Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEUIMC2)

• DOT Name: Deoxyribonuclease gamma (DNASE1L3)
• Synonyms: DNase gamma; EC 3.1.21.-; DNase I homolog protein DHP2; Deoxyribonuclease I-like 3; DNase I-like 3; Liver and spleen DNase; LS-DNase; LSD
• Gene Name: DNASE1L3
• Related Disease:
  Hepatocellular carcinoma
  Mood disorder
  OPTN-related open angle glaucoma
  Systemic sclerosis
  Advanced cancer
  Alcohol dependence
  Anxiety
  Anxiety disorder
  Autism
  Autosomal systemic lupus erythematosus type 16
  Bone osteosarcoma
  Dermatomyositis
  Lung cancer
  Lung neoplasm
  Lysosomal storage disease
  Melanoma
  Mental disorder
  Mixed anxiety and depressive disorder
  Myositis disease
  Obsessive compulsive disorder
  Osteoporosis
  Osteosarcoma
  Pathologic nystagmus
  Polymyositis
  Psychotic disorder
  Rheumatoid arthritis
  Schizophrenia
  Scleroderma
  Substance abuse
  T-cell acute lymphoblastic leukaemia
  Ankylosing spondylitis
  Autoimmune disease
  Clear cell renal carcinoma
  Hypocomplementemic urticarial vasculitis
  Asthma
  Lupus nephritis
  Lymphoma
  Neoplasm
  Post-traumatic stress disorder
  Systemic lupus erythematosus
• UniProt ID: DNSL3_HUMAN
• PDB ID: 7KIU
• EC Number: 3.1.21.-
• Pfam ID: PF03372
• Sequence:
  MSRELAPLLLLLLSIHSALAMRICSFNVRSFGESKQEDKNAMDVIVKVIKRCDIILVMEI
  KDSNNRICPILMEKLNRNSRRGITYNYVISSRLGRNTYKEQYAFLYKEKLVSVKRSYHYH
  DYQDGDADVFSREPFVVWFQSPHTAVKDFVIIPLHTTPETSVKEIDELVEVYTDVKHRWK
  AENFIFMGDFNAGCSYVPKKAWKNIRLRTDPRFVWLIGDQEDTTVKKSTNCAYDRIVLRG
  QEIVSSVVPKSNSVFDFQKAYKLTEEEALDVSDHFPVEFKLQSSRAFTNSKKSVTLRKKT
  KSKRS
• Function: Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends. Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA. Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells. Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity. Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation. Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation.
• Tissue Specificity: Liver and spleen.

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Mood disorder	DISLVMWO	Definitive	Biomarker	[2]
OPTN-related open angle glaucoma	DISDR98A	Definitive	Genetic Variation	[3]
Systemic sclerosis	DISF44L6	Definitive	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[6]
Anxiety	DISIJDBA	Strong	Biomarker	[7]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[7]
Autism	DISV4V1Z	Strong	Biomarker	[8]
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Strong	Autosomal recessive	[9]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[10]
Dermatomyositis	DIS50C5O	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Therapeutic	[12]
Lung neoplasm	DISVARNB	Strong	Therapeutic	[12]
Lysosomal storage disease	DIS6QM6U	Strong	Biomarker	[13]
Melanoma	DIS1RRCY	Strong	Biomarker	[14]
Mental disorder	DIS3J5R8	Strong	Biomarker	[15]
Mixed anxiety and depressive disorder	DISV809X	Strong	Biomarker	[16]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[4]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Altered Expression	[17]
Osteoporosis	DISF2JE0	Strong	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[10]
Pathologic nystagmus	DIS1QSPO	Strong	Biomarker	[19]
Polymyositis	DIS5DHFP	Strong	Altered Expression	[11]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[20]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[21]
Scleroderma	DISVQ342	Strong	Genetic Variation	[22]
Substance abuse	DIS327VW	Strong	Biomarker	[23]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[24]
Ankylosing spondylitis	DISRC6IR	moderate	Altered Expression	[25]
Autoimmune disease	DISORMTM	moderate	Biomarker	[25]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[26]
Hypocomplementemic urticarial vasculitis	DISM1RRV	Supportive	Autosomal recessive	[27]
Asthma	DISW9QNS	Limited	Biomarker	[28]
Lupus nephritis	DISCVGPZ	Limited	Altered Expression	[29]
Lymphoma	DISN6V4S	Limited	Biomarker	[30]
Neoplasm	DISZKGEW	Limited	Biomarker	[31]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[32]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[29]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Deoxyribonuclease gamma (DNASE1L3) increases the response to substance of Acetaminophen.	[43]

2 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 Deoxyribonuclease gamma (DNASE1L3).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Deoxyribonuclease gamma (DNASE1L3).	[42]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[35]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[36]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[37]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Deoxyribonuclease gamma (DNASE1L3).	[38]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[39]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Deoxyribonuclease gamma (DNASE1L3).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Deoxyribonuclease gamma (DNASE1L3).	[37]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Psychedelic-assisted therapies: The past, and the need to move forward responsibly.Int J Drug Policy. 2019 Aug;70:94-98. doi: 10.1016/j.drugpo.2019.05.019. Epub 2019 May 25.
• [3] Association between Platelet Parameters and Glaucoma Severity in Primary Open-Angle Glaucoma.J Ophthalmol. 2019 May 9;2019:3425023. doi: 10.1155/2019/3425023. eCollection 2019.
• [4] Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases.Ann Rheum Dis. 2019 Mar;78(3):311-319. doi: 10.1136/annrheumdis-2018-214127. Epub 2018 Dec 20.
• [5] Oncogenic effects of germline variants in lysosomal storage disease genes.Genet Med. 2019 Dec;21(12):2695-2705. doi: 10.1038/s41436-019-0588-9. Epub 2019 Jul 25.
• [6] The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.Neuropsychopharmacology. 2017 Oct;42(11):2105-2113. doi: 10.1038/npp.2017.84. Epub 2017 Apr 26.
• [7] Psychedelics and Dying Care: A Historical Look at the Relationship between Psychedelics and Palliative Care.J Psychoactive Drugs. 2019 Apr-Jun;51(2):102-107. doi: 10.1080/02791072.2019.1581308. Epub 2019 Mar 1.
• [8] Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism.Neuropsychopharmacology. 2008 Jan;33(2):353-60. doi: 10.1038/sj.npp.1301406. Epub 2007 Apr 4.
• [9] Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet. 2011 Oct 23;43(12):1186-8. doi: 10.1038/ng.975.
• [10] The Poly(ADP-ribose) polymerase-1-regulated endonuclease DNAS1L3 is required for etoposide-induced internucleosomal DNA fragmentation and increases etoposide cytotoxicity in transfected osteosarcoma cells.Cancer Res. 2002 Aug 1;62(15):4439-44.
• [11] Serum level of DNase1l3 in patients with dermatomyositis/polymyositis, systemic lupus erythematosus and rheumatoid arthritis, and its association with disease activity.Clin Exp Med. 2017 Nov;17(4):459-465. doi: 10.1007/s10238-016-0448-8. Epub 2016 Dec 30.
• [12] Cladribine enhances apoptotic cell death in lung carcinoma cells over-expressing DNase .Biol Pharm Bull. 2011;34(7):1001-4. doi: 10.1248/bpb.34.1001.
• [13] Cross-regulation of defective endolysosome trafficking and enhanced autophagy through TFEB in UNC13D deficiency.Autophagy. 2019 Oct;15(10):1738-1756. doi: 10.1080/15548627.2019.1596475. Epub 2019 Apr 5.
• [14] Antiproliferative activity of vanadium compounds: effects on the major malignant melanoma molecular pathways.Metallomics. 2019 Oct 16;11(10):1687-1699. doi: 10.1039/c9mt00174c.
• [15] The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant.Psychopharmacology (Berl). 2018 Feb;235(2):551-560. doi: 10.1007/s00213-017-4713-7. Epub 2017 Aug 23.
• [16] Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress.Int Rev Psychiatry. 2018 Aug;30(4):317-330. doi: 10.1080/09540261.2018.1482261. Epub 2018 Aug 13.
• [17] DNA hypermethylation of serotonin transporter gene promoter in drug nave patients with schizophrenia.Schizophr Res. 2014 Feb;152(2-3):373-80. doi: 10.1016/j.schres.2013.12.007. Epub 2014 Jan 8.
• [18] Improvement in viability and mineralization of osteoporotic bone marrow mesenchymal stem cell through combined application of photobiomodulation therapy and oxytocin.Lasers Med Sci. 2020 Apr;35(3):557-566. doi: 10.1007/s10103-019-02848-8. Epub 2019 Aug 9.
• [19] Lysosomal storage disease in the brain: mutations of the -mannosidase gene identified in autosomal dominant nystagmus.Genet Med. 2015 Dec;17(12):971-9. doi: 10.1038/gim.2015.10. Epub 2015 Mar 5.
• [20] Beyond LSD: A Broader Psychedelic Zeitgeist during the Early to Mid-20(th) Century.J Psychoactive Drugs. 2019 Jul-Aug;51(3):210-217. doi: 10.1080/02791072.2019.1581961. Epub 2019 Mar 6.
• [21] Drug Abuse and Psychosis: New Insights into Drug-induced Psychosis.Exp Neurobiol. 2017 Feb;26(1):11-24. doi: 10.5607/en.2017.26.1.11. Epub 2017 Feb 7.
• [22] An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3.Arthritis Res Ther. 2014 Oct 21;16(5):438. doi: 10.1186/s13075-014-0438-8.
• [23] LSD psychosis or LSD-induced schizophrenia? A multimethod inquiry.Arch Gen Psychiatry. 1983 Aug;40(8):877-83. doi: 10.1001/archpsyc.1983.01790070067008.
• [24] Eradication of Central Nervous System Leukemia of T-Cell Origin with a Brain-Permeable LSD1 Inhibitor.Clin Cancer Res. 2019 Mar 1;25(5):1601-1611. doi: 10.1158/1078-0432.CCR-18-0919. Epub 2018 Dec 5.
• [25] Serum Deoxyribonuclease 1-like 3 is a potential biomarker for diagnosis of ankylosing spondylitis.Clin Chim Acta. 2020 Apr;503:197-202. doi: 10.1016/j.cca.2019.11.028. Epub 2019 Nov 30.
• [26] Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer.Sci Rep. 2017 Mar 28;7:44997. doi: 10.1038/srep44997.
• [27] DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. Arthritis Rheum. 2013 Aug;65(8):2183-9. doi: 10.1002/art.38010.
• [28] A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma.J Allergy Clin Immunol. 2019 Jul;144(1):51-60.e11. doi: 10.1016/j.jaci.2018.12.1020. Epub 2019 Jan 22.
• [29] Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis.J Rheumatol. 2020 Mar;47(3):377-386. doi: 10.3899/jrheum.181232. Epub 2019 May 15.
• [30] Correlation between decreased sensitivity of the Daudi lymphoma cells to VP-16-induced apoptosis and deficiency in DNAS1L3 expression.Biochem Biophys Res Commun. 2006 Mar 10;341(2):653-62. doi: 10.1016/j.bbrc.2006.01.014. Epub 2006 Jan 17.
• [31] LSD and genetic damage.Science. 1971 Apr 30;172(3982):431-40. doi: 10.1126/science.172.3982.431.
• [32] Re-traumatization Cycle: Sexual Abuse, Post-Traumatic Stress Disorder and Sexual Risk Behaviors among Club Drug Users.Subst Use Misuse. 2019;54(9):1499-1508. doi: 10.1080/10826084.2019.1589521. Epub 2019 Apr 25.
• [33] 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.
• [34] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [36] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [37] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [38] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [39] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [40] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [41] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [42] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [43] Mechanism of acetaminophen-induced apoptosis in cultured cells: roles of caspase-3, DNA fragmentation factor, and the Ca2+ and Mg2+ endonuclease DNAS1L3. Basic Clin Pharmacol Toxicol. 2004 Jan;94(1):19-29.