Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEZR5GC)

• DOT Name: Mediator of RNA polymerase II transcription subunit 17 (MED17)
• Synonyms: Activator-recruited cofactor 77 kDa component; ARC77; Cofactor required for Sp1 transcriptional activation subunit 6; CRSP complex subunit 6; Mediator complex subunit 17; Thyroid hormone receptor-associated protein complex 80 kDa component; Trap80; Transcriptional coactivator CRSP77; Vitamin D3 receptor-interacting protein complex 80 kDa component; DRIP80
• Gene Name: MED17
• Related Disease:
  Intellectual disability
  3-methylcrotonyl-CoA carboxylase 1 deficiency
  3-methylcrotonyl-CoA carboxylase deficiency
  Endometriosis
  Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly
  Choreatic disease
  Isolated congenital microcephaly
  Advanced cancer
• UniProt ID: MED17_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 7NVR; 8GXQ; 8GXS
• Pfam ID: PF10156
• Sequence:
  MSGVRAVRISIESACEKQVHEVGLDGTETYLPPLSMSQNLARLAQRIDFSQGSGSEEEEA
  AGTEGDAQEWPGAGSSADQDDEEGVVKFQPSLWPWDSVRNNLRSALTEMCVLYDVLSIVR
  DKKFMTLDPVSQDALPPKQNPQTLQLISKKKSLAGAAQILLKGAERLTKSVTENQENKLQ
  RDFNSELLRLRQHWKLRKVGDKILGDLSYRSAGSLFPHHGTFEVIKNTDLDLDKKIPEDY
  CPLDVQIPSDLEGSAYIKVSIQKQAPDIGDLGTVNLFKRPLPKSKPGSPHWQTKLEAAQN
  VLLCKEIFAQLSREAVQIKSQVPHIVVKNQIISQPFPSLQLSISLCHSSNDKKSQKFATE
  KQCPEDHLYVLEHNLHLLIREFHKQTLSSIMMPHPASAPFGHKRMRLSGPQAFDKNEINS
  LQSSEGLLEKIIKQAKHIFLRSRAAATIDSLASRIEDPQIQAHWSNINDVYESSVKVLIT
  SQGYEQICKSIQLQLNIGVEQIRVVHRDGRVITLSYQEQELQDFLLSQMSQHQVHAVQQL
  AKVMGWQVLSFSNHVGLGPIESIGNASAITVASPSGDYAISVRNGPESGSKIMVQFPRNQ
  CKDLPKSDVLQDNKWSHLRGPFKEVQWNKMEGRNFVYKMELLMSALSPCLL
• Function: Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Thyroid hormone sig.ling pathway (hsa04919)
• Reactome Pathway:
  Generic Transcription Pathway (R-HSA-212436)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
3-methylcrotonyl-CoA carboxylase 1 deficiency	DISEE5OU	Strong	Genetic Variation	[2]
3-methylcrotonyl-CoA carboxylase deficiency	DIS3TZW5	Strong	Genetic Variation	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly	DISERE16	Strong	Autosomal recessive	[4]
Choreatic disease	DISH8K3M	moderate	Genetic Variation	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[7]

10 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 Mediator of RNA polymerase II transcription subunit 17 (MED17).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[18]

2 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 Mediator of RNA polymerase II transcription subunit 17 (MED17).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Mediator of RNA polymerase II transcription subunit 17 (MED17).	[16]

References

• [1] Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. J Med Genet. 2015 Feb;52(2):123-7. doi: 10.1136/jmedgenet-2014-102793. Epub 2014 Dec 19.
• [2] Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD.Genet Med. 2015 Aug;17(8):660-7. doi: 10.1038/gim.2014.157. Epub 2014 Nov 6.
• [3] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [4] Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet. 2010 Nov 12;87(5):667-70. doi: 10.1016/j.ajhg.2010.09.016. Epub 2010 Oct 14.
• [5] Distinct but milder phenotypes with choreiform movements in siblings with compound heterozygous mutations in the transcription preinitiation mediator complex subunit 17 (MED17).Brain Dev. 2016 Jan;38(1):118-23. doi: 10.1016/j.braindev.2015.05.004. Epub 2015 May 23.
• [6] Expanding the phenotype of MED 17 mutations: Description of two new cases and review of the literature.Am J Med Genet B Neuropsychiatr Genet. 2018 Dec;177(8):687-690. doi: 10.1002/ajmg.b.32677. Epub 2018 Oct 22.
• [7] Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.Genet Med. 2015 Jun;17(6):485-92. doi: 10.1038/gim.2014.134. Epub 2014 Oct 9.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [15] 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.
• [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.
• [17] 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.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.