Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5JQ913)

• DOT Name: Integrator complex subunit 4 (INTS4)
• Synonyms: Int4
• Gene Name: INTS4
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Multiple sclerosis
  Stroke
  Behcet disease
  Pleural tuberculosis
  Prostate cancer
  Prostate neoplasm
  Pulmonary disease
  Pulmonary tuberculosis
  Sarcoidosis
  Systemic sclerosis
  Latent tuberculosis infection
• UniProt ID: INT4_HUMAN
• PDB ID: 7BFP; 7BFQ; 7CUN; 7PKS; 7YCX
• Pfam ID: PF13646 ; PF20168
• Sequence:
  MAAHLKKRVYEEFTKVVQPQEEIATKKLRLTKPSKSAALHIDLCKATSPADALQYLLQFA
  RKPVEAESVEGVVRILLEHYYKENDPSVRLKIASLLGLLSKTAGFSPDCIMDDAINILQN
  EKSHQVLAQLLDTLLAIGTKLPENQAIQMRLVDVACKHLTDTSHGVRNKCLQLLGNLGSL
  EKSVTKDAEGLAARDVQKIIGDYFSDQDPRVRTAAIKAMLQLHERGLKLHQTIYNQACKL
  LSDDYEQVRSAAVQLIWVVSQLYPESIVPIPSSNEEIRLVDDAFGKICHMVSDGSWVVRV
  QAAKLLGSMEQVSSHFLEQTLDKKLMSDLRRKRTAHERAKELYSSGEFSSGRKWGDDAPK
  EEVDTGAVNLIESGACGAFVHGLEDEMYEVRIAAVEALCMLAQSSPSFAEKCLDFLVDMF
  NDEIEEVRLQSIHTMRKISNNITLREDQLDTVLAVLEDSSRDIREALHELLCCTNVSTKE
  GIHLALVELLKNLTKYPTDRDSIWKCLKFLGSRHPTLVLPLVPELLSTHPFFDTAEPDMD
  DPAYIAVLVLIFNAAKTCPTMPALFSDHTFRHYAYLRDSLSHLVPALRLPGRKLVSSAVS
  PSIIPQEDPSQQFLQQSLERVYSLQHLDPQGAQELLEFTIRDLQRLGELQSELAGVADFS
  ATYLRCQLLLIKALQEKLWNVAAPLYLKQSDLASAAAKQIMEETYKMEFMYSGVENKQVV
  IIHHMRLQAKALQLIVTARTTRGLDPLFGMCEKFLQEVDFFQRYFIADLPHLQDSFVDKL
  LDLMPRLMTSKPAEVVKILQTMLRQSAFLHLPLPEQIHKASATIIEPAGESDNPLRFTSG
  LVVALDVDATLEHVQDPQNTVKVQVLYPDGQAQMIHPKPADFRNPGPGRHRLITQVYLSH
  TAWTEACQVEVRLLLAYNSSARIPKCPWMEGGEMSPQVETSIEGTIPFSKPVKVYIMPKP
  ARR
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Biomarker	[1]
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[2]
Stroke	DISX6UHX	Definitive	Biomarker	[1]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[3]
Pleural tuberculosis	DISD09EG	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[6]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[7]
Sarcoidosis	DISE5B8Z	Strong	Genetic Variation	[8]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[9]
Latent tuberculosis infection	DIS6R1EH	Limited	Genetic Variation	[10]

6 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 4 (INTS4).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Integrator complex subunit 4 (INTS4).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Integrator complex subunit 4 (INTS4).	[13]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of Integrator complex subunit 4 (INTS4).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Integrator complex subunit 4 (INTS4).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Integrator complex subunit 4 (INTS4).	[11]

2 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 decreases the methylation of Integrator complex subunit 4 (INTS4).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of Integrator complex subunit 4 (INTS4).	[16]

References

• [1] How much for a broken heart? Costs of cardiovascular disease in Colombia using a person-based approach.PLoS One. 2018 Dec 19;13(12):e0208513. doi: 10.1371/journal.pone.0208513. eCollection 2018.
• [2] NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple Sclerosis.J Clin Immunol. 2010 Jul;30(4):583-6. doi: 10.1007/s10875-010-9422-5. Epub 2010 Apr 20.
• [3] Genetic susceptibility to Behet's syndrome is associated with NRAMP1 (SLC11A1) polymorphism in Turkish patients.Rheumatol Int. 2009 May;29(7):787-91. doi: 10.1007/s00296-008-0763-9. Epub 2008 Nov 8.
• [4] NRAMP1 genetic polymorphisms as a risk factor of tuberculous pleurisy.Int J Tuberc Lung Dis. 2003 Apr;7(4):370-5.
• [5] The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.Cell Death Dis. 2014 Apr 24;5(4):e1195. doi: 10.1038/cddis.2014.157.
• [6] NRAMP1 gene polymorphism and susceptibility to nontuberculous mycobacterial lung diseases.Chest. 2005 Jul;128(1):94-101. doi: 10.1378/chest.128.1.94.
• [7] NRAMP1 D543N and INT4 polymorphisms in susceptibility to pulmonary tuberculosis: A meta-analysis.Infect Genet Evol. 2017 Oct;54:91-97. doi: 10.1016/j.meegid.2017.06.022. Epub 2017 Jun 22.
• [8] The functional SLC11A1 gene polymorphisms are associated with sarcoidosis in Turkish population.Mol Biol Rep. 2012 Apr;39(4):5009-16. doi: 10.1007/s11033-011-1297-x. Epub 2011 Dec 8.
• [9] NRAMP1 (SLC11A1): a plausible candidate gene for systemic sclerosis (SSc) with interstitial lung involvement.J Clin Immunol. 2008 Jan;28(1):73-7. doi: 10.1007/s10875-007-9134-7. Epub 2007 Sep 18.
• [10] Polymorphisms of the NRAMP1 gene: distribution and susceptibility to the development of pulmonary tuberculosis in the Greek population.Med Sci Monit. 2011 Jan;17(1):PH1-6. doi: 10.12659/msm.881312.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [15] 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.
• [16] 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.