Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTB3AVE)

• DOT Name: Superkiller complex protein 3 (SKIC3)
• Synonyms: Ski3; Tetratricopeptide repeat protein 37; TPR repeat protein 37; Tricho-hepatic-enteric syndrome protein; Thespin
• Gene Name: SKIC3
• Related Disease:
  Trichohepatoenteric syndrome 1
  Trichohepatoenteric syndrome
• UniProt ID: SKI3_HUMAN
• PDB ID: 7QDR; 7QDS; 7QDY; 7QDZ
• Pfam ID: PF13432 ; PF14559 ; PF13181
• Sequence:
  MSSKEVKTALKSARDAIRNKEYKEALKHCKTVLKQEKNNYNAWVFIGVAAAELEQPDQAQ
  SAYKKAAELEPDQLLAWQGLANLYEKYNHINAKDDLPGVYQKLLDLYESVDKQKWCDVCK
  KLVDLYYQEKKHLEVARTWHKLIKTRQEQGAENEELHQLWRKLTQFLAESTEDQNNETQQ
  LLFTAFENALGLSDKIPSEDHQVLYRHFIQSLSKFPHESARLKKACEGMINIYPTVQYPL
  EVLCLHLIESGNLTDEGQQYCCRLVEMDSKSGPGLIGLGIKALQDKKYEDAVRNLTEGLK
  ESPVCTSGWYHLAEAQVKMHRPKEAVLSCSQALKIVDNLGASGNSLYQRNLCLHLKAEAL
  IKLSDYDSSEEAIRTLDQISDADNIPGLLVLKSLAYRNKGSFDEAAKIMEDLLSSYPDLA
  EVHALEALIHFTKKDYLQAEKCFQRALEKDTEVAEYHYQLGLTYWFMGEETRKDKTKALT
  HFLKAARLDTYMGKVFCYLGHYYRDVVGDKNRARGCYRKAFELDDTDAESGAAAVDLSVE
  LEDMEMALAILTTVTQKASAGTAKWAWLRRGLYYLKAGQHSQAVADLQAALRADPKDFNC
  WESLGEAYLSRGGYTTALKSFTKASELNPESIYSVFKVAAIQQILGKYKEAVAQYQMIIK
  KKEDYVPALKGLGECHLMMAKAALVDYLDGKAVDYIEKALEYFTCALQHRADVSCLWKLA
  GDACTCLYAVAPSKVNVHVLGVLLGQKEGKQVLKKNELLHLGGRCYGRALKLMSTSNTWC
  DLGINYYRQAQHLAETGSNMNDLKELLEKSLHCLKKAVRLDSNNHLYWNALGVVACYSGI
  GNYALAQHCFIKSIQSEQINAVAWTNLGVLYLTNENIEQAHEAFKMAQSLDPSYLMCWIG
  QALIAEAVGSYDTMDLFRHTTELNMHTEGALGYAYWVCTTLQDKSNRETELYQYNILQMN
  AIPAAQVILNKYVERIQNYAPAFTMLGYLNEHLQLKKEAANAYQRAILLLQTAEDQDTYN
  VAIRNYGRLLCSTGEYDKAIQAFKSTPLEVLEDIIGFALALFMKGLYKESSKAYERALSI
  VESEQDKAHILTALAITEYKQGKTDVAKTLLFKCSILKEPTTESLQALCALGLAMQDATL
  SKAALNELLKHIKHKDSNYQRCLLTSAIYALQGRSVAVQKQISKAVHSNPGDPALWSLLS
  RVVAQYAQRNAKGGVVAGNVAHILDSNHGKKALLYTAVNQLAMGSSSAEDEKNTALKTIQ
  KAALLSPGDPAIWAGLMAACHADDKLALVNNTQPKRIDLYLALLSAVSASIKDEKFFENY
  NQSLEKWSLSQAVTGLIDTGRISEAETLCTKNLKSNPDQPAVILLLRQVQCKPLLESQKP
  LPDAVLEELQKTVMSNSTSVPAWQWLAHVYQSQGMMRAAEMCYRKSLQLASQRGSWSGKL
  SSLLRLALLALKVCMANISNDHWPSLVQEATTEALKLCFCPLAVLLQALLQFKRKMGARE
  TRRLLERVVYQPGYPKSIASTARWYLLRHLYAKDDYELIDVLVNNAKTHGDTRALELNQR
  LSSQ
• Function: Component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways. The SKI complex catalyzes mRNA extraction from 80S ribosomal complexes in the 3'-5' direction and channels mRNA to the cytosolic exosome for degradation. SKI-mediated extraction of mRNA from stalled ribosomes allow binding of the Pelota-HBS1L complex and subsequent ribosome disassembly by ABCE1 for ribosome recycling. In the nucleus, the SKI complex associates with transcriptionally active genes in a manner dependent on PAF1 complex (PAF1C).
• Tissue Specificity: Widely expressed with the highest levels observed in vascular tissues, lymph node, pituitary, lung and intestine. Not expressed in the liver.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway: mRNA decay by 3' to 5' exoribonuclease (R-HSA-429958)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Trichohepatoenteric syndrome 1	DIS0S0ON	Definitive	Autosomal recessive	[1]
Trichohepatoenteric syndrome	DISL3ODF	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Superkiller complex protein 3 (SKIC3).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Selenium	DM25CGV	Approved	Selenium decreases the expression of Superkiller complex protein 3 (SKIC3).	[4]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Superkiller complex protein 3 (SKIC3).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Superkiller complex protein 3 (SKIC3).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Superkiller complex protein 3 (SKIC3).	[6]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Superkiller complex protein 3 (SKIC3).	[7]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Superkiller complex protein 3 (SKIC3).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Superkiller complex protein 3 (SKIC3).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Superkiller complex protein 3 (SKIC3).	[10]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Superkiller complex protein 3 (SKIC3).	[11]

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] Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis. 2013 Jan 9;8:5. doi: 10.1186/1750-1172-8-5.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] 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.
• [5] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [6] 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.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.