Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHJQ1DZ)

• DOT Name: DNA-directed RNA polymerase II subunit RPB1 (POLR2A)
• Synonyms: RNA polymerase II subunit B1; EC 2.7.7.6; 3'-5' exoribonuclease; EC 3.1.13.-; DNA-directed RNA polymerase II subunit A; DNA-directed RNA polymerase III largest subunit; RNA-directed RNA polymerase II subunit RPB1; EC 2.7.7.48
• Gene Name: POLR2A
• Related Disease:
  Autism, susceptibility to, 15
  Melanoma
  Meningioma
  Acute myelogenous leukaemia
  Cardiac failure
  Cardiomyopathy
  Central nervous system neoplasm
  Colorectal carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  Gastric cancer
  Glioma
  Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities
  Onychomycosis
  Ovarian cancer
  Ovarian neoplasm
  Schizophrenia
  Stomach cancer
  Advanced cancer
  Influenza
  Neoplasm
  Triple negative breast cancer
  Non-small-cell lung cancer
  Castration-resistant prostate carcinoma
  Clear cell renal carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
• UniProt ID: RPB1_HUMAN
• PDB ID: 2GHQ ; 2GHT ; 2LTO ; 3D9K ; 3D9L ; 3D9M ; 3D9N ; 3D9O ; 3D9P ; 4JXT ; 5IY6 ; 5IY7 ; 5IY8 ; 5IY9 ; 5IYA ; 5IYB ; 5IYC ; 5IYD ; 5M3H ; 5M3J ; 6DRD ; 6F5P ; 6G0R ; 6IC8 ; 6IC9 ; 6O9L ; 6Q5Y ; 6XKB ; 6XRE ; 7EGB ; 7EGC ; 7LBM ; 7YCX ; 7Z1K ; 7Z42
• EC Number: 2.7.7.48; 2.7.7.6; 3.1.13.-
• Pfam ID: PF04997 ; PF00623 ; PF04983 ; PF05000 ; PF04998 ; PF04992 ; PF04990 ; PF05001
• Sequence:
  MHGGGPPSGDSACPLRTIKRVQFGVLSPDELKRMSVTEGGIKYPETTEGGRPKLGGLMDP
  RQGVIERTGRCQTCAGNMTECPGHFGHIELAKPVFHVGFLVKTMKVLRCVCFFCSKLLVD
  SNNPKIKDILAKSKGQPKKRLTHVYDLCKGKNICEGGEEMDNKFGVEQPEGDEDLTKEKG
  HGGCGRYQPRIRRSGLELYAEWKHVNEDSQEKKILLSPERVHEIFKRISDEECFVLGMEP
  RYARPEWMIVTVLPVPPLSVRPAVVMQGSARNQDDLTHKLADIVKINNQLRRNEQNGAAA
  HVIAEDVKLLQFHVATMVDNELPGLPRAMQKSGRPLKSLKQRLKGKEGRVRGNLMGKRVD
  FSARTVITPDPNLSIDQVGVPRSIAANMTFAEIVTPFNIDRLQELVRRGNSQYPGAKYII
  RDNGDRIDLRFHPKPSDLHLQTGYKVERHMCDGDIVIFNRQPTLHKMSMMGHRVRILPWS
  TFRLNLSVTTPYNADFDGDEMNLHLPQSLETRAEIQELAMVPRMIVTPQSNRPVMGIVQD
  TLTAVRKFTKRDVFLERGEVMNLLMFLSTWDGKVPQPAILKPRPLWTGKQIFSLIIPGHI
  NCIRTHSTHPDDEDSGPYKHISPGDTKVVVENGELIMGILCKKSLGTSAGSLVHISYLEM
  GHDITRLFYSNIQTVINNWLLIEGHTIGIGDSIADSKTYQDIQNTIKKAKQDVIEVIEKA
  HNNELEPTPGNTLRQTFENQVNRILNDARDKTGSSAQKSLSEYNNFKSMVVSGAKGSKIN
  ISQVIAVVGQQNVEGKRIPFGFKHRTLPHFIKDDYGPESRGFVENSYLAGLTPTEFFFHA
  MGGREGLIDTAVKTAETGYIQRRLIKSMESVMVKYDATVRNSINQVVQLRYGEDGLAGES
  VEFQNLATLKPSNKAFEKKFRFDYTNERALRRTLQEDLVKDVLSNAHIQNELEREFERMR
  EDREVLRVIFPTGDSKVVLPCNLLRMIWNAQKIFHINPRLPSDLHPIKVVEGVKELSKKL
  VIVNGDDPLSRQAQENATLLFNIHLRSTLCSRRMAEEFRLSGEAFDWLLGEIESKFNQAI
  AHPGEMVGALAAQSLGEPATQMTLNTFHYAGVSAKNVTLGVPRLKELINISKKPKTPSLT
  VFLLGQSARDAERAKDILCRLEHTTLRKVTANTAIYYDPNPQSTVVAEDQEWVNVYYEMP
  DFDVARISPWLLRVELDRKHMTDRKLTMEQIAEKINAGFGDDLNCIFNDDNAEKLVLRIR
  IMNSDENKMQEEEEVVDKMDDDVFLRCIESNMLTDMTLQGIEQISKVYMHLPQTDNKKKI
  IITEDGEFKALQEWILETDGVSLMRVLSEKDVDPVRTTSNDIVEIFTVLGIEAVRKALER
  ELYHVISFDGSYVNYRHLALLCDTMTCRGHLMAITRHGVNRQDTGPLMKCSFEETVDVLM
  EAAAHGESDPMKGVSENIMLGQLAPAGTGCFDLLLDAEKCKYGMEIPTNIPGLGAAGPTG
  MFFGSAPSPMGGISPAMTPWNQGATPAYGAWSPSVGSGMTPGAAGFSPSAASDASGFSPG
  YSPAWSPTPGSPGSPGPSSPYIPSPGGAMSPSYSPTSPAYEPRSPGGYTPQSPSYSPTSP
  SYSPTSPSYSPTSPNYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSP
  TSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPSYSPTSPS
  YSPTSPNYSPTSPNYTPTSPSYSPTSPSYSPTSPNYTPTSPNYSPTSPSYSPTSPSYSPT
  SPSYSPSSPRYTPQSPTYTPSSPSYSPSSPSYSPASPKYTPTSPSYSPSSPEYTPTSPKY
  SPTSPKYSPTSPKYSPTSPTYSPTTPKYSPTSPTYSPTSPVYTPTSPKYSPTSPTYSPTS
  PKYSPTSPTYSPTSPKGSTYSPTSPGYSPTSPTYSLTSPAISPDDSDEEN
• 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 second largest subunit POLR2B/RPB2. 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 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. Through its unique C-terminal domain (CTD, 52 heptapeptide tandem repeats) serves as a platform for assembly of factors that regulate transcription initiation, elongation and termination. CTD phosphorylation on Ser-5 mediates Pol II promoter escape, whereas phosphorylation on Ser-2 is required for Pol II pause release during transcription elongation and further pre-mRNA processing. Additionally, the regulation of gene expression levels depends on the balance between methylation and acetylation levels of the CTD-lysines. Initiation or early elongation steps of transcription of growth-factor-induced immediate early genes are regulated by the acetylation status of the CTD. Methylation and dimethylation have a repressive effect on target genes expression. Cooperates with mRNA splicing machinery in co-transcriptional 5'-end capping and co-transcriptional splicing of pre-mRNA ; 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; (Microbial infection) Acts as an RNA-dependent RNA polymerase when associated with small delta antigen of Hepatitis delta virus, acting both as a replicase and transcriptase for the viral RNA circular genome.
• 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

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism, susceptibility to, 15	DISYCG6A	Definitive	Autosomal dominant	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Meningioma	DISPT4TG	Definitive	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[5]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[5]
Central nervous system neoplasm	DISFC18W	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[9]
Glioma	DIS5RPEH	Strong	Genetic Variation	[6]
Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities	DISDLBTL	Strong	Autosomal dominant	[10]
Onychomycosis	DISE4C4D	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Influenza	DIS3PNU3	moderate	Biomarker	[14]
Neoplasm	DISZKGEW	moderate	Altered Expression	[4]
Triple negative breast cancer	DISAMG6N	moderate	Biomarker	[15]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[16]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Genetic Variation	[17]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[18]
Prostate cancer	DISF190Y	Limited	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[19]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[27]
Selenium	DM25CGV	Approved	Selenium increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[28]
Aspirin	DM672AH	Approved	Aspirin increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[30]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[31]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[34]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[36]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[38]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[40]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[43]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[23]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[29]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[32]
Deferasirox	DM6ETS0	Approved	Deferasirox decreases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[23]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[32]
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole	DM3JB6S	Investigative	5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole decreases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[45]
H-8	DM80QF9	Investigative	H-8 decreases the phosphorylation of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[32]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of DNA-directed RNA polymerase II subunit RPB1 (POLR2A).	[35]

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