General Information of Drug Off-Target (DOT) (ID: OTS3F0H2)

DOT Name DNA-directed RNA polymerase II subunit RPB2 (POLR2B)
Synonyms
EC 2.7.7.6; 3'-5' exoribonuclease; EC 3.1.13.-; DNA-directed RNA polymerase II 140 kDa polypeptide; DNA-directed RNA polymerase II subunit B; RNA polymerase II subunit 2; RNA polymerase II subunit B2; RNA-directed RNA polymerase II subunit RPB2; EC 2.7.7.48
Gene Name POLR2B
Related Disease
Colorectal carcinoma ( )
Influenza ( )
Keratitis ( )
UniProt ID
RPB2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5IY6; 5IY7; 5IY8; 5IY9; 5IYA; 5IYB; 5IYC; 5IYD; 6DRD; 6O9L; 6XRE; 7LBM
EC Number
2.7.7.48; 2.7.7.6; 3.1.13.-
Pfam ID
PF04563 ; PF04561 ; PF04565 ; PF04566 ; PF04567 ; PF00562 ; PF04560
Sequence
MYDADEDMQYDEDDDEITPDLWQEACWIVISSYFDEKGLVRQQLDSFDEFIQMSVQRIVE
DAPPIDLQAEAQHASGEVEEPPRYLLKFEQIYLSKPTHWERDGAPSPMMPNEARLRNLTY
SAPLYVDITKTVIKEGEEQLQTQHQKTFIGKIPIMLRSTYCLLNGLTDRDLCELNECPLD
PGGYFIINGSEKVLIAQEKMATNTVYVFAKKDSKYAYTGECRSCLENSSRPTSTIWVSML
ARGGQGAKKSAIGQRIVATLPYIKQEVPIIIVFRALGFVSDRDILEHIIYDFEDPEMMEM
VKPSLDEAFVIQEQNVALNFIGSRGAKPGVTKEKRIKYAKEVLQKEMLPHVGVSDFCETK
KAYFLGYMVHRLLLAALGRRELDDRDHYGNKRLDLAGPLLAFLFRGMFKNLLKEVRIYAQ
KFIDRGKDFNLELAIKTRIISDGLKYSLATGNWGDQKKAHQARAGVSQVLNRLTFASTLS
HLRRLNSPIGRDGKLAKPRQLHNTLWGMVCPAETPEGHAVGLVKNLALMAYISVGSQPSP
ILEFLEEWSMENLEEISPAAIADATKIFVNGCWVGIHKDPEQLMNTLRKLRRQMDIIVSE
VSMIRDIREREIRIYTDAGRICRPLLIVEKQKLLLKKRHIDQLKEREYNNYSWQDLVASG
VVEYIDTLEEETVMLAMTPDDLQEKEVAYCSTYTHCEIHPSMILGVCASIIPFPDHNQSP
RNTYQSAMGKQAMGVYITNFHVRMDTLAHVLYYPQKPLVTTRSMEYLRFRELPAGINSIV
AIASYTGYNQEDSVIMNRSAVDRGFFRSVFYRSYKEQESKKGFDQEEVFEKPTRETCQGM
RHAIYDKLDDDGLIAPGVRVSGDDVIIGKTVTLPENEDELESTNRRYTKRDCSTFLRTSE
TGIVDQVMVTLNQEGYKFCKIRVRSVRIPQIGDKFASRHGQKGTCGIQYRQEDMPFTCEG
ITPDIIINPHAIPSRMTIGHLIECLQGKVSANKGEIGDATPFNDAVNVQKISNLLSDYGY
HLRGNEVLYNGFTGRKITSQIFIGPTYYQRLKHMVDDKIHSRARGPIQILNRQPMEGRSR
DGGLRFGEMERDCQIAHGAAQFLRERLFEASDPYQVHVCNLCGIMAIANTRTHTYECRGC
RNKTQISLVRMPYACKLLFQELMSMSIAPRMMSV
Function
Catalytic core component of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase which synthesizes mRNA precursors and many functional non-coding RNAs using the four ribonucleoside triphosphates as substrates. Pol II-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol II pre-initiation complex (PIC) is recruited to DNA promoters, with focused-type promoters containing either the initiator (Inr) element, or the TATA-box found in cell-type specific genes and dispersed-type promoters that often contain hypomethylated CpG islands usually found in housekeeping genes. 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. Transcription termination involves the release of the RNA transcript and polymerase from the DNA. Forms Pol II active center together with the largest subunit POLR2A/RPB1. Appends one nucleotide at a time to the 3' end of the nascent RNA, with POLR2A/RPB1 most likely contributing a Mg(2+)-coordinating DxDGD motif, and POLR2A/RPB1 most likely contributing a Mg(2+)-coordinating DxDGD motif, and POLR2B/RPB2 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 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. The reversible pyrophosphorolysis can occur at high pyrophosphate concentrations. Can proofread the nascent RNA transcript by means of a 3' -> 5' exonuclease activity. If a ribonucleotide is mis-incorporated, backtracks along the template DNA and cleaves the phosphodiester bond releasing the mis-incorporated 5'-ribonucleotide ; RNA-dependent RNA polymerase that catalyzes the extension of a non-coding RNA (ncRNA) at the 3'-end using the four ribonucleoside triphosphates as substrates. An internal ncRNA sequence near the 3'-end serves as a template in a single-round Pol II-mediated RNA polymerization reaction. May decrease the stability of ncRNAs that repress Pol II-mediated gene transcription.
KEGG Pathway
R. polymerase (hsa03020 )
Nucleotide excision repair (hsa03420 )
Huntington disease (hsa05016 )
Reactome Pathway
Formation of the Early Elongation Complex (R-HSA-113418 )
Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152 )
Formation of the HIV-1 Early Elongation Complex (R-HSA-167158 )
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160 )
HIV Transcription Initiation (R-HSA-167161 )
RNA Polymerase II HIV Promoter Escape (R-HSA-167162 )
Transcription of the HIV genome (R-HSA-167172 )
Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200 )
Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238 )
Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242 )
Tat-mediated HIV elongation arrest and recovery (R-HSA-167243 )
Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246 )
HIV elongation arrest and recovery (R-HSA-167287 )
Pausing and recovery of HIV elongation (R-HSA-167290 )
Viral Messenger RNA Synthesis (R-HSA-168325 )
MicroRNA (miRNA) biogenesis (R-HSA-203927 )
Transcriptional regulation by small RNAs (R-HSA-5578749 )
PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884 )
Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472 )
RNA Polymerase II Pre-transcription Events (R-HSA-674695 )
Formation of TC-NER Pre-Incision Complex (R-HSA-6781823 )
Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827 )
Dual incision in TC-NER (R-HSA-6782135 )
Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210 )
TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648 )
FGFR2 alternative splicing (R-HSA-6803529 )
RNA polymerase II transcribes snRNA genes (R-HSA-6807505 )
mRNA Capping (R-HSA-72086 )
mRNA Splicing - Major Pathway (R-HSA-72163 )
mRNA Splicing - Minor Pathway (R-HSA-72165 )
Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203 )
RNA Polymerase II Promoter Escape (R-HSA-73776 )
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening (R-HSA-73779 )
RNA Polymerase II Transcription Initiation (R-HSA-75953 )
RNA Polymerase II Transcription Elongation (R-HSA-75955 )
RNA Polymerase II Transcription Initiation And Promoter Clearance (R-HSA-76042 )
RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075 )
Signaling by FGFR2 IIIa TM (R-HSA-8851708 )
Estrogen-dependent gene expression (R-HSA-9018519 )
Inhibition of DNA recombination at telomere (R-HSA-9670095 )
Formation of RNA Pol II elongation complex (R-HSA-112382 )

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Colorectal carcinoma DIS5PYL0 Strong Biomarker [1]
Influenza DIS3PNU3 moderate Genetic Variation [2]
Keratitis DISMFOEI moderate Biomarker [3]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Estradiol DMUNTE3 Approved Estradiol increases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [4]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [5]
Testosterone DM7HUNW Approved Testosterone decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [6]
Fulvestrant DM0YZC6 Approved Fulvestrant decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [4]
Afimoxifene DMFORDT Phase 2 Afimoxifene decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [4]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [7]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [8]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of DNA-directed RNA polymerase II subunit RPB2 (POLR2B). [9]
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⏷ Show the Full List of 8 Drug(s)

References

1 Aberrant DNA Methylation: Implications in Racial Health Disparity.PLoS One. 2016 Apr 25;11(4):e0153125. doi: 10.1371/journal.pone.0153125. eCollection 2016.
2 Directed Evolution of an Influenza Reporter Virus To Restore Replication and Virulence and Enhance Noninvasive Bioluminescence Imaging in Mice.J Virol. 2018 Jul 31;92(16):e00593-18. doi: 10.1128/JVI.00593-18. Print 2018 Aug 15.
3 Phylogenetic diversity and microsphere array-based genotyping of human pathogenic Fusaria, including isolates from the multistate contact lens-associated U.S. keratitis outbreaks of 2005 and 2006.J Clin Microbiol. 2007 Jul;45(7):2235-48. doi: 10.1128/JCM.00533-07. Epub 2007 May 16.
4 Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
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 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.
7 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
8 RNA-binding proteins and heat-shock protein 90 are constituents of the cytoplasmic capping enzyme interactome. J Biol Chem. 2018 Oct 26;293(43):16596-16607. doi: 10.1074/jbc.RA118.004973. Epub 2018 Aug 30.
9 Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.