).	[41]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Three-prime repair exonuclease 1 (TREX1).	[41]
Selenium	DM25CGV	Approved	Selenium increases the expression of Three-prime repair exonuclease 1 (TREX1).	[42]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Three-prime repair exonuclease 1 (TREX1).	[30]
Topotecan	DMP6G8T	Approved	Topotecan increases the expression of Three-prime repair exonuclease 1 (TREX1).	[30]
Fotemustine	DMV62ED	Approved	Fotemustine increases the expression of Three-prime repair exonuclease 1 (TREX1).	[30]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Three-prime repair exonuclease 1 (TREX1).	[44]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Three-prime repair exonuclease 1 (TREX1).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Three-prime repair exonuclease 1 (TREX1).	[45]

References

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• [2] TREX1 variants in Sjogren's syndrome related lymphomagenesis.Cytokine. 2020 Aug;132:154781. doi: 10.1016/j.cyto.2019.154781. Epub 2019 Jul 18.
• [3] The AIM2-like Receptors Are Dispensable for the Interferon Response to Intracellular DNA.Immunity. 2016 Aug 16;45(2):255-66. doi: 10.1016/j.immuni.2016.06.015. Epub 2016 Aug 2.
• [4] Review: Vascular dementia: clinicopathologic and genetic considerations.Neuropathol Appl Neurobiol. 2018 Apr;44(3):247-266. doi: 10.1111/nan.12472. Epub 2018 Mar 1.
• [5] TREX1 D18N mice fail to process erythroblast DNA resulting in inflammation and dysfunctional erythropoiesis.Autoimmunity. 2018 Nov;51(7):333-344. doi: 10.1080/08916934.2018.1522305. Epub 2018 Nov 13.
• [6] Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease.Biochem Soc Trans. 2009 Jun;37(Pt 3):535-8. doi: 10.1042/BST0370535.
• [7] Immunostimulatory Endogenous Nucleic Acids Drive the Lesional Inflammation in Cutaneous Lupus Erythematosus.J Invest Dermatol. 2017 Jul;137(7):1484-1492. doi: 10.1016/j.jid.2017.03.018. Epub 2017 Mar 27.
• [8] The crystal structure of TREX1 explains the 3' nucleotide specificity and reveals a polyproline II helix for protein partnering.J Biol Chem. 2007 Apr 6;282(14):10537-43. doi: 10.1074/jbc.M700039200. Epub 2007 Feb 9.
• [9] Exosomes Shuttle TREX1-Sensitive IFN-Stimulatory dsDNA from Irradiated Cancer Cells to DCs.Cancer Immunol Res. 2018 Aug;6(8):910-920. doi: 10.1158/2326-6066.CIR-17-0581. Epub 2018 Jun 15.
• [10] A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain.J Chin Med Assoc. 2013 Jun;76(6):319-24. doi: 10.1016/j.jcma.2013.03.002. Epub 2013 Apr 18.
• [11] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [12] Familial chilblain lupus--a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.Dermatology. 2009;219(2):162-6. doi: 10.1159/000222430. Epub 2009 May 28.
• [13] Polymorphisms in TREX1 and susceptibility to HIV-1 infection.Int J Immunogenet. 2013 Dec;40(6):492-4. doi: 10.1111/iji.12071. Epub 2013 Jun 15.
• [14] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [15] Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.Am J Med Genet A. 2015 Feb;167A(2):296-312. doi: 10.1002/ajmg.a.36887. Epub 2015 Jan 16.
• [16] A homozygote TREX1 mutation in two siblings with different phenotypes: Chilblains and cerebral vasculitis.Eur J Med Genet. 2017 Dec;60(12):690-694. doi: 10.1016/j.ejmg.2017.09.004. Epub 2017 Sep 13.
• [17] cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model.J Autoimmun. 2019 Jun;100:84-94. doi: 10.1016/j.jaut.2019.03.001. Epub 2019 Mar 11.
• [18] Genetics of migraine: an update with special attention to genetic comorbidity.Curr Opin Neurol. 2008 Jun;21(3):288-93. doi: 10.1097/WCO.0b013e3282fd171a.
• [19] Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5117-22. doi: 10.1073/pnas.1423804112. Epub 2015 Apr 6.
• [20] Trex-1 deficiency in rheumatoid arthritis synovial fibroblasts.Arthritis Rheum. 2010 Sep;62(9):2673-9. doi: 10.1002/art.27567.
• [21] TREX through Cutaneous HealthandDisease.J Invest Dermatol. 2016 Dec;136(12):2337-2339. doi: 10.1016/j.jid.2016.06.628.
• [22] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [23] Review: molecular genetics and pathology of hereditary small vessel diseases of the brain.Neuropathol Appl Neurobiol. 2011 Feb;37(1):94-113. doi: 10.1111/j.1365-2990.2010.01147.x.
• [24] TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia.Brain Pathol. 2018 Nov;28(6):806-821. doi: 10.1111/bpa.12626. Epub 2018 Oct 10.
• [25] Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity.Arthritis Rheum. 2012 Aug;64(8):2746-52. doi: 10.1002/art.34490.
• [26] A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutires syndrome.Am J Med Genet A. 2010 Oct;152A(10):2612-7. doi: 10.1002/ajmg.a.33620.
• [27] Retinal Vasculopathy With Cerebral Leukodystrophy: Clinicopathologic Features of an Autopsied Patient With a Heterozygous TREX 1 Mutation.J Neuropathol Exp Neurol. 2019 Feb 1;78(2):181-186. doi: 10.1093/jnen/nly115.
• [28] TREX1 Cuts Down on Cancer Immunogenicity.Trends Cell Biol. 2017 Aug;27(8):543-545. doi: 10.1016/j.tcb.2017.06.001. Epub 2017 Jun 15.
• [29] A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1.Genes Dev. 2017 Feb 15;31(4):353-369. doi: 10.1101/gad.289769.116. Epub 2017 Mar 9.
• [30] Human three prime exonuclease TREX1 is induced by genotoxic stress and involved in protection of glioma and melanoma cells to anticancer drugs. Biochim Biophys Acta. 2013 Aug;1833(8):1832-43. doi: 10.1016/j.bbamcr.2013.03.029. Epub 2013 Apr 8.
• [31] Immune Diseases Associated with TREX1 and STING Dysfunction.J Interferon Cytokine Res. 2017 May;37(5):198-206. doi: 10.1089/jir.2016.0086.
• [32] Aicardi-Goutires Syndrome. 2005 Jun 29 [updated 2016 Nov 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [33] Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2017 Feb;76(2):468-472. doi: 10.1136/annrheumdis-2016-209841. Epub 2016 Aug 26.
• [34] Aicardi-Goutires syndrome protein TREX1 suppresses L1 and maintains genome integrity through exonuclease-independent ORF1p depletion.Nucleic Acids Res. 2017 May 5;45(8):4619-4631. doi: 10.1093/nar/gkx178.
• [35] [Clinical and genetic analysis of a family with Aicardi-Goutires syndrome and literature review].Zhonghua Er Ke Za Zhi. 2014 Nov;52(11):822-7.
• [36] Tumor-specific macrophage targeting through recognition of retinoid X receptor beta.J Control Release. 2019 May 10;301:42-53. doi: 10.1016/j.jconrel.2019.03.009. Epub 2019 Mar 11.
• [37] Inhibition of neuroblastoma cell growth by TREX1-mutated human lymphocytes.Oncol Rep. 2012 May;27(5):1689-94. doi: 10.3892/or.2012.1696. Epub 2012 Feb 22.
• [38] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [39] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [40] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [41] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [42] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [43] Human three prime exonuclease TREX1 is induced by genotoxic stress and involved in protection of glioma and melanoma cells to anticancer drugs. Biochim Biophys Acta. 2013 Aug;1833(8):1832-43. doi: 10.1016/j.bbamcr.2013.03.029. Epub 2013 Apr 8.
• [44] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [45] Three prime exonuclease I (TREX1) is Fos/AP-1 regulated by genotoxic stress and protects against ultraviolet light and benzo(a)pyrene-induced DNA damage. Nucleic Acids Res. 2010 Oct;38(19):6418-32. doi: 10.1093/nar/gkq455. Epub 2010 May 28.