Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO8ZEY5)

• DOT Name: Zinc finger CCHC domain-containing protein 8
• Synonyms: TRAMP-like complex RNA-binding factor ZCCHC8
• Gene Name: ZCCHC8
• Related Disease:
  Intellectual disability
  Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5
• UniProt ID: ZCHC8_HUMAN
• PDB ID: 5LXR; 5LXY; 6C90; 7S7B; 7S7C; 7Z4Y; 7Z4Z; 7Z52
• Pfam ID: PF04046 ; PF00098
• Sequence:
  MAAEVYFGDLELFEPFDHPEESIPKPVHTRFKDDDGDEEDENGVGDAELRERLRQCEETI
  EQLRAENQELKRKLNILTRPSGILVNDTKLDGPILQILFMNNAISKQYHQEIEEFVSNLV
  KRFEEQQKNDVEKTSFNLLPQPSSIVLEEDHKVEESCAIKNNKEAFSVVGSVLYFTNFCL
  DKLGQPLLNENPQLSEGWEIPKYHQVFSHIVSLEGQEIQVKAKRPKPHCFNCGSEEHQMK
  DCPMPRNAARISEKRKEYMDACGEANNQNFQQRYHAEEVEERFGRFKPGVISEELQDALG
  VTDKSLPPFIYRMRQLGYPPGWLKEAELENSGLALYDGKDGTDGETEVGEIQQNKSVTYD
  LSKLVNYPGFNISTPRGIPDEWRIFGSIPMQACQQKDVFANYLTSNFQAPGVKSGNKRSS
  SHSSPGSPKKQKNESNSAGSPADMELDSDMEVPHGSQSSESFQFQPPLPPDTPPLPRGTP
  PPVFTPPLPKGTPPLTPSDSPQTRTASGAVDEDALTLEELEEQQRRIWAALEQAESVNSD
  SDVPVDTPLTGNSVASSPCPNELDLPVPEGKTSEKQTLDEPEVPEIFTKKSEAGHASSPD
  SEVTSLCQKEKAELAPVNTEGALLDNGSVVPNCDISNGGSQKLFPADTSPSTATKIHSPI
  PDMSKFATGITPFEFENMAESTGMYLRIRSLLKNSPRNQQKNKKASE
• Function: Scaffolding subunit of the trimeric nuclear exosome targeting (NEXT) complex that is involved in the surveillance and turnover of aberrant transcripts and non-coding RNAs. NEXT functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation. May be involved in pre-mRNA splicing (Probable). It is required for 3'-end maturation of telomerase RNA component (TERC), TERC 3'-end targeting to the nuclear RNA exosome, and for telomerase function.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[1]
Pulmonary fibrosis and/or bone marrow failure, telomere-related, 5	DISL2FBU	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Zinc finger CCHC domain-containing protein 8.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Zinc finger CCHC domain-containing protein 8.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Zinc finger CCHC domain-containing protein 8.	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Zinc finger CCHC domain-containing protein 8.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Zinc finger CCHC domain-containing protein 8.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Zinc finger CCHC domain-containing protein 8.	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Zinc finger CCHC domain-containing protein 8.	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Zinc finger CCHC domain-containing protein 8.	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Zinc finger CCHC domain-containing protein 8.	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Zinc finger CCHC domain-containing protein 8.	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Zinc finger CCHC domain-containing protein 8.	[16]

4 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 affects the methylation of Zinc finger CCHC domain-containing protein 8.	[12]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Zinc finger CCHC domain-containing protein 8.	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Zinc finger CCHC domain-containing protein 8.	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Zinc finger CCHC domain-containing protein 8.	[15]

References

• [1] 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.
• [2] ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 2019 Oct 1;33(19-20):1381-1396. doi: 10.1101/gad.326785.119. Epub 2019 Sep 5.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] 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.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] 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.