Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDWI0TG)

• DOT Name: DNA-directed RNA polymerase I subunit RPA1 (POLR1A)
• Synonyms: RNA polymerase I subunit A1; EC 2.7.7.6; A190; DNA-directed RNA polymerase I largest subunit; DNA-directed RNA polymerase I subunit A; RNA polymerase I 194 kDa subunit; RPA194
• Gene Name: POLR1A
• Related Disease:
  Acrofacial dysostosis
  Acrofacial dysostosis Cincinnati type
  Advanced cancer
  Scleroderma
  Systemic sclerosis
  Leukodystrophy
  Treacher-Collins syndrome
  Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
  Leishmaniasis
• UniProt ID: RPA1_HUMAN
• PDB ID: 7OB9; 7OBA; 7OBB; 7VBA; 7VBB; 7VBC; 8A43
• EC Number: 2.7.7.6
• Pfam ID: PF04997 ; PF00623 ; PF04983 ; PF05000 ; PF04998
• Sequence:
  MLISKNMPWRRLQGISFGMYSAEELKKLSVKSITNPRYLDSLGNPSANGLYDLALGPADS
  KEVCSTCVQDFSNCSGHLGHIELPLTVYNPLLFDKLYLLLRGSCLNCHMLTCPRAVIHLL
  LCQLRVLEVGALQAVYELERILNRFLEENPDPSASEIREELEQYTTEIVQNNLLGSQGAH
  VKNVCESKSKLIALFWKAHMNAKRCPHCKTGRSVVRKEHNSKLTITFPAMVHRTAGQKDS
  EPLGIEEAQIGKRGYLTPTSAREHLSALWKNEGFFLNYLFSGMDDDGMESRFNPSVFFLD
  FLVVPPSRYRPVSRLGDQMFTNGQTVNLQAVMKDVVLIRKLLALMAQEQKLPEEVATPTT
  DEEKDSLIAIDRSFLSTLPGQSLIDKLYNIWIRLQSHVNIVFDSEMDKLMMDKYPGIRQI
  LEKKEGLFRKHMMGKRVDYAARSVICPDMYINTNEIGIPMVFATKLTYPQPVTPWNVQEL
  RQAVINGPNVHPGASMVINEDGSRTALSAVDMTQREAVAKQLLTPATGAPKPQGTKIVCR
  HVKNGDILLLNRQPTLHRPSIQAHRARILPEEKVLRLHYANCKAYNADFDGDEMNAHFPQ
  SELGRAEAYVLACTDQQYLVPKDGQPLAGLIQDHMVSGASMTTRGCFFTREHYMELVYRG
  LTDKVGRVKLLSPSILKPFPLWTGKQVVSTLLINIIPEDHIPLNLSGKAKITGKAWVKET
  PRSVPGFNPDSMCESQVIIREGELLCGVLDKAHYGSSAYGLVHCCYEIYGGETSGKVLTC
  LARLFTAYLQLYRGFTLGVEDILVKPKADVKRQRIIEESTHCGPQAVRAALNLPEAASYD
  EVRGKWQDAHLGKDQRDFNMIDLKFKEEVNHYSNEINKACMPFGLHRQFPENSLQMMVQS
  GAKGSTVNTMQISCLLGQIELEGRRPPLMASGKSLPCFEPYEFTPRAGGFVTGRFLTGIK
  PPEFFFHCMAGREGLVDTAVKTSRSGYLQRCIIKHLEGLVVQYDLTVRDSDGSVVQFLYG
  EDGLDIPKTQFLQPKQFPFLASNYEVIMKSQHLHEVLSRADPKKALHHFRAIKKWQSKHP
  NTLLRRGAFLSYSQKIQEAVKALKLESENRNGRSPGTQEMLRMWYELDEESRRKYQKKAA
  ACPDPSLSVWRPDIYFASVSETFETKVDDYSQEWAAQTEKSYEKSELSLDRLRTLLQLKW
  QRSLCEPGEAVGLLAAQSIGEPSTQMTLNTFHFAGRGEMNVTLGIPRLREILMVASANIK
  TPMMSVPVLNTKKALKRVKSLKKQLTRVCLGEVLQKIDVQESFCMEEKQNKFQVYQLRFQ
  FLPHAYYQQEKCLRPEDILRFMETRFFKLLMESIKKKNNKASAFRNVNTRRATQRDLDNA
  GELGRSRGEQEGDEEEEGHIVDAEAEEGDADASDAKRKEKQEEEVDYESEEEEEREGEEN
  DDEDMQEERNPHREGARKTQEQDEEVGLGTEEDPSLPALLTQPRKPTHSQEPQGPEAMER
  RVQAVREIHPFIDDYQYDTEESLWCQVTVKLPLMKINFDMSSLVVSLAHGAVIYATKGIT
  RCLLNETTNNKNEKELVLNTEGINLPELFKYAEVLDLRRLYSNDIHAIANTYGIEAALRV
  IEKEIKDVFAVYGIAVDPRHLSLVADYMCFEGVYKPLNRFGIRSNSSPLQQMTFETSFQF
  LKQATMLGSHDELRSPSACLVVGKVVRGGTGLFELKQPLR
• 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 second largest subunit POLR1B/RPA2. 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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acrofacial dysostosis	DISNBM5T	Strong	Biomarker	[1]
Acrofacial dysostosis Cincinnati type	DIS91YJ3	Strong	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Scleroderma	DISVQ342	Strong	Biomarker	[3]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[3]
Leukodystrophy	DISVY1TT	moderate	Biomarker	[4]
Treacher-Collins syndrome	DIS2GXZ1	moderate	Biomarker	[4]
Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome	DISI9JIG	Supportive	Autosomal recessive	[2]
Leishmaniasis	DISABTW7	Disputed	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[15]

2 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 decreases the methylation of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA-directed RNA polymerase I subunit RPA1 (POLR1A).	[14]

References

• [1] Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am J Hum Genet. 2014 Dec 4;95(6):698-707. doi: 10.1016/j.ajhg.2014.10.014. Epub 2014 Nov 26.
• [2] Acrofacial Dysostosis, Cincinnati Type, a Mandibulofacial Dysostosis Syndrome with Limb Anomalies, Is Caused by POLR1A Dysfunction. Am J Hum Genet. 2015 May 7;96(5):765-74. doi: 10.1016/j.ajhg.2015.03.011. Epub 2015 Apr 23.
• [3] Protective Effect Against Cancer of Antibodies to the LargeSubunits of Both RNA Polymerases I and III in Scleroderma.Arthritis Rheumatol. 2019 Sep;71(9):1571-1579. doi: 10.1002/art.40893. Epub 2019 Aug 1.
• [4] Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.Eur J Hum Genet. 2017 Feb;25(3):315-323. doi: 10.1038/ejhg.2016.183. Epub 2017 Jan 4.
• [5] Leishmania braziliensis replication protein A subunit 1: molecular modelling, protein expression and analysis of its affinity for both DNA and RNA.Parasit Vectors. 2014 Dec 12;7:573. doi: 10.1186/s13071-014-0573-8.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.