Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKREU8M)

• DOT Name: DNA-directed RNA polymerase I subunit RPA2 (POLR1B)
• Synonyms: RNA polymerase I subunit 2; EC 2.7.7.6; DNA-directed RNA polymerase I 135 kDa polypeptide; RPA135
• Gene Name: POLR1B
• Related Disease:
  Obesity
  Treacher Collins syndrome 4
  Treacher-Collins syndrome
• UniProt ID: RPA2_HUMAN
• PDB ID: 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43
• EC Number: 2.7.7.6
• Pfam ID: PF06883 ; PF04563 ; PF04561 ; PF04565 ; PF00562 ; PF04560
• Sequence:
  MDPGSRWRNLPSGPSLKHLTDPSYGIPREQQKAALQELTRAHVESFNYAVHEGLGLAVQA
  IPPFEFAFKDERISFTILDAVISPPTVPKGTICKEANVYPAECRGRRSTYRGKLTADINW
  AVNGISKGIIKQFLGYVPIMVKSKLCNLRNLPPQALIEHHEEAEEMGGYFIINGIEKVIR
  MLIMPRRNFPIAMIRPKWKTRGPGYTQYGVSMHCVREEHSAVNMNLHYLENGTVMLNFIY
  RKELFFLPLGFALKALVSFSDYQIFQELIKGKEDDSFLRNSVSQMLRIVMEEGCSTQKQV
  LNYLGECFRVKLNVPDWYPNEQAAEFLFNQCICIHLKSNTEKFYMLCLMTRKLFALAKGE
  CMEDNPDSLVNQEVLTPGQLFLMFLKEKLEGWLVSIKIAFDKKAQKTSVSMNTDNLMRIF
  TMGIDLTKPFEYLFATGNLRSKTGLGLLQDSGLCVVADKLNFIRYLSHFRCVHRGADFAK
  MRTTTVRRLLPESWGFLCPVHTPDGEPCGLMNHLTAVCEVVTQFVYTASIPALLCNLGVT
  PIDGAPHRSYSECYPVLLDGVMVGWVDKDLAPGIADSLRHFKVLREKRIPPWMEVVLIPM
  TGKPSLYPGLFLFTTPCRLVRPVQNLALGKEELIGTMEQIFMNVAIFEDEVFAGVTTHQE
  LFPHSLLSVIANFIPFSDHNQSPRNMYQCQMGKQTMGFPLLTYQDRSDNKLYRLQTPQSP
  LVRPSMYDYYDMDNYPIGTNAIVAVISYTGYDMEDAMIVNKASWERGFAHGSVYKSEFID
  LSEKIKQGDSSLVFGIKPGDPRVLQKLDDDGLPFIGAKLQYGDPYYSYLNLNTGESFVMY
  YKSKENCVVDNIKVCSNDTGSGKFKCVCITMRVPRNPTIGDKFASRHGQKGILSRLWPAE
  DMPFTESGMVPDILFNPHGFPSRMTIGMLIESMAGKSAALHGLCHDATPFIFSEENSALE
  YFGEMLKAAGYNFYGTERLYSGISGLELEADIFIGVVYYQRLRHMVSDKFQVRTTGARDR
  VTNQPIGGRNVQGGIRFGEMERDALLAHGTSFLLHDRLFNCSDRSVAHVCVKCGSLLSPL
  LEKPPPSWSAMRNRKYNCTLCSRSDTIDTVSVPYVFRYFVAELAAMNIKVKLDVV
• Function: Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Transcribes 47S pre-rRNAs from multicopy rRNA gene clusters, giving rise to 5.8S, 18S and 28S ribosomal RNAs. Pol I-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol I pre-initiation complex (PIC) is recruited by the selectivity factor 1 (SL1/TIF-IB) complex bound to the core promoter that precedes an rDNA repeat unit. The PIC assembly bends the promoter favoring the formation of the transcription bubble and promoter escape. Once the polymerase has escaped from the promoter it enters the elongation phase during which RNA is actively polymerized, based on complementarity with the template DNA strand. Highly processive, assembles in structures referred to as 'Miller trees' where many elongating Pol I complexes queue and transcribe the same rDNA coding regions. At terminator sequences downstream of the rDNA gene, PTRF interacts with Pol I and halts Pol I transcription leading to the release of the RNA transcript and polymerase from the DNA. Forms Pol I active center together with the largest subunit POLR1A/RPA1. Appends one nucleotide at a time to the 3' end of the nascent RNA, with POLR1A/RPA1 contributing a Mg(2+)-coordinating DxDGD motif, and POLR1B/RPA2 participating in the coordination of a second Mg(2+) ion and providing lysine residues believed to facilitate Watson-Crick base pairing between the incoming nucleotide and the template base. Typically, Mg(2+) ions direct a 5' nucleoside triphosphate to form a phosphodiester bond with the 3' hydroxyl of the preceding nucleotide of the nascent RNA, with the elimination of pyrophosphate. Has proofreading activity: Pauses and backtracks to allow the cleavage of a missincorporated nucleotide via POLR1H/RPA12. High Pol I processivity is associated with decreased transcription fidelity.
• KEGG Pathway: R. polymerase (hsa03020)
• Reactome Pathway:
  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)
  NoRC negatively regulates rRNA expression (R-HSA-427413)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obesity	DIS47Y1K	Strong	Genetic Variation	[1]
Treacher Collins syndrome 4	DISNZ1SL	Strong	Autosomal dominant	[2]
Treacher-Collins syndrome	DIS2GXZ1	Supportive	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[21]

1 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 increases the methylation of DNA-directed RNA polymerase I subunit RPA2 (POLR1B).	[17]

References

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• [2] POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genet Med. 2020 Mar;22(3):547-556. doi: 10.1038/s41436-019-0669-9. Epub 2019 Oct 24.
• [3] Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet Med. 2016 Jan;18(1):49-56. doi: 10.1038/gim.2015.29. Epub 2015 Mar 19.
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• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] 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.
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• [12] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [15] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.