POLR2B

Summary

POLR2B (RNA polymerase II subunit B, HGNC:9188) is a protein-coding gene on chromosome 4q12, encoding DNA-directed RNA polymerase II subunit RPB2 (P30876). 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. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes the second largest subunit of RNA polymerase II (Pol II), a DNA-dependent RNA polymerase that catalyzes the transcription of DNA into precursors of mRNA, snRNA and microRNA. This subunit and the largest subunit form opposite sides of the center cleft of Pol II. Deletion of the flap loop region of this subunit results in a decrease in the rate of transcriptional elongation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5431 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 74 total — 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_000938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9188
Approved symbol	POLR2B
Name	RNA polymerase II subunit B
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	RPB2
Ensembl gene	ENSG00000047315
Ensembl biotype	protein_coding
OMIM	180661
Entrez	5431

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000314595, ENST00000381227, ENST00000431623, ENST00000433463, ENST00000441246, ENST00000450656, ENST00000464918, ENST00000478188, ENST00000484821, ENST00000495311, ENST00000497845, ENST00000510355

RefSeq mRNA: 3 — MANE Select: NM_000938 NM_000938, NM_001303268, NM_001303269

CCDS: CCDS3511, CCDS77915

Canonical transcript exons

ENST00000314595 — 25 exons

Exon	Start	End
ENSE00003461391	57023662	57023751
ENSE00003474432	57015502	57015656
ENSE00003498158	57023330	57023580
ENSE00003509568	57024886	57024999
ENSE00003514641	57030204	57030399
ENSE00003519187	57017560	57017728
ENSE00003521209	57010989	57011100
ENSE00003543135	57010748	57010887
ENSE00003552221	57022152	57022246
ENSE00003586875	57030899	57031158
ENSE00003609949	57010361	57010504
ENSE00003628603	57020899	57020995
ENSE00003640897	56986354	56986426
ENSE00003652818	57025377	57025537
ENSE00003687361	57017043	57017241
ENSE00003688949	57024005	57024112
ENSE00003888789	56994647	56994866
ENSE00003889960	56994404	56994516
ENSE00003890097	56990748	56990898
ENSE00003890719	57005246	57005442
ENSE00003893313	56978896	56979004
ENSE00003894148	57005600	57005719
ENSE00003894323	56999617	56999781
ENSE00003894797	57006816	57007002
ENSE00003894812	56995251	56995409

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 81.4441 / max 1148.3947, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47755	71.7418	1823
47754	7.3585	1690
47752	1.9689	1145
47753	0.3748	164

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	99.27	gold quality
germinal epithelium of ovary	UBERON:0001304	99.01	gold quality
endothelial cell	CL:0000115	98.90	gold quality
middle temporal gyrus	UBERON:0002771	98.88	gold quality
tibia	UBERON:0000979	98.86	gold quality
esophagus squamous epithelium	UBERON:0006920	98.57	gold quality
penis	UBERON:0000989	98.43	gold quality
gingival epithelium	UBERON:0001949	98.40	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.36	gold quality
parietal pleura	UBERON:0002400	98.35	gold quality
calcaneal tendon	UBERON:0003701	98.22	gold quality
urethra	UBERON:0000057	98.21	gold quality
tendon of biceps brachii	UBERON:0008188	98.17	gold quality
synovial joint	UBERON:0002217	98.15	gold quality
amniotic fluid	UBERON:0000173	98.12	gold quality
jejunum	UBERON:0002115	98.11	gold quality
visceral pleura	UBERON:0002401	98.11	gold quality
pleura	UBERON:0000977	98.10	gold quality
superior surface of tongue	UBERON:0007371	98.04	gold quality
tendon	UBERON:0000043	97.97	gold quality
gingiva	UBERON:0001828	97.96	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.94	gold quality
pylorus	UBERON:0001166	97.92	gold quality
cortical plate	UBERON:0005343	97.91	gold quality
seminal vesicle	UBERON:0000998	97.80	gold quality
jejunal mucosa	UBERON:0000399	97.78	gold quality
oral cavity	UBERON:0000167	97.69	gold quality
bronchial epithelial cell	CL:0002328	97.55	gold quality
skin of hip	UBERON:0001554	97.54	gold quality
ganglionic eminence	UBERON:0004023	97.54	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CLC
KLK3

Upstream regulators (CollecTRI, top): NR1H2, PAX1

miRNA regulators (miRDB)

12 targeting POLR2B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-3145-3P	98.85	69.07	2031

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• Human CRSP interacts with RNA polymerase II CTD and adopts a specific CTD-bound conformation (PMID:12050112)
• The highly conserved glutamic acid 791 of Rpb2 is involved in the binding of magnesium and is required for both for the polymerization and cleavage reactions. (PMID:15886393)
• the human Maf1 protein negatively regulates transcription by all three nuclear Pols, Pol I, Pol II and Pol III (PMID:17499043)
• By reducing transcriptional fidelity in terms of not only discrimination of incoming nucleotides but also recognition of templates, HDAg may facilitate the unusual RNA-dependent RNA synthesis by Pol II. (PMID:17584298)
• Studies indicate transcription of many genes, is regulated after the initiation step, by pausing of RNA polymerase II during elongation through the promoter-proximal region. (PMID:21081187)
• ARS2/SRRT: at the nexus of RNA polymerase II transcription, transcript maturation and quality control. (PMID:34060620)
• The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma. (PMID:37423037)
• M6A-methylated circPOLR2B forms an R-loop and regulates the biological behavior of glioma stem cells through positive feedback loops. (PMID:39090090)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr2b	ENSDARG00000098783
		ENSDARG00000104434
mus_musculus	Polr2b	ENSMUSG00000029250
rattus_norvegicus	Polr2b	ENSRNOG00000024779
drosophila_melanogaster	Polr2B	FBGN0262955
caenorhabditis_elegans		WBGENE00016140

Paralogs (2): POLR3B (ENSG00000013503), POLR1B (ENSG00000125630)

Protein

Protein identifiers

DNA-directed RNA polymerase II subunit RPB2 — P30876 (reviewed: P30876)

Alternative names: 3’-5’ exoribonuclease, 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

All UniProt accessions (5): C9J2Y9, C9J4M6, C9JMN3, P30876, C9JZW8

UniProt curated annotations — full annotation on UniProt →

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 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.

Subunit / interactions. Component of the RNA polymerase II (Pol II) core complex consisting of 12 subunits: a ten-subunit catalytic core composed of POLR2A/RPB1, POLR2B/RPB2, POLR2C/RPB3, POLR2I/RPB9, POLR2J/RPB11, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5 and a mobile stalk composed of two subunits POLR2D/RPB4 and POLR2G/RPB7, protruding from the core and functioning primarily in transcription initiation. Part of Pol II(G) complex, in which Pol II core associates with an additional subunit POLR2M; unlike conventional Pol II, Pol II(G) functions as a transcriptional repressor. Part of TBP-based Pol II pre-initiation complex (PIC), in which Pol II core assembles with general transcription factors and other specific initiation factors including GTF2E1, GTF2E2, GTF2F1, GTF2F2, TCEA1, ERCC2, ERCC3, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2A1, GTF2A2, GTF2B and TBP; this large multi-subunit PIC complex mediates DNA unwinding and targets Pol II core to the transcription start site where the first phosphodiester bond forms. Interacts with WDR82. Interacts with MEN1.

Subcellular location. Nucleus.

Activity regulation. Pol II enzymatic activities are inhibited by alpha-amanitin. 3’->5’ exonuclease activity is stimulated by TFIIS, whereas pyrophosphorolysis is enhanced by TFIIF.

Cofactor. Two Mg(2+) ions are coordinated by both the catalytic residues and the nucleic acid substrate to enhance substrate recognition and catalytic efficiency.

Similarity. Belongs to the RNA polymerase beta chain family.

RefSeq proteins (3): NP_000929, NP_001290197, NP_001290198 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007120	DNA-dir_RNAP_su2_dom	Domain
IPR007121	RNA_pol_bsu_CS	Conserved_site
IPR007641	RNA_pol_Rpb2_7	Domain
IPR007642	RNA_pol_Rpb2_2	Domain
IPR007644	RNA_pol_bsu_protrusion	Domain
IPR007645	RNA_pol_Rpb2_3	Domain
IPR007646	RNA_pol_Rpb2_4	Domain
IPR007647	RNA_pol_Rpb2_5	Domain
IPR014724	RNA_pol_RPB2_OB-fold	Homologous_superfamily
IPR015712	DNA-dir_RNA_pol_su2	Family
IPR037033	DNA-dir_RNAP_su2_hyb_sf	Homologous_superfamily
IPR037034	RNA_pol_Rpb2_2_sf	Homologous_superfamily

Pfam: PF00562, PF04560, PF04561, PF04563, PF04565, PF04566, PF04567

Catalyzed reactions (Rhea), 2 shown:

• RNA(n) + a ribonucleoside 5’-triphosphate = RNA(n+1) + diphosphate (RHEA:21248)
• a 3’-end ribonucleotidyl-ribonucleotide-RNA + H2O = a 3’-end ribonucleotide-RNA + a ribonucleoside 5’-phosphate + H(+) (RHEA:77763)

UniProt features (140 total): strand 61, helix 35, turn 27, binding site 13, modified residue 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
9EHZ	ELECTRON MICROSCOPY	2.6
8XSO	ELECTRON MICROSCOPY	2.7
8XRM	ELECTRON MICROSCOPY	3.13
9EI1	ELECTRON MICROSCOPY	3.2
9EI3	ELECTRON MICROSCOPY	3.2
8XRJ	ELECTRON MICROSCOPY	3.6
9EI4	ELECTRON MICROSCOPY	3.7
5IYB	ELECTRON MICROSCOPY	3.9
5IYC	ELECTRON MICROSCOPY	3.9
5IYD	ELECTRON MICROSCOPY	3.9
6DRD	ELECTRON MICROSCOPY	3.9
8XVS	ELECTRON MICROSCOPY	4.1
6XRE	ELECTRON MICROSCOPY	4.6
7LBM	ELECTRON MICROSCOPY	4.8
5IYA	ELECTRON MICROSCOPY	5.4
5IY9	ELECTRON MICROSCOPY	6.3
5IY6	ELECTRON MICROSCOPY	7.2
6O9L	ELECTRON MICROSCOPY	7.2
5IY8	ELECTRON MICROSCOPY	7.9
5IY7	ELECTRON MICROSCOPY	8.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30876-F1	90.01	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (13): 1085; 1119; 1122; 1137; 1140; 409; 456; 731; 792; 841; 890; 942 …

Post-translational modifications (2): 937, 1052

Function

Pathways and Gene Ontology

Reactome pathways

76 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-113418	Formation of the Early Elongation Complex
R-HSA-167152	Formation of HIV elongation complex in the absence of HIV Tat
R-HSA-167158	Formation of the HIV-1 Early Elongation Complex
R-HSA-167160	RNA Pol II CTD phosphorylation and interaction with CE during HIV infection
R-HSA-167161	HIV Transcription Initiation
R-HSA-167162	RNA Polymerase II HIV Promoter Escape
R-HSA-167172	Transcription of the HIV genome
R-HSA-167200	Formation of HIV-1 elongation complex containing HIV-1 Tat
R-HSA-167238	Pausing and recovery of Tat-mediated HIV elongation
R-HSA-167242	Abortive elongation of HIV-1 transcript in the absence of Tat
R-HSA-167243	Tat-mediated HIV elongation arrest and recovery
R-HSA-167246	Tat-mediated elongation of the HIV-1 transcript
R-HSA-167287	HIV elongation arrest and recovery
R-HSA-167290	Pausing and recovery of HIV elongation
R-HSA-168325	Viral Messenger RNA Synthesis
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5601884	PIWI-interacting RNA (piRNA) biogenesis
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6803529	FGFR2 alternative splicing
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-72086	mRNA Capping
R-HSA-72163	mRNA Splicing - Major Pathway

MSigDB gene sets: 191 (showing top): TGCGCANK_UNKNOWN, TTTGTAG_MIR520D, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, REACTOME_SIGNALING_BY_FGFR, MITSIADES_RESPONSE_TO_APLIDIN_DN, PUJANA_CHEK2_PCC_NETWORK, REACTOME_HIV_INFECTION, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, DER_IFN_BETA_RESPONSE_UP, KEGG_HUNTINGTONS_DISEASE, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, REACTOME_MRNA_SPLICING, SCHLOSSER_SERUM_RESPONSE_DN

GO Biological Process (3): transcription by RNA polymerase II (GO:0006366), RNA-templated transcription (GO:0001172), DNA-templated transcription (GO:0006351)

GO Molecular Function (13): DNA binding (GO:0003677), chromatin binding (GO:0003682), RNA binding (GO:0003723), DNA-directed RNA polymerase activity (GO:0003899), RNA-directed RNA polymerase activity (GO:0003968), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), ribonucleoside binding (GO:0032549), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), 5’-3’ RNA polymerase activity (GO:0034062), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II, core complex (GO:0005665), membrane (GO:0016020), DNA-directed RNA polymerase complex (GO:0000428), chromosome, telomeric region (GO:0000781)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Transcription of the HIV genome	8
HIV Transcription Elongation	3
Gene Silencing by RNA	3
RNA Polymerase II Transcription Elongation	2
Late Phase of HIV Life Cycle	1
Tat-mediated elongation of the HIV-1 transcript	1
Influenza Viral RNA Transcription and Replication	1
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA biosynthetic process	3
gene expression	2
nucleic acid binding	2
binding	2
5’-3’ RNA polymerase activity	2
catalytic activity	2
cellular anatomical structure	2
DNA-templated transcription	1
RNA-templated transcription	1
transition metal ion binding	1
nucleoside binding	1
transferase activity, transferring phosphorus-containing groups	1
RNA polymerase activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
RNA polymerase II, holoenzyme	1
nuclear DNA-directed RNA polymerase complex	1
RNA polymerase complex	1
chromosomal region	1

Protein interactions and networks

STRING

6382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR2B	POLR2A	P24928	999
POLR2B	POLR2C	P19387	998
POLR2B	POLR2G	P52433	991
POLR2B	POLR2E	P19388	991
POLR2B	POLR2F	P41584	988
POLR2B	POLR2I	P36954	978
POLR2B	POLR2L	P52436	976
POLR2B	POLR2J	P52435	970
POLR2B	POLR2D	O15514	963
POLR2B	POLR2K	P53803	939
POLR2B	TCEA1	P23193	878
POLR2B	SUPT5H	O00267	870
POLR2B	POLR2H	P52434	850
POLR2B	GTF2B	Q00403	830
POLR2B	SUPT4H1	P63272	814

IntAct

240 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
MED31	MED19	psi-mi:“MI:0914”(association)	0.840
MED7	MED19	psi-mi:“MI:0914”(association)	0.840
MED11	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2G	POLR2D	psi-mi:“MI:0914”(association)	0.840
POLR2J	POLR1C	psi-mi:“MI:0914”(association)	0.830
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
MED30	MED19	psi-mi:“MI:0914”(association)	0.790
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED14	MED19	psi-mi:“MI:0914”(association)	0.790
POLR2G	RECQL5	psi-mi:“MI:0914”(association)	0.730
RPRD1B	RECQL5	psi-mi:“MI:0914”(association)	0.730
POLR2D	MED19	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	psi-mi:“MI:0914”(association)	0.730
RPRD1B	POLR2D	psi-mi:“MI:0914”(association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
MED21	POLR2D	psi-mi:“MI:0914”(association)	0.730
MED28	MED7	psi-mi:“MI:0914”(association)	0.730
POLR2A	POLR2D	psi-mi:“MI:0914”(association)	0.730
POLR2C	POLR2D	psi-mi:“MI:0914”(association)	0.730
POLR2D	POLR2C	psi-mi:“MI:0914”(association)	0.730

BioGRID (606): POLR2B (Co-localization), POLR2B (Co-localization), POLR2B (Co-localization), ESR1 (Co-localization), SRC (Co-localization), PSMB9 (Co-localization), POLR2B (Co-localization), TCEB3 (Co-localization), POLR2B (Affinity Capture-MS), POLR2B (Affinity Capture-MS), POLR2B (Affinity Capture-MS), POLR2B (Reconstituted Complex), POLR2B (Affinity Capture-MS), POLR2B (Affinity Capture-MS), POLR2B (Affinity Capture-MS)

ESM2 similar proteins: A0AF63, A1SEK1, A5DHT2, A5PJW8, B3DTE2, B7GUG7, B8DEY8, B9DKV0, C1KYJ3, F4I366, F4KD38, O74633, P08266, P08518, P22138, P22276, P25167, P30876, P38420, P59470, Q02061, Q03587, Q04E85, Q10233, Q10578, Q27493, Q42877, Q49V52, Q4L3K3, Q54BM1, Q54J75, Q5HRL0, Q6FLD5, Q724F0, Q753Q4, Q75DS1, Q82Z40, Q8CFI7, Q8CQ84, Q8ETY8

Diamond homologs: A0LII4, A0M3Y9, A1BD23, A1KB34, A2BT61, A2C6S8, A2T324, A3PEX4, A3PGI9, A4WVL6, A5DHT2, A5FIJ3, A5PJW8, A6GYU0, A6U851, A6YGE0, A8G6Y6, A8Z5T3, A9NAL4, B0R8D5, B0R8D6, B3E163, B3QC00, B5EFP3, B8YB55, C3MAX2, F4KD38, O27123, O27124, O28392, P06272, P08266, P08518, P09844, P09845, P0CX03, P0CX04, P11513, P22276, P23579

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLR2B	“form complex”	“RNA Polymerase II”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FGFR2 mutant receptor activation	11	67.5×	6e-18
Signaling by FGFR2 IIIa TM	12	58.2×	3e-18
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	16	52.6×	7e-23
RNA Pol II CTD phosphorylation and interaction with CE	16	52.6×	7e-23
Abortive elongation of HIV-1 transcript in the absence of Tat	13	52.0×	8e-19
mRNA Capping	16	49.1×	3e-22
Pausing and recovery of Tat-mediated HIV elongation	14	41.6×	2e-18
Tat-mediated HIV elongation arrest and recovery	14	41.6×	2e-18

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	20	37.9×	6e-24
RNA polymerase II preinitiation complex assembly	20	34.2×	2e-23
positive regulation of transcription initiation by RNA polymerase II	20	34.2×	2e-23
transcription initiation at RNA polymerase II promoter	11	25.9×	8e-11
somatic stem cell population maintenance	10	15.6×	1e-07
transcription by RNA polymerase II	18	8.0×	3e-09
protein ubiquitination	19	5.0×	2e-06
protein phosphorylation	11	4.7×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

74 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	43
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
916568	NM_000938.3(POLR2B):c.2123C>T (p.Ala708Val)	Likely pathogenic

SpliceAI

3437 predictions. Top by Δscore:

Variant	Effect	Δscore
4:56978890:G:GT	donor_gain	1.0000
4:56986348:TTACA:T	acceptor_loss	1.0000
4:56986349:TACAG:T	acceptor_loss	1.0000
4:56986350:ACAGA:A	acceptor_loss	1.0000
4:56986351:CAGA:C	acceptor_loss	1.0000
4:56986352:A:AG	acceptor_gain	1.0000
4:56986352:A:C	acceptor_loss	1.0000
4:56986353:G:GA	acceptor_gain	1.0000
4:56986353:G:GC	acceptor_loss	1.0000
4:56986353:GAT:G	acceptor_gain	1.0000
4:56986353:GATAT:G	acceptor_gain	1.0000
4:56986422:ATCAG:A	donor_gain	1.0000
4:56986423:TCAG:T	donor_loss	1.0000
4:56986424:CAG:C	donor_loss	1.0000
4:56986425:AG:A	donor_loss	1.0000
4:56986426:GG:G	donor_loss	1.0000
4:56986427:GT:G	donor_loss	1.0000
4:56986428:T:G	donor_loss	1.0000
4:56990746:A:AG	acceptor_gain	1.0000
4:56990747:G:GG	acceptor_gain	1.0000
4:56994396:A:AG	acceptor_gain	1.0000
4:56994402:A:AG	acceptor_gain	1.0000
4:56994403:G:GA	acceptor_gain	1.0000
4:56994403:GC:G	acceptor_gain	1.0000
4:56994403:GCC:G	acceptor_gain	1.0000
4:56994403:GCCA:G	acceptor_gain	1.0000
4:56994403:GCCAC:G	acceptor_gain	1.0000
4:56994508:G:GT	donor_gain	1.0000
4:56994513:TCACG:T	donor_loss	1.0000
4:56994514:CACGT:C	donor_loss	1.0000

AlphaMissense

7769 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:56994489:C:A	P110H	1.000
4:56994498:C:A	A113D	1.000
4:56994501:G:C	R114T	1.000
4:56994502:A:C	R114S	1.000
4:56994502:A:T	R114S	1.000
4:56994507:G:T	R116M	1.000
4:56994513:T:C	L118P	1.000
4:56994661:T:C	L124P	1.000
4:56994738:G:A	G150R	1.000
4:56994738:G:C	G150R	1.000
4:56994739:G:A	G150E	1.000
4:56994748:C:A	P153Q	1.000
4:56994771:T:C	C161R	1.000
4:56994773:C:G	C161W	1.000
4:56994819:T:C	C177R	1.000
4:56994837:G:C	G183R	1.000
4:56994838:G:A	G183D	1.000
4:56994855:G:A	G189R	1.000
4:56994855:G:C	G189R	1.000
4:56994856:G:A	G189E	1.000
4:56994856:G:T	G189V	1.000
4:56995261:C:A	A196D	1.000
4:56999705:C:A	A275E	1.000
4:56999722:G:C	D281H	1.000
4:57005295:C:A	A317E	1.000
4:57005298:T:C	L318P	1.000
4:57005307:T:A	I321N	1.000
4:57005309:G:C	G322R	1.000
4:57005310:G:A	G322D	1.000
4:57005441:G:A	G366R	1.000

dbSNP variants (sampled 300 via entrez): RS1000009816 (4:57020284 G>A), RS10000395 (4:57008288 T>A,C,G), RS1000148356 (4:56978691 A>G), RS10002090 (4:56993426 T>C), RS1000212588 (4:56980165 A>G), RS10002269 (4:56993571 T>C), RS1000245610 (4:56985376 C>T), RS1000276015 (4:57017215 A>G), RS1000319724 (4:56985244 T>A), RS1000331638 (4:56980237 C>A), RS1000345407 (4:56998621 G>A), RS1000426401 (4:56991361 C>T), RS1000454733 (4:56978308 C>T), RS1000507423 (4:57020086 T>C), RS1000826029 (4:56989446 G>A)

Disease associations

OMIM: gene MIM:180661 | disease phenotypes: MIM:189960

GenCC curated gene-disease

Mondo (1): esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (1): Esophageal atresia (Orphanet:1199)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000817_43	Height	4.000000e-11
GCST001232_2	Age-related macular degeneration	2.000000e-08
GCST002702_46	Height	3.000000e-09
GCST002702_47	Height	2.000000e-08
GCST004721_18	Congenital heart disease (maternal effect)	8.000000e-06
GCST005196_116	Coronary artery disease	2.000000e-09
GCST005973_8	White blood cell count	1.000000e-08
GCST008522_70	Bitter alcoholic beverage consumption	2.000000e-06
GCST009391_1312	Metabolite levels	8.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0010519	pantothenic acid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066157 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.98	Kd	104	nM	MOLIBRESIB
6.82	IC50	150	nM	MOLIBRESIB
6.74	Kd	180.6	nM	CHEMBL5653589
6.74	ED50	180.6	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 9 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179147: Binding affinity against POLR2B (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.1040	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149033: Binding affinity to human POLR2B incubated for 45 mins by Kinobead based pull down assay	kd	0.1806	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	increases palmitoylation, decreases expression, decreases reaction, increases abundance	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
geldanamycin	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
afimoxifene	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzene	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Nickel	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652075	Binding	Binding affinity to human POLR2B incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair