Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWABM04)

• DOT Name: DIS3-like exonuclease 2 (DIS3L2)
• Synonyms: hDIS3L2; EC 3.1.13.-
• Gene Name: DIS3L2
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Liver cancer
  Perlman syndrome
  Advanced cancer
  Childhood kidney Wilms tumor
  Chromosomal disorder
  Colorectal carcinoma
  Neoplasm
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Wilms tumor
• UniProt ID: DI3L2_HUMAN
• PDB ID: 8E27; 8E28; 8E29; 8E2A
• EC Number: 3.1.13.-
• Pfam ID: PF17877 ; PF17849 ; PF00773 ; PF17216
• Sequence:
  MSHPDYRMNLRPLGTPRGVSAVAGPHDIGASPGDKKSKNRSTRGKKKSIFETYMSKEDVS
  EGLKRGTLIQGVLRINPKKFHEAFIPSPDGDRDIFIDGVVARNRALNGDLVVVKLLPEEH
  WKVVKPESNDKETEAAYESDIPEELCGHHLPQQSLKSYNDSPDVIVEAQFDGSDSEDGHG
  ITQNVLVDGVKKLSVCVSEKGREDGDAPVTKDETTCISQDTRALSEKSLQRSAKVVYILE
  KKHSRAATGFLKLLADKNSELFRKYALFSPSDHRVPRIYVPLKDCPQDFVARPKDYANTL
  FICRIVDWKEDCNFALGQLAKSLGQAGEIEPETEGILTEYGVDFSDFSSEVLECLPQGLP
  WTIPPEEFSKRRDLRKDCIFTIDPSTARDLDDALSCKPLADGNFKVGVHIADVSYFVPEG
  SDLDKVAAERATSVYLVQKVVPMLPRLLCEELCSLNPMSDKLTFSVIWTLTPEGKILDEW
  FGRTIIRSCTKLSYEHAQSMIESPTEKIPAKELPPISPEHSSEEVHQAVLNLHGIAKQLR
  QQRFVDGALRLDQLKLAFTLDHETGLPQGCHIYEYRESNKLVEEFMLLANMAVAHKIHRA
  FPEQALLRRHPPPQTRMLSDLVEFCDQMGLPVDFSSAGALNKSLTQTFGDDKYSLARKEV
  LTNMCSRPMQMALYFCSGLLQDPAQFRHYALNVPLYTHFTSPIRRFADVLVHRLLAAALG
  YRERLDMAPDTLQKQADHCNDRRMASKRVQELSTSLFFAVLVKESGPLESEAMVMGILKQ
  AFDVLVLRYGVQKRIYCNALALRSHHFQKVGKKPELTLVWEPEDMEQEPAQQVITIFSLV
  EVVLQAESTALKYSAILKRPGTQGHLGPEKEEEESDGEPEDSSTS
• Function: 3'-5'-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3' end and mediates their degradation. Component of an exosome-independent RNA degradation pathway that mediates degradation of both mRNAs and miRNAs that have been polyuridylated by a terminal uridylyltransferase, such as ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have been deadenylated and subsequently uridylated at their 3'. Mediates degradation of uridylated pre-let-7 miRNAs, contributing to the maintenance of embryonic stem (ES) cells. Essential for correct mitosis, and negatively regulates cell proliferation.
• Reactome Pathway: Z-decay (R-HSA-9820865)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Liver cancer	DISDE4BI	Definitive	Biomarker	[1]
Perlman syndrome	DISN3KMO	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Genetic Variation	[7]
Wilms tumor	DISB6T16	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of DIS3-like exonuclease 2 (DIS3L2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of DIS3-like exonuclease 2 (DIS3L2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DIS3-like exonuclease 2 (DIS3L2).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of DIS3-like exonuclease 2 (DIS3L2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DIS3-like exonuclease 2 (DIS3L2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DIS3-like exonuclease 2 (DIS3L2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DIS3-like exonuclease 2 (DIS3L2).	[16]

References

• [1] DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing.Cancer Res. 2019 Oct 1;79(19):4923-4936. doi: 10.1158/0008-5472.CAN-19-0376. Epub 2019 Jul 22.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Regulation of RNA decay and cellular function by 3'-5' exoribonuclease DIS3L2.RNA Biol. 2019 Feb;16(2):160-165. doi: 10.1080/15476286.2018.1564466. Epub 2019 Jan 13.
• [4] Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells.Genes Dev. 2018 Jul 1;32(13-14):903-908. doi: 10.1101/gad.315804.118. Epub 2018 Jun 27.
• [5] Genetic and epigenetic analyses guided by high resolution whole-genome SNP array reveals a possible role of CHEK2 in Wilms tumour susceptibility.Oncotarget. 2018 Sep 25;9(75):34079-34089. doi: 10.18632/oncotarget.26123. eCollection 2018 Sep 25.
• [6] Knockdown of a DIS3L2 promoter upstream long noncoding RNA (AC105461.1) enhances colorectal cancer stem cell properties in vitro by down-regulating DIS3L2.Onco Targets Ther. 2017 May 2;10:2367-2376. doi: 10.2147/OTT.S132708. eCollection 2017.
• [7] Establishment and characterization of a new patient-derived anaplastic thyroid cancer cell line (C3948), obtained through fine-needle aspiration cytology.Endocrine. 2019 Nov;66(2):288-300. doi: 10.1007/s12020-019-02009-5. Epub 2019 Jul 31.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] 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.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] 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.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] 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.
• [17] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.