Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNV4CDH)

• DOT Name: TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C)
• Synonyms: RNA polymerase I-specific TBP-associated factor 110 kDa; TAFI110; TATA box-binding protein-associated factor 1C; TBP-associated factor 1C; Transcription initiation factor SL1/TIF-IB subunit C
• Gene Name: TAF1C
• Related Disease:
  Non-insulin dependent diabetes
  Autism
  Colorectal carcinoma
  High blood pressure
  Complex neurodevelopmental disorder
• UniProt ID: TAF1C_HUMAN
• Pfam ID: PF20641 ; PF20643 ; PF20642
• Sequence:
  MDFPSSLRPALFLTGPLGLSDVPDLSFMCSWRDALTLPEAQPQNSENGALHVTKDLLWEP
  ATPGPLPMLPPLIDPWDPGLTARDLLFRGGCRYRKRPRVVLDVTEQISRFLLDHGDVAFA
  PLGKLMLENFKLEGAGSRTKKKTVVSVKKLLQDLGGHQPWGCPWAYLSNRQRRFSILGGP
  ILGTSVASHLAELLHEELVLRWEQLLLDEACTGGALAWVPGRTPQFGQLVYPAGGAQDRL
  HFQEVVLTPGDNPQFLGKPGRIQLQGPVRQVVTCTVQGESKALIYTFLPHWLTCYLTPGP
  FHPSSALLAVRSDYHCAVWKFGKQWQPTLLQAMQVEKGATGISLSPHLPGELAICSRSGA
  VCLWSPEDGLRQIYRDPETLVFRDSSSWRWADFTAHPRVLTVGDRTGVKMLDTQGPPGCG
  LLLFRLGAEASCQKGERVLLTQYLGHSSPKCLPPTLHLVCTQFSLYLVDERLPLVPMLKW
  NHGLPSPLLLARLLPPPRPSCVQPLLLGGQGGQLQLLHLAGEGASVPRLAGPPQSLPSRI
  DSLPAFPLLEPKIQWRLQERLKAPTIGLAAVVPPLPSAPTPGLVLFQLSAAGDVFYQQLR
  PQVDSSLRRDAGPPGDTQPDCHAPTASWTSQDTAGCSQWLKALLKVPLAPPVWTAPTFTH
  RQMLGSTELRREEEEGQRLGVLRKAMARGQLLLQRDLGSLPAAEPPPAPESGLEDKLSER
  LGEAWAGRGAAWWERQQGRTSEPGRQTRRPKRRTQLSSSFSLSGHVDPSEDTSSPHSPEW
  PPADALPLPPTTPPSQELTPDACAQGVPSEQRQMLRDYMAKLPPQRDTPGCATTPPHSQA
  SSVRATRSQQHTPVLSSSQPLRKKPRMGF
• Function: Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits. Recruits RNA polymerase I to the rRNA gene promoter via interaction with RRN3.
• Reactome Pathway:
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  B-WICH complex positively regulates rRNA expression (R-HSA-5250924)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  SIRT1 negatively regulates rRNA expression (R-HSA-427359)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[4]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[5]

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 TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[13]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C).	[14]

References

• [1] Association of TATA box-binding protein-associated factor RNA polymerase I subunit C (TAF1C) with T2DM.Gene. 2019 Jul 20;706:43-51. doi: 10.1016/j.gene.2019.04.076. Epub 2019 Apr 27.
• [2] Individual common variants exert weak effects on the risk for autism spectrum disorders.Hum Mol Genet. 2012 Nov 1;21(21):4781-92. doi: 10.1093/hmg/dds301. Epub 2012 Jul 26.
• [3] Frameshift mutations of TAF1C gene, a core component for transcription by RNA polymerase I, and its regional heterogeneity in gastric and colorectal cancers.Pathology. 2015 Feb;47(2):101-4. doi: 10.1097/PAT.0000000000000212.
• [4] Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.Hypertension. 2017 Jan;69(1):51-59. doi: 10.1161/HYPERTENSIONAHA.116.08267. Epub 2016 Oct 31.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] 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.
• [7] 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.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.