Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7TY1M1)

• DOT Name: Integrator complex subunit 1 (INTS1)
• Synonyms: Int1
• Gene Name: INTS1
• Related Disease:
  Intellectual disability
  Breast carcinoma
  Cataract
  Colorectal carcinoma
  Linear skin defects with multiple congenital anomalies 1
  Lung cancer
  Lung carcinoma
  Mycosis fungoides
  Myelodysplastic syndrome
  Myelofibrosis
  Myotonia fluctuans
  Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies
  Primary myelofibrosis
  Renal cell carcinoma
  Advanced cancer
  Chronic obstructive pulmonary disease
  Clear cell renal carcinoma
  Neoplasm
  X-linked sideroblastic anemia 1
  Acute myelogenous leukaemia
  Chromosomal disorder
  Neurodevelopmental disorder
• UniProt ID: INT1_HUMAN
• PDB ID: 7CUN; 7PKS; 7YCX
• Pfam ID: PF12432
• Sequence:
  MNRAKPTTVRRPSAAAKPSGHPPPGDFIALGSKGQANESKTASTLLKPAPSGLPSERKRD
  AAAALSSASALTGLTKRPKLSSTPPLSALGRLAEAAVAEKRAISPSIKEPSVVPIEVLPT
  VLLDEIEAAELEGNDDRIEGVLCGAVKQLKVTRAKPDSTLYLSLMYLAKIKPNIFATEGV
  IEALCSLLRRDASINFKAKGNSLVSVLACNLLMAAYEEDENWPEIFVKVYIEDSLGERIW
  VDSPHCKTFVDNIQTAFNTRMPPRSVLLQGEAGRVAGDLGAGSSPHPSLTEEEDSQTELL
  IAEEKLSPEQEGQLMPRYEELAESVEEYVLDMLRDQLNRRQPIDNVSRNLLRLLTSTCGY
  KEVRLLAVQKLEMWLQNPKLTRPAQDLLMSVCMNCNTHGSEDMDVISHLIKIRLKPKVLL
  NHFMLCIRELLSAHKDNLGTTIKLVIFNELSSARNPNNMQVLYTALQHSSELAPKFLAMV
  FQDLLTNKDDYLRASRALLREIIKQTKHEINFQAFCLGLMQERKEPQYLEMEFKERFVVH
  ITDVLAVSMMLGITAQVKEAGIAWDKGEKRNLEVLRSFQNQIAAIQRDAVWWLHTVVPSI
  SKLAPKDYVHCLHKVLFTEQPETYYKWDNWPPESDRNFFLRLCSEVPILEDTLMRILVIG
  LSRELPLGPADAMELADHLVKRAAAVQADDVEVLKVGRTQLIDAVLNLCTYHHPENIQLP
  PGYQPPNLAISTLYWKAWPLLLVVAAFNPENIGLAAWEEYPTLKMLMEMVMTNNYSYPPC
  TLTDEETRTEMLNRELQTAQREKQEILAFEGHLAAASTKQTITESSSLLLSQLTSLDPQG
  PPRRPPPHILDQVKSLNQSLRLGHLLCRSRNPDFLLHIIQRQASSQSMPWLADLVQSSEG
  SLDVLPVQCLCEFLLHDAVDDAASGEEDDEGESKEQKAKKRQRQQKQRQLLGRLQDLLLG
  PKADEQTTCEVLDYFLRRLGSSQVASRVLAMKGLSLVLSEGSLRDGEEKEPPMEEDVGDT
  DVLQGYQWLLRDLPRLPLFDSVRSTTALALQQAIHMETDPQTISAYLIYLSQHTPVEEQA
  QHSDLALDVARLVVERSTIMSHLFSKLSPSAASDAVLSALLSIFSRYVRRMRQSKEGEEV
  YSWSESQDQVFLRWSSGETATMHILVVHAMVILLTLGPPRADDSEFQALLDIWFPEEKPL
  PTAFLVDTSEEALLLPDWLKLRMIRSEVLRLVDAALQDLEPQQLLLFVQSFGIPVSSMSK
  LLQFLDQAVAHDPQTLEQNIMDKNYMAHLVEVQHERGASGGQTFHSLLTASLPPRRDSTE
  APKPKSSPEQPIGQGRIRVGTQLRVLGPEDDLAGMFLQIFPLSPDPRWQSSSPRPVALAL
  QQALGQELARVVQGSPEVPGITVRVLQALATLLSSPHGGALVMSMHRSHFLACPLLRQLC
  QYQRCVPQDTGFSSLFLKVLLQMLQWLDSPGVEGGPLRAQLRMLASQASAGRRLSDVRGG
  LLRLAEALAFRQDLEVVSSTVRAVIATLRSGEQCSVEPDLISKVLQGLIEVRSPHLEELL
  TAFFSATADAASPFPACKPVVVVSSLLLQEEEPLAGGKPGADGGSLEAVRLGPSSGLLVD
  WLEMLDPEVVSSCPDLQLRLLFSRRKGKGQAQVPSFRPYLLTLFTHQSSWPTLHQCIRVL
  LGKSREQRFDPSASLDFLWACIHVPRIWQGRDQRTPQKRREELVLRVQGPELISLVELIL
  AEAETRSQDGDTAACSLIQARLPLLLSCCCGDDESVRKVTEHLSGCIQQWGDSVLGRRCR
  DLLLQLYLQRPELRVPVPEVLLHSEGAASSSVCKLDGLIHRFITLLADTSDSRALENRGA
  DASMACRKLAVAHPLLLLRHLPMIAALLHGRTHLNFQEFRQQNHLSCFLHVLGLLELLQP
  HVFRSEHQGALWDCLLSFIRLLLNYRKSSRHLAAFINKFVQFIHKYITYNAPAAISFLQK
  HADPLHDLSFDNSDLVMLKSLLAGLSLPSRDDRTDRGLDEEGEEESSAGSLPLVSVSLFT
  PLTAAEMAPYMKRLSRGQTVEDLLEVLSDIDEMSRRRPEILSFFSTNLQRLMSSAEECCR
  NLAFSLALRSMQNSPSIAAAFLPTFMYCLGSQDFEVVQTALRNLPEYALLCQEHAAVLLH
  RAFLVGMYGQMDPSAQISEALRILHMEAVM
• Function: Component of the Integrator (INT) 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 (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cataract	DISUD7SL	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Mycosis fungoides	DIS62RB8	Strong	Genetic Variation	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[7]
Myelofibrosis	DISIMP21	Strong	Biomarker	[6]
Myotonia fluctuans	DISGCBNH	Strong	Genetic Variation	[6]
Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies	DISFQ66H	Strong	Autosomal recessive	[8]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[11]
Neoplasm	DISZKGEW	moderate	Altered Expression	[11]
X-linked sideroblastic anemia 1	DISWBQC7	moderate	Genetic Variation	[12]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[13]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[14]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[15]

4 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 1 (INTS1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Integrator complex subunit 1 (INTS1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Integrator complex subunit 1 (INTS1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Integrator complex subunit 1 (INTS1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integrator complex subunit 1 (INTS1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Integrator complex subunit 1 (INTS1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Integrator complex subunit 1 (INTS1).	[19]
Selenium	DM25CGV	Approved	Selenium increases the expression of Integrator complex subunit 1 (INTS1).	[20]

References

• [1] Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies.Eur J Hum Genet. 2019 Apr;27(4):582-593. doi: 10.1038/s41431-018-0298-9. Epub 2019 Jan 8.
• [2] Analysis of the int-1, int-2, c-myc, and neu oncogenes in human breast carcinomas.Cancer Res. 1990 Sep 15;50(18):5911-8.
• [3] Increased DNA integrity in colorectal cancer.In Vivo. 2014 May-Jun;28(3):299-303.
• [4] Translocation t(12;16)(q13;p11) in myxoid liposarcoma of a child and implication of the human int-1 gene in tumorigenesis.Jpn J Cancer Res. 1989 Oct;80(10):958-62. doi: 10.1111/j.1349-7006.1989.tb01633.x.
• [5] Wnt3 knockdown sensitizes human non-small cell type lung cancer (NSCLC) cells to cisplatin via regulating the cell proliferation and apoptosis.Eur Rev Med Pharmacol Sci. 2018 Mar;22(5):1323-1332. doi: 10.26355/eurrev_201803_14474.
• [6] Genetically inspired prognostic scoring system (GIPSS) outperforms dynamic international prognostic scoring system (DIPSS) in myelofibrosis patients.Am J Hematol. 2019 Jan;94(1):87-92. doi: 10.1002/ajh.25335. Epub 2018 Nov 25.
• [7] Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study.Leukemia. 2018 Jun;32(6):1380-1392. doi: 10.1038/s41375-018-0089-x. Epub 2018 Mar 6.
• [8] 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.
• [9] Diverse CD8+ T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte-macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine.Cancer Res. 2005 Feb 1;65(3):1079-88.
• [10] Reduced Frizzled Receptor 4 Expression Prevents WNT/-Catenin-driven Alveolar Lung Repair in Chronic Obstructive Pulmonary Disease.Am J Respir Crit Care Med. 2017 Jul 15;196(2):172-185. doi: 10.1164/rccm.201605-0904OC.
• [11] Nephrometry score correlated with tumor proliferative activity inT1 clear cell renal cell carcinoma.Urol Oncol. 2019 May;37(5):301.e19-301.e25. doi: 10.1016/j.urolonc.2019.02.005. Epub 2019 Feb 27.
• [12] Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation.Nucleic Acids Res. 2017 Jan 25;45(2):657-671. doi: 10.1093/nar/gkw901. Epub 2016 Oct 7.
• [13] Lenalidomide does not increase AML progression risk in RBC transfusion-dependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis.Leukemia. 2013 Apr;27(5):1072-9. doi: 10.1038/leu.2012.369. Epub 2012 Dec 21.
• [14] Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q.Blood. 2008 Jan 1;111(1):86-93. doi: 10.1182/blood-2007-01-068833. Epub 2007 Sep 24.
• [15] Biallelic INTS1 Mutations Cause a Rare Neurodevelopmental Disorder in Two Chinese Siblings.J Mol Neurosci. 2020 Jan;70(1):1-8. doi: 10.1007/s12031-019-01393-x. Epub 2019 Aug 19.
• [16] 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.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.