Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT48SKET)

• DOT Name: DNA ligase 3 (LIG3)
• Synonyms: EC 6.5.1.1; DNA ligase III; Polydeoxyribonucleotide synthase 3
• Gene Name: LIG3
• Related Disease:
  Neural tube defect
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Ataxia-telangiectasia
  Bladder cancer
  Cerebellar ataxia
  Childhood acute lymphoblastic leukemia
  Colorectal carcinoma
  Depression
  Esophageal squamous cell carcinoma
  Essential thrombocythemia
  Fuchs' endothelial dystrophy
  Gastric cancer
  Keratoconus
  Mitochondrial DNA depletion syndrome 20 (mngie type)
  Myelofibrosis
  Pancreatic cancer
  Polycythemia vera
  Primary myelofibrosis
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Leukemia
  Plasma cell myeloma
  Breast cancer
  Breast carcinoma
  Colorectal adenoma
  Neuroblastoma
• UniProt ID: DNLI3_HUMAN
• PDB ID: 1IMO; 1IN1; 1UW0; 3L2P; 3PC7; 3PC8; 3QVG; 6WH1
• EC Number: 6.5.1.1
• Pfam ID: PF04679 ; PF01068 ; PF04675 ; PF16759 ; PF00645
• Sequence:
  MSLAFKIFFPQTLRALSRKELCLFRKHHWRDVRQFSQWSETDLLHGHPLFLRRKPVLSFQ
  GSHLRSRATYLVFLPGLHVGLCSGPCEMAEQRFCVDYAKRGTAGCKKCKEKIVKGVCRIG
  KVVPNPFSESGGDMKEWYHIKCMFEKLERARATTKKIEDLTELEGWEELEDNEKEQITQH
  IADLSSKAAGTPKKKAVVQAKLTTTGQVTSPVKGASFVTSTNPRKFSGFSAKPNNSGEAP
  SSPTPKRSLSSSKCDPRHKDCLLREFRKLCAMVADNPSYNTKTQIIQDFLRKGSAGDGFH
  GDVYLTVKLLLPGVIKTVYNLNDKQIVKLFSRIFNCNPDDMARDLEQGDVSETIRVFFEQ
  SKSFPPAAKSLLTIQEVDEFLLRLSKLTKEDEQQQALQDIASRCTANDLKCIIRLIKHDL
  KMNSGAKHVLDALDPNAYEAFKASRNLQDVVERVLHNAQEVEKEPGQRRALSVQASLMTP
  VQPMLAEACKSVEYAMKKCPNGMFSEIKYDGERVQVHKNGDHFSYFSRSLKPVLPHKVAH
  FKDYIPQAFPGGHSMILDSEVLLIDNKTGKPLPFGTLGVHKKAAFQDANVCLFVFDCIYF
  NDVSLMDRPLCERRKFLHDNMVEIPNRIMFSEMKRVTKALDLADMITRVIQEGLEGLVLK
  DVKGTYEPGKRHWLKVKKDYLNEGAMADTADLVVLGAFYGQGSKGGMMSIFLMGCYDPGS
  QKWCTVTKCAGGHDDATLARLQNELDMVKISKDPSKIPSWLKVNKIYYPDFIVPDPKKAA
  VWEITGAEFSKSEAHTADGISIRFPRCTRIRDDKDWKSATNLPQLKELYQLSKEKADFTV
  VAGDEGSSTTGGSSEENKGPSGSAVSRKAPSKPSASTKKAEGKLSNSNSKDGNMQTAKPS
  AMKVGEKLATKSSPVKVGEKRKAADETLCQTKVLLDIFTGVRLYLPPSTPDFSRLRRYFV
  AFDGDLVQEFDMTSATHVLGSRDKNPAAQQVSPEWIWACIRKRRLVAPC
• Function: Isoform 3 functions as a heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents. Isoform 1 is targeted to mitochondria, where it functions as a DNA ligase in mitochondrial base-excision DNA repair.
• Tissue Specificity: Testis, thymus, prostate and heart.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway (R-HSA-5649702)
  HDR through MMEJ (alt-NHEJ) (R-HSA-5685939)
  Gap-filling DNA repair synthesis and ligation in GG-NER (R-HSA-5696397)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Resolution of AP sites via the single-nucleotide replacement pathway (R-HSA-110381)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[6]
Cerebellar ataxia	DIS9IRAV	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Depression	DIS3XJ69	Strong	Genetic Variation	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[10]
Essential thrombocythemia	DISWWK11	Strong	Altered Expression	[11]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Genetic Variation	[12]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[3]
Keratoconus	DISOONXH	Strong	Genetic Variation	[12]
Mitochondrial DNA depletion syndrome 20 (mngie type)	DISIQS66	Strong	Autosomal recessive	[13]
Myelofibrosis	DISIMP21	Strong	Altered Expression	[11]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[14]
Polycythemia vera	DISB5FPO	Strong	Altered Expression	[11]
Primary myelofibrosis	DIS6L0CN	Strong	Altered Expression	[11]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[3]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[6]
Leukemia	DISNAKFL	moderate	Altered Expression	[15]
Plasma cell myeloma	DIS0DFZ0	Disputed	Biomarker	[16]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[17]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[17]
Colorectal adenoma	DISTSVHM	Limited	Biomarker	[18]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA ligase 3 (LIG3).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DNA ligase 3 (LIG3).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DNA ligase 3 (LIG3).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA ligase 3 (LIG3).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA ligase 3 (LIG3).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA ligase 3 (LIG3).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA ligase 3 (LIG3).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA ligase 3 (LIG3).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of DNA ligase 3 (LIG3).	[25]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of DNA ligase 3 (LIG3).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of DNA ligase 3 (LIG3).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DNA ligase 3 (LIG3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA ligase 3 (LIG3).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA ligase 3 (LIG3).	[32]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA ligase 3 (LIG3).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of DNA ligase 3 (LIG3).	[34]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of DNA ligase 3 (LIG3).	[35]

References

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• [12] Polymorphism of the LIG3 gene in keratoconus and Fuchs endothelial corneal dystrophy.Cell Mol Biol (Noisy-le-grand). 2015 Mar 28;61(1):56-63.
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• [14] DNA repair gene polymorphisms and risk of pancreatic cancer.Clin Cancer Res. 2009 Jan 15;15(2):740-6. doi: 10.1158/1078-0432.CCR-08-1607.
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• [16] miR-22 suppresses DNA ligase III addiction in multiple myeloma.Leukemia. 2019 Feb;33(2):487-498. doi: 10.1038/s41375-018-0238-2. Epub 2018 Aug 17.
• [17] Polymorphisms in homologous recombination repair genes and the risk and survival of breast cancer.J Gene Med. 2017 Sep;19(9-10). doi: 10.1002/jgm.2988. Epub 2017 Oct 10.
• [18] Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk.PLoS One. 2013 Aug 12;8(8):e71211. doi: 10.1371/journal.pone.0071211. eCollection 2013.
• [19] Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma.Mol Cancer Res. 2015 Mar;13(3):470-82. doi: 10.1158/1541-7786.MCR-14-0337. Epub 2015 Jan 6.
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• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] 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.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [25] Curcumin prevents DNA damage and enhances the repair potential in a chronically arsenic-exposed human population in West Bengal, India. Eur J Cancer Prev. 2011 Mar;20(2):123-31. doi: 10.1097/cej.0b013e328341017a.
• [26] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [27] 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.
• [28] Genistein-induced changes in gene expression in Panc 1 cells at physiological concentrations of genistein. Pancreas. 2004 Aug;29(2):93-8.
• [29] 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.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [32] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [33] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [34] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [35] APE1 modulates cellular responses to organophosphate pesticide-induced oxidative damage in non-small cell lung carcinoma A549 cells. Mol Cell Biochem. 2018 Apr;441(1-2):201-216.