Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8SCI48)

• DOT Name: Mediator of RNA polymerase II transcription subunit 16 (MED16)
• Synonyms: Mediator complex subunit 16; Thyroid hormone receptor-associated protein 5; Thyroid hormone receptor-associated protein complex 95 kDa component; Trap95; Vitamin D3 receptor-interacting protein complex 92 kDa component; DRIP92
• Gene Name: MED16
• Related Disease:
  Endometriosis
  Schwannomatosis
• UniProt ID: MED16_HUMAN
• PDB ID: 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 8GXQ; 8GXS
• Pfam ID: PF20718 ; PF20719 ; PF11635 ; PF00400
• Sequence:
  MCDLRRPAAGGMMDLAYVCEWEKWSKSTHCPSVPLACAWSCRNLIAFTMDLRSDDQDLTR
  MIHILDTEHPWDLHSIPSEHHEAITCLEWDQSGSRLLSADADGQIKCWSMADHLANSWES
  SVGSLVEGDPIVALSWLHNGVKLALHVEKSGASSFGEKFSRVKFSPSLTLFGGKPMEGWI
  AVTVSGLVTVSLLKPSGQVLTSTESLCRLRGRVALADIAFTGGGNIVVATADGSSASPVQ
  FYKVCVSVVSEKCRIDTEILPSLFMRCTTDLNRKDKFPAITHLKFLARDMSEQVLLCASS
  QTSSIVECWSLRKEGLPVNNIFQQISPVVGDKQPTILKWRILSATNDLDRVSAVALPKLP
  ISLTNTDLKVASDTQFYPGLGLALAFHDGSVHIVHRLSLQTMAVFYSSAAPRPVDEPAMK
  RPRTAGPAVHLKAMQLSWTSLALVGIDSHGKLSVLRLSPSMGHPLEVGLALRHLLFLLEY
  CMVTGYDWWDILLHVQPSMVQSLVEKLHEEYTRQTAALQQVLSTRILAMKASLCKLSPCT
  VTRVCDYHTKLFLIAISSTLKSLLRPHFLNTPDKSPGDRLTEICTKITDVDIDKVMINLK
  TEEFVLDMNTLQALQQLLQWVGDFVLYLLASLPNQGSLLRPGHSFLRDGTSLGMLRELMV
  VIRIWGLLKPSCLPVYTATSDTQDSMSLLFRLLTKLWICCRDEGPASEPDEALVDECCLL
  PSQLLIPSLDWLPASDGLVSRLQPKQPLRLQFGRAPTLPGSAATLQLDGLARAPGQPKID
  HLRRLHLGACPTEECKACTRCGCVTMLKSPNRTTAVKQWEQRWIKNCLAVEGRGPDACVT
  SRASEEAPAFVQLGPQSTHHSPRTPRSLDHLHPEDRP
• 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.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometriosis	DISX1AG8	Strong	Biomarker	[1]
Schwannomatosis	DISDWAM1	Strong	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Mediator of RNA polymerase II transcription subunit 16 (MED16) affects the response to substance of Methotrexate.	[11]

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 Mediator of RNA polymerase II transcription subunit 16 (MED16).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[8]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Mediator of RNA polymerase II transcription subunit 16 (MED16).	[9]

References

• [1] 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.
• [2] A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.Genet Med. 2014 Oct;16(10):787-92. doi: 10.1038/gim.2014.39. Epub 2014 Apr 24.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] 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.
• [9] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [10] 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.
• [11] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.