Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SRRLM)

• DOT Name: Integrator complex subunit 8 (INTS8)
• Synonyms: Int8; Protein kaonashi-1
• Gene Name: INTS8
• Related Disease:
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Periventricular nodular heterotopia
  Thrombocytopenia 1
  Wiskott-Aldrich syndrome
  Neurodevelopmental disorder with cerebellar hypoplasia and spasticity
• UniProt ID: INT8_HUMAN
• PDB ID: 7CUN; 7PKS; 7YCX
• Sequence:
  MSAEAADREAATSSRPCTPPQTCWFEFLLEESLLEKHLRKPCPDPAPVQLIVQFLEQASK
  PSVNEQNQVQPPPDNKRNRILKLLALKVAAHLKWDLDILEKSLSVPVLNMLLNELLCISK
  VPPGTKHVDMDLATLPPTTAMAVLLYNRWAIRTIVQSSFPVKQAKPGPPQLSVMNQMQQE
  KELTENILKVLKEQAADSILVLEAALKLNKDLYVHTMRTLDLLAMEPGMVNGETESSTAG
  LKVKTEEMQCQVCYDLGAAYFQQGSTNSAVYENAREKFFRTKELIAEIGSLSLHCTIDEK
  RLAGYCQACDVLVPSSDSTSQQLTPYSQVHICLRSGNYQEVIQIFIEDNLTLSLPVQFRQ
  SVLRELFKKAQQGNEALDEICFKVCACNTVRDILEGRTISVQFNQLFLRPNKEKIDFLLE
  VCSRSVNLEKASESLKGNMAAFLKNVCLGLEDLQYVFMISSHELFITLLKDEERKLLVDQ
  MRKRSPRVNLCIKPVTSFYDIPASASVNIGQLEHQLILSVDPWRIRQILIELHGMTSERQ
  FWTVSNKWEVPSVYSGVILGIKDNLTRDLVYILMAKGLHCSTVKDFSHAKQLFAACLELV
  TEFSPKLRQVMLNEMLLLDIHTHEAGTGQAGERPPSDLISRVRGYLEMRLPDIPLRQVIA
  EECVAFMLNWRENEYLTLQVPAFLLQSNPYVKLGQLLAATCKELPGPKESRRTAKDLWEV
  VVQICSVSSQHKRGNDGRVSLIKQRESTLGIMYRSELLSFIKKLREPLVLTIILSLFVKL
  HNVREDIVNDITAEHISIWPSSIPNLQSVDFEAVAITVKELVRYTLSINPNNHSWLIIQA
  DIYFATNQYSAALHYYLQAGAVCSDFFNKAVPPDVYTDQVIKRMIKCCSLLNCHTQVAIL
  CQFLREIDYKTAFKSLQEQNSHDAMDSYYDYIWDVTILEYLTYLHHKRGETDKRQIAIKA
  IGQTELNASNPEEVLQLAAQRRKKKFLQAMAKLYF
• Function: Component of the Integrator complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Biomarker	[3]
Thrombocytopenia 1	DISTC3AW	Strong	Genetic Variation	[4]
Wiskott-Aldrich syndrome	DISATMDB	Strong	Genetic Variation	[4]
Neurodevelopmental disorder with cerebellar hypoplasia and spasticity	DISDHD0H	Limited	Autosomal recessive	[3]

5 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 Integrator complex subunit 8 (INTS8).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrator complex subunit 8 (INTS8).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Integrator complex subunit 8 (INTS8).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrator complex subunit 8 (INTS8).	[9]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Integrator complex subunit 8 (INTS8).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Integrator complex subunit 8 (INTS8).	[8]

References

• [1] INTS8 accelerates the epithelial-to-mesenchymal transition in hepatocellular carcinoma by upregulating the TGF- signaling pathway.Cancer Manag Res. 2019 Feb 26;11:1869-1879. doi: 10.2147/CMAR.S184392. eCollection 2019.
• [2] Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.PLoS Genet. 2014 Aug 7;10(8):e1004517. doi: 10.1371/journal.pgen.1004517. eCollection 2014 Aug.
• [3] Human mutations in integrator complex subunits link transcriptome integrity to brain development. PLoS Genet. 2017 May 25;13(5):e1006809. doi: 10.1371/journal.pgen.1006809. eCollection 2017 May.
• [4] Clinical aspects and genetic analysis of taiwanese patients with wiskott-Aldrich syndrome protein mutation: the first identification of x-linked thrombocytopenia in the chinese with novel mutations.J Clin Immunol. 2010 Jul;30(4):593-601. doi: 10.1007/s10875-010-9381-x. Epub 2010 Mar 16.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] 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.
• [10] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.