POLR2E

Summary

POLR2E (RNA polymerase II, I and III subunit E, HGNC:9192) is a protein-coding gene on chromosome 19p13.3, encoding DNA-directed RNA polymerases I, II, and III subunit RPABC1 (P19388). DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene encodes the fifth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This subunit is shared by the other two DNA-directed RNA polymerases and is present in two-fold molar excess over the other polymerase subunits. An interaction between this subunit and a hepatitis virus transactivating protein has been demonstrated, suggesting that interaction between transcriptional activators and the polymerase can occur through this subunit. A pseudogene is located on chromosome 11. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 5434 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 49 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_002695

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9192
Approved symbol	POLR2E
Name	RNA polymerase II, I and III subunit E
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	RPB5, RPABC1, XAP4, hRPB25, hsRPB5
Ensembl gene	ENSG00000099817
Ensembl biotype	protein_coding
OMIM	180664
Entrez	5434

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 33 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000215587, ENST00000585838, ENST00000586215, ENST00000586746, ENST00000586817, ENST00000589737, ENST00000590060, ENST00000591709, ENST00000591767, ENST00000592597, ENST00000612655, ENST00000614705, ENST00000615234, ENST00000619917, ENST00000885895, ENST00000885896, ENST00000885897, ENST00000885898, ENST00000885899, ENST00000885900, ENST00000885901, ENST00000885902, ENST00000885903, ENST00000885904, ENST00000885905, ENST00000885906, ENST00000885907, ENST00000885908, ENST00000885909, ENST00000885910, ENST00000885911, ENST00000885912, ENST00000885913, ENST00000885914, ENST00000885915, ENST00000885916, ENST00000885917, ENST00000938006, ENST00000938007, ENST00000938008, ENST00000964410, ENST00000964411

RefSeq mRNA: 3 — MANE Select: NM_002695 NM_001316323, NM_001316324, NM_002695

CCDS: CCDS12056

Canonical transcript exons

ENST00000615234 — 8 exons

Exon	Start	End
ENSE00000892420	1095259	1095375
ENSE00003548029	1090087	1090145
ENSE00003551695	1089884	1089962
ENSE00003577440	1093904	1094078
ENSE00003611295	1089472	1089551
ENSE00003645660	1091792	1091907
ENSE00003667407	1090908	1090988
ENSE00003719629	1086574	1088720

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.4092 / max 214.4538, expressed in 1819 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177966	55.3028	1819
177962	0.0948	17
177963	0.0116	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.32	gold quality
right lobe of liver	UBERON:0001114	98.19	gold quality
prefrontal cortex	UBERON:0000451	98.17	gold quality
right frontal lobe	UBERON:0002810	98.08	gold quality
lower esophagus	UBERON:0013473	97.97	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.97	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.89	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.81	gold quality
right adrenal gland	UBERON:0001233	97.78	gold quality
popliteal artery	UBERON:0002250	97.78	gold quality
adipose tissue of abdominal region	UBERON:0007808	97.78	gold quality
tibial artery	UBERON:0007610	97.77	gold quality
omental fat pad	UBERON:0010414	97.77	gold quality
left coronary artery	UBERON:0001626	97.76	gold quality
coronary artery	UBERON:0001621	97.73	gold quality
peritoneum	UBERON:0002358	97.73	gold quality
right coronary artery	UBERON:0001625	97.70	gold quality
left adrenal gland cortex	UBERON:0035825	97.70	gold quality
right uterine tube	UBERON:0001302	97.66	gold quality
ventricular zone	UBERON:0003053	97.66	gold quality
left adrenal gland	UBERON:0001234	97.65	gold quality
cingulate cortex	UBERON:0003027	97.65	gold quality
apex of heart	UBERON:0002098	97.64	gold quality
esophagus	UBERON:0001043	97.60	gold quality
lower esophagus mucosa	UBERON:0035834	97.60	gold quality
anterior cingulate cortex	UBERON:0009835	97.59	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.58	gold quality
right adrenal gland cortex	UBERON:0035827	97.58	gold quality
gastrocnemius	UBERON:0001388	97.57	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	21.83
E-MTAB-8911	no	192.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting POLR2E, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-7974	99.24	65.48	1137
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-939-3P	98.97	65.07	2347

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• Results pinpoint critical residues for RNA polymerase II subunit 5 binding to RAP30 and/or to HBx, and identify these residues in both mammalian cells and in an in vitro binding assay. (PMID:16169872)
• Is part of an RNA polymerase II-associated complex with possible chaperone activity. (PMID:19450687)
• RPB5-mediating protein is required for the proliferation of hepatocellular carcinoma cells. (PMID:21310960)
• crystal of RPB5 diffracted to 2.8 A resolution and belonged to space group P4(3)2(1)2. (PMID:22102239)
• ELL has an early and essential role during rapid high-amplitude gene expression that is required for both Pol II pause site entry and release (PMID:22252557)
• POLR2E rs3787016 C/T and HULC rs7763881 were associated with a significantly decreased risk for ESCC 0.005). ANRIL rs2151280 T/C SNP was not associated with risk of ESCC. (PMID:25874495)
• POLR2E rs3787016T allele was associated with an increased cancer risk in Chinese population (PMID:29724531)
• we here conducted a case-control study to investigate the association of POLR2E rs3787016 polymorphism with risk of liver and lung cancer..Although no significant association was found for rs3787016 with risk of liver or lung cancer, the further stratified analysis identified that rs3787016 contributed to liver cancer risk particularly for over than 60 years individuals who drink (PMID:30291213)
• rs3787016 T/rs1046040 C significantly increased the risk of prostate cancer compared to C/C (p = 0.037 (PMID:30587086)
• Our results indicated that the rs3787016 polymorphism in polymerase II polypeptide E was associated with the risk of both breast cancer and cervical cancer (PMID:30846411)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr2eb	ENSDARG00000026183
danio_rerio	POLR2E	ENSDARG00000074274
mus_musculus	Polr2e	ENSMUSG00000004667
rattus_norvegicus	Polr2e	ENSRNOG00000013545
drosophila_melanogaster	Polr2E	FBGN0033571
caenorhabditis_elegans	rpb-5	WBGENE00019246

Protein

Protein identifiers

DNA-directed RNA polymerases I, II, and III subunit RPABC1 — P19388 (reviewed: P19388)

Alternative names: DNA-directed RNA polymerase II 23 kDa polypeptide, DNA-directed RNA polymerase II subunit E, RPB5 homolog, XAP4

All UniProt accessions (8): P19388, A0A087WVN5, A0A087WVZ9, A0A087WWX0, A0A0A0MQR7, E5KT65, K7EJ87, K7EQN2

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPABC1 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template.

Subunit / interactions. Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively. Pol I complex consists of a ten-subunit catalytic core composed of POLR1A/RPA1, POLR1B/RPA2, POLR1C/RPAC1, POLR1D/RPAC2, POLR1H/RPA12, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk subunit POLR1F/RPA43 protruding from the core and additional subunits homologous to general transcription factors POLR1E/RPA49 and POLR1G/RPA34. Part of Pol I pre-initiation complex (PIC), in which Pol I core assembles with RRN3 and promoter-bound UTBF and SL1/TIF-IB complex. Pol II complex contains 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. 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. In Pol II complex, this subunit is present in 2-fold molar excess over the other subunits. Pol III complex consists of a ten-subunit catalytic core composed of POLR3A/RPC1, POLR3B/RPC2, POLR1C/RPAC1, POLR1D/RPAC2, POLR3K/RPC10, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk composed of two subunits POLR3H/RPC8 and CRCP/RPC9, protruding from the core and functioning primarily in transcription initiation; and additional subunits homologous to general transcription factors of the RNA polymerase II machinery, POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer required for transcription initiation and POLR3D/RPC4-POLR3E/RPC5 heterodimer involved in both transcription initiation and termination. Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92. Interacts with URI1. (Microbial infection) Interacts with HBV protein X.

Subcellular location. Nucleus. Nucleolus.

Similarity. Belongs to the archaeal Rpo5/eukaryotic RPB5 RNA polymerase subunit family.

RefSeq proteins (3): NP_001303252, NP_001303253, NP_002686* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000783	RNA_pol_subH/Rpb5_C	Domain
IPR005571	RNA_pol_Rpb5_N	Domain
IPR014381	Arch_Rpo5/euc_Rpb5	Family
IPR020608	RNA_pol_subH/Rpb5_CS	Conserved_site
IPR035913	RPB5-like_sf	Homologous_superfamily
IPR036710	RNA_pol_Rpb5_N_sf	Homologous_superfamily

Pfam: PF01191, PF03871

UniProt features (34 total): strand 15, helix 10, sequence conflict 4, chain 1, modified residue 1, turn 1, cross-link 1, sequence variant 1

Structure

Experimental structures (PDB)

57 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9EHZ	ELECTRON MICROSCOPY	2.6
7OB9	ELECTRON MICROSCOPY	2.7
8XSO	ELECTRON MICROSCOPY	2.7
7AE1	ELECTRON MICROSCOPY	2.8
9K39	ELECTRON MICROSCOPY	2.8
7VBB	ELECTRON MICROSCOPY	2.81
7VBA	ELECTRON MICROSCOPY	2.89
7D58	ELECTRON MICROSCOPY	2.9
9K36	ELECTRON MICROSCOPY	2.9
9K2G	ELECTRON MICROSCOPY	3
9K3U	ELECTRON MICROSCOPY	3
7VBC	ELECTRON MICROSCOPY	3.01
7AE3	ELECTRON MICROSCOPY	3.1
7D59	ELECTRON MICROSCOPY	3.1
7OBA	ELECTRON MICROSCOPY	3.1
9K38	ELECTRON MICROSCOPY	3.1
8XRM	ELECTRON MICROSCOPY	3.13
9EI1	ELECTRON MICROSCOPY	3.2
9EI3	ELECTRON MICROSCOPY	3.2
9FSO	ELECTRON MICROSCOPY	3.28
7A6H	ELECTRON MICROSCOPY	3.3
7OBB	ELECTRON MICROSCOPY	3.3
9LXN	ELECTRON MICROSCOPY	3.3
7DU2	ELECTRON MICROSCOPY	3.35
9FSP	ELECTRON MICROSCOPY	3.39
7AEA	ELECTRON MICROSCOPY	3.4
8IUH	ELECTRON MICROSCOPY	3.4
7DN3	ELECTRON MICROSCOPY	3.5
9K3V	ELECTRON MICROSCOPY	3.5
9LKT	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19388-F1	93.18	0.89

Functional residue map

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

Post-translational modifications (2): 1, 81

Function

Pathways and Gene Ontology

Reactome pathways

97 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-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
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

MSigDB gene sets: 228 (showing top): REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, REACTOME_SIGNALING_BY_FGFR, REACTOME_RNA_POLYMERASE_I_TRANSCRIPTION_INITIATION, GOBP_TRNA_METABOLIC_PROCESS, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, GOBP_RRNA_TRANSCRIPTION, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, RICKMAN_METASTASIS_DN, REACTOME_HIV_INFECTION, REACTOME_MRNA_3_END_PROCESSING

GO Biological Process (5): transcription elongation by RNA polymerase I (GO:0006362), transcription by RNA polymerase II (GO:0006366), tRNA transcription by RNA polymerase III (GO:0042797), protein stabilization (GO:0050821), DNA-templated transcription (GO:0006351)

GO Molecular Function (3): DNA binding (GO:0003677), DNA-directed RNA polymerase activity (GO:0003899), protein binding (GO:0005515)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II, core complex (GO:0005665), RNA polymerase III complex (GO:0005666), RNA polymerase I complex (GO:0005736), cytosol (GO:0005829), RPAP3/R2TP/prefoldin-like complex (GO:1990062), DNA-directed RNA polymerase complex (GO:0000428), nucleolus (GO:0005730)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Transcription of the HIV genome	8
HIV Transcription Elongation	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
Innate Immune System	1
Gene Silencing by RNA	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA biosynthetic process	2
nuclear lumen	2
cellular anatomical structure	2
DNA-directed RNA polymerase complex	2
nuclear protein-containing complex	2
DNA-templated transcription elongation	1
transcription by RNA polymerase I	1
DNA-templated transcription	1
transcription by RNA polymerase III	1
tRNA transcription	1
regulation of protein stability	1
gene expression	1
nucleic acid binding	1
5’-3’ RNA polymerase activity	1
binding	1
intracellular membrane-bounded organelle	1
RNA polymerase II, holoenzyme	1
nuclear DNA-directed RNA polymerase complex	1
nucleolus	1
cytoplasm	1
protein-containing complex	1
RNA polymerase complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4173 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR2E	POLR2F	P41584	998
POLR2E	URI1	O94763	997
POLR2E	POLR2H	P52434	996
POLR2E	POLR2A	P24928	995
POLR2E	POLR2L	P52436	993
POLR2E	PFDN2	Q9UHV9	993
POLR2E	POLR2B	P30876	991
POLR2E	POLR2G	P52433	989
POLR2E	POLR2I	P36954	985
POLR2E	DNAAF10	Q96MX6	984
POLR2E	POLR2C	P19387	983
POLR2E	POLR2K	P53803	979
POLR2E	PFDN6	O15212	955
POLR2E	PDRG1	Q9NUG6	950
POLR2E	POLR2D	O15514	933

IntAct

298 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
POLR2E	POLR3A	psi-mi:“MI:0914”(association)	0.870
POLR2E	POLR3A	psi-mi:“MI:0915”(physical association)	0.870
MED18	MED19	psi-mi:“MI:0914”(association)	0.840
MED31	MED19	psi-mi:“MI:0914”(association)	0.840
MED11	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2E	POLR2D	psi-mi:“MI:0915”(physical association)	0.790
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
MED14	MED19	psi-mi:“MI:0914”(association)	0.790
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
GTF2B	POLR2E	psi-mi:“MI:0915”(physical association)	0.740
RPRD1B	RECQL5	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	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
MED18	MED7	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 (603): POLR2E (Co-localization), POLR2E (Co-localization), POLR2E (Co-localization), ESR1 (Co-localization), SRC (Co-localization), PSMB9 (Co-localization), POLR2E (Co-localization), TCEB3 (Co-localization), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS), POLR2E (Affinity Capture-MS)

ESM2 similar proteins: A1DH48, A6RRW0, A8PB32, A8XFM8, A8XGH1, B0BNE2, B3MK91, B4JQM7, B4KKD5, B4LS49, C5DWG7, D0NKK0, O44952, P19388, P20434, P30182, P36776, P48612, P50444, P52874, P93655, Q07803, Q08BB1, Q09191, Q09817, Q0V3J4, Q2T9T3, Q2U3T4, Q54EH2, Q59HJ6, Q5R587, Q5U567, Q6BIJ0, Q6C255, Q6CA26, Q6CJ62, Q6FQA6, Q74ZG2, Q757H7, Q7ZWC4

Diamond homologs: A0B555, A1RWW7, A2BN32, A2SSM7, A3DMP2, A4FWF9, A4YCQ7, A6UV53, A6VGU6, A8XGH1, A9A458, A9A9V3, B0BNE2, B0R8D7, B6YT14, B8YB60, C3MRK1, C3MY97, C3MZM6, C3N7P8, C3NFS5, C4KIV6, C5A210, C6A1F8, O27122, O28394, O74019, O81098, P0CX06, P11521, P19388, P20434, P31815, P41559, P61519, Q03588, Q09191, Q12WS3, Q2NEK1, Q2T9T3

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
POLR2E	“form complex”	“RNA Polymerase III”	binding
POLR2E	“form complex”	“RNA Polymerase II”	binding
POLR2E	“form complex”	“PAQosome co-chaperone complex”	binding
GTF2F2	“up-regulates activity”	POLR2E	binding
POLR2E	“form complex”	“RNA Polymerase I”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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	6	38.7×	6e-08
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	11	38.0×	1e-13
RNA Pol II CTD phosphorylation and interaction with CE	11	38.0×	1e-13
Signaling by FGFR2 IIIa TM	7	35.7×	9e-09
mRNA Capping	11	35.5×	3e-13
Abortive elongation of HIV-1 transcript in the absence of Tat	8	33.7×	1e-09
RNA Polymerase III Chain Elongation	6	32.3×	2e-07
Maturation of hRSV A proteins	5	32.3×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription elongation by RNA polymerase II	18	39.8×	5e-22
RNA polymerase II preinitiation complex assembly	19	38.0×	1e-22
positive regulation of transcription initiation by RNA polymerase II	16	32.0×	8e-18
transcription initiation at RNA polymerase II promoter	9	24.8×	2e-08
somatic stem cell population maintenance	9	16.4×	7e-07
protein stabilization	14	6.9×	3e-06
transcription by RNA polymerase II	12	6.2×	7e-05
protein ubiquitination	14	4.3×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
599581	NM_002695.5(POLR2E):c.233-2A>G	Pathogenic

SpliceAI

1315 predictions. Top by Δscore:

Variant	Effect	Δscore
19:1085656:TTAG:T	acceptor_loss	1.0000
19:1085657:TAG:T	acceptor_loss	1.0000
19:1085658:A:AG	acceptor_gain	1.0000
19:1085658:AG:A	acceptor_loss	1.0000
19:1085659:G:GA	acceptor_gain	1.0000
19:1085659:GA:G	acceptor_gain	1.0000
19:1089548:CCAC:C	acceptor_gain	1.0000
19:1089549:CAC:C	acceptor_gain	1.0000
19:1089549:CACC:C	acceptor_gain	1.0000
19:1089550:ACC:A	acceptor_loss	1.0000
19:1089551:CCTGC:C	acceptor_loss	1.0000
19:1089552:C:CC	acceptor_gain	1.0000
19:1089552:CTGCA:C	acceptor_loss	1.0000
19:1090903:CCCA:C	donor_loss	1.0000
19:1090904:CCAC:C	donor_loss	1.0000
19:1090905:CA:C	donor_loss	1.0000
19:1090906:A:AT	donor_loss	1.0000
19:1090907:C:A	donor_loss	1.0000
19:1090984:AGGGA:A	acceptor_gain	1.0000
19:1090985:GGGA:G	acceptor_gain	1.0000
19:1090986:GGA:G	acceptor_gain	1.0000
19:1090987:GA:G	acceptor_gain	1.0000
19:1090987:GAC:G	acceptor_loss	1.0000
19:1090988:ACTGG:A	acceptor_loss	1.0000
19:1090989:C:A	acceptor_loss	1.0000
19:1090989:C:CC	acceptor_gain	1.0000
19:1090990:T:G	acceptor_loss	1.0000
19:1091787:CCCA:C	donor_loss	1.0000
19:1091788:CCAC:C	donor_loss	1.0000
19:1091789:CACCT:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000018092 (19:1086523 G>A), RS1000068220 (19:1089139 G>A,C), RS1000079166 (19:1088972 C>T), RS1000276483 (19:1095603 T>C), RS1000299192 (19:1092269 C>G,T), RS1000540815 (19:1088879 C>A), RS1000630725 (19:1094634 C>T), RS1000635686 (19:1088770 C>T), RS1000748926 (19:1091985 G>A,C), RS1001267275 (19:1086112 G>A,C), RS1001625714 (19:1092216 G>A,T), RS1001727942 (19:1095903 C>T), RS1001970232 (19:1092377 G>A,C), RS1002015077 (19:1086197 A>G), RS1002088548 (19:1089061 G>A)

Disease associations

OMIM: gene MIM:180664 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005312_41	Menopause (age at onset)	2.000000e-10
GCST006135_14	Cortical amyloid beta load	7.000000e-06
GCST006135_9	Cortical amyloid beta load	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007707	cerebral amyloid deposition measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066322 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.25	Kd	5.612	nM	CHEMBL5653589
8.25	ED50	5.612	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149034: Binding affinity to human POLR2E incubated for 45 mins by Kinobead based pull down assay	kd	0.0056	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects expression	4
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	4
Cyclosporine	decreases expression	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
1-nitropyrene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	decreases expression	1
nickel acetate	affects expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
MT19c compound	decreases expression	1
bisphenol AF	increases expression	1
Oxaliplatin	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases expression	1
Carmustine	decreases expression	1
Coumestrol	increases expression	1
Ivermectin	decreases expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652076	Binding	Binding affinity to human POLR2E 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)

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