Details of Drug Off-Target (DOT)

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

• DOT Name: Protein POLR1D, isoform 2 (POLR1D)
• Gene Name: POLR1D
• Related Disease:
  Treacher Collins syndrome 2
  Drug dependence
  Lung adenocarcinoma
  Multiple sclerosis
  Neoplasm
  Parkinson disease
  Substance abuse
  Substance dependence
  Treacher-Collins syndrome
  Acute myelogenous leukaemia
  Colorectal carcinoma
  Nervous system inflammation
• UniProt ID: RPC22_HUMAN
• Sequence:
  MEEDQELERKAIEELLKEAKRGKTRAETMGPMGWMKCPLASTNKRFLINTIKNTLPSHKE
  QDHEQKEGDKEPAKSQAQKEENPKKHRSHPYKHSFRARGSASYSPPRKRSSQDKYEKRSN
  RR
• 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 III Chain Elongation (R-HSA-73780)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  RNA Polymerase III Transcription Termination (R-HSA-73980)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)
  RNA Polymerase III Transcription Initiation From Type 1 Promoter (R-HSA-76061)
  RNA Polymerase III Transcription Initiation From Type 2 Promoter (R-HSA-76066)
  RNA Polymerase III Transcription Initiation From Type 3 Promoter (R-HSA-76071)
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Treacher Collins syndrome 2	DIS64061	Definitive	Autosomal dominant	[1]
Drug dependence	DIS9IXRC	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Parkinson disease	DISQVHKL	Strong	Biomarker	[6]
Substance abuse	DIS327VW	Strong	Biomarker	[2]
Substance dependence	DISDRAAR	Strong	Biomarker	[2]
Treacher-Collins syndrome	DIS2GXZ1	Supportive	Autosomal dominant	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[5]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[9]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein POLR1D, isoform 2 (POLR1D).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein POLR1D, isoform 2 (POLR1D).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein POLR1D, isoform 2 (POLR1D).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein POLR1D, isoform 2 (POLR1D).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein POLR1D, isoform 2 (POLR1D).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein POLR1D, isoform 2 (POLR1D).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein POLR1D, isoform 2 (POLR1D).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein POLR1D, isoform 2 (POLR1D).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Protein POLR1D, isoform 2 (POLR1D).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein POLR1D, isoform 2 (POLR1D).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein POLR1D, isoform 2 (POLR1D).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Protein POLR1D, isoform 2 (POLR1D).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Protein POLR1D, isoform 2 (POLR1D).	[22]

References

• [1] Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet. 2011 Jan;43(1):20-2. doi: 10.1038/ng.724. Epub 2010 Dec 5.
• [2] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [3] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [4] Polymerase-1 pathway activation in acute multiple sclerosis relapse.Autoimmun Rev. 2018 Dec;17(12):1235-1239. doi: 10.1016/j.autrev.2018.07.006. Epub 2018 Oct 11.
• [5] Expression and Clinical Significance of POLR1D in Colorectal Cancer.Oncology. 2020;98(3):138-145. doi: 10.1159/000504174. Epub 2019 Nov 13.
• [6] Identification of potential diagnostic biomarkers for Parkinson's disease.FEBS Open Bio. 2019 Aug;9(8):1460-1468. doi: 10.1002/2211-5463.12687. Epub 2019 Jul 3.
• [7] Treacher Collins Syndrome. 2004 Jul 20 [updated 2020 Aug 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] Experimental Autoimmune Encephalomyelitis Ameliorated by Passive Transfer of Polymerase 1-Silenced MOG35-55 Lymphatic Node Cells: Verification of a Novel Therapeutic Approach in Multiple Sclerosis.Neuromolecular Med. 2017 Sep;19(2-3):406-412. doi: 10.1007/s12017-017-8456-8. Epub 2017 Jul 28.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] 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.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.