Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM4KWB3)

• DOT Name: Deoxyribonuclease-1 (DNASE1)
• Synonyms: EC 3.1.21.1; Deoxyribonuclease I; DNase I; Dornase alfa
• Gene Name: DNASE1
• Related Disease:
  Autosomal systemic lupus erythematosus type 16
  Systemic lupus erythematosus
• UniProt ID: DNAS1_HUMAN
• PDB ID: 4AWN
• EC Number: 3.1.21.1
• Pfam ID: PF03372
• Sequence:
  MRGMKLLGALLALAALLQGAVSLKIAAFNIQTFGETKMSNATLVSYIVQILSRYDIALVQ
  EVRDSHLTAVGKLLDNLNQDAPDTYHYVVSEPLGRNSYKERYLFVYRPDQVSAVDSYYYD
  DGCEPCGNDTFNREPAIVRFFSRFTEVREFAIVPLHAAPGDAVAEIDALYDVYLDVQEKW
  GLEDVMLMGDFNAGCSYVRPSQWSSIRLWTSPTFQWLIPDSADTTATPTHCAYDRIVVAG
  MLLRGAVVPDSALPFNFQAAYGLSDQLAQAISDHYPVEVMLK
• Function: Serum endocuclease secreted into body fluids by a wide variety of exocrine and endocrine organs. Expressed by non-hematopoietic tissues and preferentially cleaves protein-free DNA. Among other functions, seems to be involved in cell death by apoptosis. Binds specifically to G-actin and blocks actin polymerization. Together with DNASE1L3, 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: Principally in tissues of the digestive system. Highest levels found in urine, but also relatively abundant in semen and saliva.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal systemic lupus erythematosus type 16	DIS9RKY9	Supportive	Autosomal dominant	[1]
Systemic lupus erythematosus	DISI1SZ7	No Known	Unknown	[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 Deoxyribonuclease-1 (DNASE1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Deoxyribonuclease-1 (DNASE1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Deoxyribonuclease-1 (DNASE1).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Deoxyribonuclease-1 (DNASE1).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Deoxyribonuclease-1 (DNASE1).	[4]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Deoxyribonuclease-1 (DNASE1).	[7]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Deoxyribonuclease-1 (DNASE1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Deoxyribonuclease-1 (DNASE1).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Deoxyribonuclease-1 (DNASE1).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Deoxyribonuclease-1 (DNASE1).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Deoxyribonuclease-1 (DNASE1).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Deoxyribonuclease-1 (DNASE1).	[12]

References

• [1] Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001 Aug;28(4):313-4. doi: 10.1038/91070.
• [2] Dnase1-deficient mice spontaneously develop a systemic lupus erythematosus-like disease. Eur J Immunol. 2019 Apr;49(4):590-599. doi: 10.1002/eji.201847875. Epub 2019 Feb 21.
• [3] 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.
• [4] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [7] 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.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.