Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7NX4CD)

• DOT Name: Integrator complex subunit 3 (INTS3)
• Synonyms: Int3; SOSS complex subunit A; Sensor of single-strand DNA complex subunit A; SOSS-A; Sensor of ssDNA subunit A
• Gene Name: INTS3
• Related Disease:
  Fibrodysplasia ossificans progressiva
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Neoplasm
  Primary myelofibrosis
  Prostate neoplasm
  Prediabetes syndrome
• UniProt ID: INT3_HUMAN
• PDB ID: 4OWT; 4OWW; 4OWX; 6WLG; 7BV7
• Pfam ID: PF10189
• Sequence:
  MELQKGKGAAAAAAASGAAGGGGGGAGAGAPGGGRLLLSTSLDAKDELEERLERCMSIVT
  SMTAGVSEREANDALNAYVCKGLPQHEEICLGLFTLILTEPAQAQKCYRDLALVSRDGMN
  IVLNKINQILMEKYLKLQDTCRTQLVWLVRELVKSGVLGADGVCMTFMKQIAGGGDVTAK
  NIWLAESVLDILTEQREWVLKSSILIAMAVYTYLRLIVDHHGTAQLQALRQKEVDFCISL
  LRERFMECLMIGRDLVRLLQNVARIPEFELLWKDIIHNPQALSPQFTGILQLLQSRTSRK
  FLACRLTPDMETKLLFMTSRVRFGQQKRYQDWFQRQYLSTPDSQSLRCDLIRYICGVVHP
  SNEVLSSDILPRWAIIGWLLTTCTSNVAASNAKLALFYDWLFFSPDKDSIMNIEPAILVM
  HHSMKPHPAITATLLDFMCRIIPNFYPPLEGHVRQGVFSSLNHIVEKRVLAHLAPLFDNP
  KLDKELRAMLREKFPEFCSSPSPPVEVKIEEPVSMEMDNHMSDKDESCYDNAEAAFSDDE
  EDLNSKGKKREFRFHPIKETVVEEPVDITPYLDQLDESLRDKVLQLQKGSDTEAQCEVMQ
  EIVDQVLEEDFDSEQLSVLASCLQELFKAHFRGEVLPEEITEESLEESVGKPLYLIFRNL
  CQMQEDNSSFSLLLDLLSELYQKQPKIGYHLLYYLRASKAAAGKMNLYESFAQATQLGDL
  HTCLMMDMKACQEDDVRLLCHLTPSIYTEFPDETLRSGELLNMIVAVIDSAQLQELVCHV
  MMGNLVMFRKDSVLNILIQSLDWETFEQYCAWQLFLAHNIPLETIIPILQHLKYKEHPEA
  LSCLLLQLRREKPSEEMVKMVLSRPCHPDDQFTTSILRHWCMKHDELLAEHIKSLLIKNN
  SLPRKRQSLRSSSSKLAQLTLEQILEHLDNLRLNLTNTKQNFFSQTPILQALQHVQASCD
  EAHKMKFSDLFSLAEEYEDSSTKPPKSRRKAALSSPRSRKNATQPPNAEEESGSSSASEE
  EDTKPKPTKRKRKGSSAVGSDSD
• Function: Component of the Integrator (INT) complex. The Integrator complex is 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 (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex ; Component of the SOSS complex, a multiprotein complex that functions downstream of the MRN complex to promote DNA repair and G2/M checkpoint. The SOSS complex associates with single-stranded DNA at DNA lesions and influences diverse endpoints in the cellular DNA damage response including cell-cycle checkpoint activation, recombinational repair and maintenance of genomic stability. The SOSS complex is required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ATM-dependent signaling pathways. In the SOSS complex, it is required for the assembly of the complex and for stabilization of the complex at DNA damage sites.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fibrodysplasia ossificans progressiva	DISAT6WU	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
leukaemia	DISS7D1V	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Primary myelofibrosis	DIS6L0CN	Strong	Genetic Variation	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Prediabetes syndrome	DISH2I53	Limited	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Integrator complex subunit 3 (INTS3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Integrator complex subunit 3 (INTS3).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Integrator complex subunit 3 (INTS3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Integrator complex subunit 3 (INTS3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Integrator complex subunit 3 (INTS3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrator complex subunit 3 (INTS3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrator complex subunit 3 (INTS3).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Integrator complex subunit 3 (INTS3).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Integrator complex subunit 3 (INTS3).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Integrator complex subunit 3 (INTS3).	[15]

References

• [1] Identification of submicroscopic genetic changes and precise breakpoint mapping in myelofibrosis using high resolution mate-pair sequencing.Am J Hematol. 2013 Sep;88(9):741-6. doi: 10.1002/ajh.23495. Epub 2013 Aug 1.
• [2] CREB3L4, INTS3, and SNAPAP are targets for the 1q21 amplicon frequently detected in hepatocellular carcinoma.Cancer Genet Cytogenet. 2008 Jan 1;180(1):30-6. doi: 10.1016/j.cancergencyto.2007.09.013.
• [3] Identification of a gene element essential for leukemia-specific expression of transgenes.Leukemia. 2004 Mar;18(3):415-9. doi: 10.1038/sj.leu.2403260.
• [4] The ANK repeats of Notch-4/Int3 activate NF-B canonical pathway in the absence of Rbpj and causes mammary tumorigenesis.Sci Rep. 2017 Oct 20;7(1):13690. doi: 10.1038/s41598-017-13989-7.
• [5] Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response.J Cell Sci. 2015 Feb 15;128(4):728-40. doi: 10.1242/jcs.160051. Epub 2015 Jan 20.
• [6] Impact of short-term exercise training intensity on -cell function in older obese adults with prediabetes.J Appl Physiol (1985). 2018 Dec 1;125(6):1979-1986. doi: 10.1152/japplphysiol.00680.2018. Epub 2018 Oct 11.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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.