SUPT5H

Summary

SUPT5H (SPT5 homolog, DSIF elongation factor subunit, HGNC:11469) is a protein-coding gene on chromosome 19q13.2, encoding Transcription elongation factor SPT5 (O00267). Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

Enables enzyme binding activity and protein heterodimerization activity. Involved in positive regulation of macroautophagy; regulation of DNA-templated transcription; and transcription elongation by RNA polymerase II. Located in nucleoplasm. Part of DSIF complex.

Source: NCBI Gene 6829 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 154 total
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_001111020

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11469
Approved symbol	SUPT5H
Name	SPT5 homolog, DSIF elongation factor subunit
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	SPT5H, SPT5, FLJ34157
Ensembl gene	ENSG00000196235
Ensembl biotype	protein_coding
OMIM	602102
Entrez	6829

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 12 protein_coding, 10 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000359191, ENST00000396843, ENST00000402194, ENST00000432763, ENST00000593727, ENST00000594729, ENST00000594990, ENST00000595368, ENST00000596208, ENST00000598117, ENST00000598459, ENST00000598520, ENST00000598725, ENST00000598786, ENST00000599117, ENST00000599335, ENST00000599907, ENST00000600818, ENST00000601515, ENST00000601978, ENST00000917285, ENST00000946279, ENST00000946280

RefSeq mRNA: 6 — MANE Select: NM_001111020 NM_001111020, NM_001130824, NM_001130825, NM_001319990, NM_001319991, NM_003169

CCDS: CCDS12536, CCDS46072

Canonical transcript exons

ENST00000432763 — 30 exons

Exon	Start	End
ENSE00003007874	39445582	39445637
ENSE00003466723	39472409	39472493
ENSE00003472163	39445804	39445965
ENSE00003488484	39470119	39470274
ENSE00003489200	39473416	39473521
ENSE00003552399	39459892	39459960
ENSE00003564437	39458294	39458305
ENSE00003566810	39473012	39473114
ENSE00003589146	39473203	39473330
ENSE00003591267	39469262	39469398
ENSE00003597857	39471357	39471503
ENSE00003600674	39470377	39470523
ENSE00003601967	39474234	39474402
ENSE00003602950	39459184	39459249
ENSE00003613205	39453356	39453521
ENSE00003619000	39476256	39476670
ENSE00003620405	39458818	39458887
ENSE00003632892	39459559	39459589
ENSE00003636630	39472810	39472929
ENSE00003641048	39471605	39471730
ENSE00003644783	39469079	39469172
ENSE00003689318	39473963	39474121
ENSE00003694460	39459005	39459073
ENSE00003784307	39457675	39457740
ENSE00003888767	39474515	39474718
ENSE00003890190	39476081	39476176
ENSE00003890391	39464798	39465049
ENSE00003891724	39466675	39466745
ENSE00003892917	39468756	39468861
ENSE00003893828	39466480	39466569

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 88.4628 / max 1248.3055, expressed in 1828 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175772	67.4786	1827
175773	13.8777	1778
175771	4.0043	1520
175774	1.1366	609
175769	0.9336	526
175770	0.7362	384
175775	0.2959	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.03	gold quality
right testis	UBERON:0004534	99.03	gold quality
adenohypophysis	UBERON:0002196	98.97	gold quality
sural nerve	UBERON:0015488	98.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.35	gold quality
right lobe of thyroid gland	UBERON:0001119	98.23	gold quality
cerebellar hemisphere	UBERON:0002245	98.23	gold quality
cerebellar cortex	UBERON:0002129	98.16	gold quality
right uterine tube	UBERON:0001302	98.14	gold quality
left lobe of thyroid gland	UBERON:0001120	98.04	gold quality
pituitary gland	UBERON:0000007	97.85	gold quality
apex of heart	UBERON:0002098	97.75	gold quality
metanephros cortex	UBERON:0010533	97.70	gold quality
testis	UBERON:0000473	97.60	gold quality
right frontal lobe	UBERON:0002810	97.56	gold quality
left ovary	UBERON:0002119	97.52	gold quality
mucosa of transverse colon	UBERON:0004991	97.43	gold quality
right lobe of liver	UBERON:0001114	97.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.38	gold quality
right ovary	UBERON:0002118	97.37	gold quality
body of pancreas	UBERON:0001150	97.30	gold quality
endocervix	UBERON:0000458	97.25	gold quality
thyroid gland	UBERON:0002046	97.24	gold quality
body of stomach	UBERON:0001161	97.22	gold quality
right adrenal gland	UBERON:0001233	97.20	gold quality
mucosa of stomach	UBERON:0001199	97.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.18	gold quality
right adrenal gland cortex	UBERON:0035827	97.17	gold quality
body of uterus	UBERON:0009853	97.13	gold quality
tibial nerve	UBERON:0001323	97.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	11.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ANKRD37

miRNA regulators (miRDB)

23 targeting SUPT5H, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4662B	98.33	66.37	1163
HSA-MIR-4647	98.30	66.41	1139

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 31)

• phosphorylation by cdk9; binds pin1 protein after phosphorylation (PMID:11575923)
• phosphorylated by P-TEFb kinase during HIV-1 transcription in Tat/TAR dependent manner (PMID:15564463)
• hSpt5 function in transcription regulation and mRNA capping is essential for a subset of cellular and viral genes and may not be required for global gene expression. (PMID:15620346)
• evolutionarily conserved repetitive heptapeptide motif (consensus = G-S-R/Q-T-P) in the C-terminal region of hSpt5, like the C-terminal domain of RNA Pol II, is highly phosphorylated by P-TEFb (PMID:16427012)
• Upon induction of NF-kappaB, a subset of target genes is regulated differentially by either P-TEFb or DSIF.[P-TEFb, DSIF] (PMID:17502349)
• These findings reveal a dynamic regulation of DSIF involving either E-box or NF-kappaB depending on the physiological circumstances. (PMID:17962196)
• These results suggest that one of the functions of Spt5 is to suppress senescence and apoptosis, and that this function is exerted through its association with Spt4 and Pol II. (PMID:19210550)
• RNA polymerase II elongation repression is critically dependent on the C-terminus of Spt5 (PMID:19742326)
• crystal structure of hSpt4 in complex with the dimerization region of hSpt5 (PMID:19860741)
• he Paf1 complex (Paf1C) and Tat-SF1, two factors implicated previously in elongation control, collaborate with DSIF to facilitate efficient elongation (PMID:19952111)
• DSIF Is Selectively Required for mRNA Splicing and Export of NF-kappaB Target Genes. (PMID:23041311)
• Data indicate that the Plus3 domain of the Rtf1 subunit mediates Paf1C recruitment to genes by binding a repeating domain within the phosphorylated elongation factor Spt5. (PMID:24101474)
• SPT5 contributes to the up-regulation of hTERT expression and colonic tumor development. (PMID:26418880)
• A transcription-independent effect of tumor necrosis factor alpha on RNA splicing, mediated by Spt5. (PMID:26903558)
• These findings are consistent with a central role of Spt5 in maintenance of TFIID-promoter association and promoter escape to support rapid transcriptional induction and re-initiation of inflammatory-response genes. (PMID:27180651)
• OGA is physically associated with the known RNA polymerase II (pol II) pausing/elongation factors SPT5 and TRIM28-KAP1-TIF1beta, and a purified OGA-SPT5-TIF1beta complex has elongation properties. (PMID:27601472)
• The mobile C-terminal region of DSIF is located near exiting RNA, where it can recruit factors for RNA processing. (PMID:28892040)
• Here, the authors identified Legionella pneumophila Lpw27461 as a new nuclear-localised effector that we have termed SnpL. Protein interaction studies showed that SnpL bound to the central Kyprides, Ouzounis, Woese motif region of SUPT5H. Ectopic expression of SnpL led to massive upregulation of host gene expression and macrophage cell death. (PMID:29691989)
• the solution structures of the human Spt5 KOW4 and the C-terminal domain by nuclear magnetic resonance spectroscopy, are reported. (PMID:30076330)
• cryo-EM structure of an activated elongation complex of Sus scrofa Pol II and Homo sapiens DSIF, PAF and SPT6 was determined at 3.1 A resolution and compared to the structure of the paused elongation complex formed by Pol II, DSIF and NELF (PMID:30135578)
• cryo-electron microscopy structure of a paused transcription elongation complex containing Sus scrofa Pol II and Homo sapiens DSIF and NELF at 3.2 A resolution (PMID:30135580)
• Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II (PMID:30928206)
• Poly(A) site-dependent deceleration caused by PNUTS-PP1 and Spt5 dephosphorylation is required to convert Pol II into a viable target for the Xrn2 terminator exonuclease, leading to transcription termination. (PMID:31677974)
• SUPT5H Post-Transcriptional Silencing Modulates PIN1 Expression, Inhibits Tumorigenicity, and Induces Apoptosis of Human Breast Cancer Cells. (PMID:32961044)
• CRISPRi-mediated depletion of Spt4 and Spt5 reveals a role for DSIF in the control of HIV latency. (PMID:33333262)
• SPT5 stabilization of promoter-proximal RNA polymerase II. (PMID:34480849)
• SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape. (PMID:34534457)
• ZWC complex-mediated SPT5 phosphorylation suppresses divergent antisense RNA transcription at active gene promoters. (PMID:35325203)
• A stepwise haematological screening and whole-exome sequencing reveal multiple mutations from SUPT5H causing an elevation of Hb A2 from a cohort of 47336 individuals. (PMID:36054783)
• RBM22 regulates RNA polymerase II 5’ pausing, elongation rate, and termination by coordinating 7SK-P-TEFb complex and SPT5. (PMID:38641822)
• Loss-of-Function Variants in SUPT5H as Modifying Factors in Beta-Thalassemia. (PMID:39201615)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	supt5h	ENSDARG00000042724
mus_musculus	Supt5	ENSMUSG00000003435
rattus_norvegicus	Supt5h	ENSRNOG00000032034
drosophila_melanogaster	Spt5	FBGN0040273
caenorhabditis_elegans		WBGENE00005015

Protein

Protein identifiers

Transcription elongation factor SPT5 — O00267 (reviewed: O00267)

Alternative names: DRB sensitivity-inducing factor 160 kDa subunit, DRB sensitivity-inducing factor large subunit, Tat-cotransactivator 1 protein

All UniProt accessions (4): O00267, M0QYL9, M0R105, M0R2M5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. DSIF positively regulates mRNA capping by stimulating the mRNA guanylyltransferase activity of RNGTT/CAP1A. DSIF also acts cooperatively with the negative elongation factor complex (NELF complex) to enhance transcriptional pausing at sites proximal to the promoter. Transcriptional pausing may facilitate the assembly of an elongation competent RNA polymerase II complex. DSIF and NELF promote pausing by inhibition of the transcription elongation factor TFIIS/S-II. TFIIS/S-II binds to RNA polymerase II at transcription pause sites and stimulates the weak intrinsic nuclease activity of the enzyme. Cleavage of blocked transcripts by RNA polymerase II promotes the resumption of transcription from the new 3’ terminus and may allow repeated attempts at transcription through natural pause sites. Following phosphorylation by CDK9, DSIF can also positively regulate transcriptional elongation. Required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. DSIF acts to suppress transcriptional pausing in transcripts derived from the HIV-1 LTR and blocks premature release of HIV-1 transcripts at terminator sequences.

Subunit / interactions. Interacts with SUPT4H1 to form DSIF. DSIF interacts with the positive transcription elongation factor b complex (P-TEFb complex), which is composed of CDK9 and cyclin-T (CCNT1 or CCNT2). DSIF interacts with RNA polymerase II (Pol II); forms DNA and RNA clamps that stabilize Pol II elongation complex while maintaining the nontemplate DNA strand in the transcription bubble and nascent RNA in the exit channel. This interaction is reduced by phosphorylation of the C-terminal domain (CTD) of POLR2A by P-TEFb. DSIF also interacts with the NELF complex, which is composed of NELFA, NELFB, NELFD and NELFE, and this interaction occurs following prior binding of DSIF to RNA polymerase II. DSIF also interacts with PRMT1/HRMT1L2, HTATSF1/TATSF1, RNGTT/CAP1A, PRMT5/SKB1, SUPT6H, and can interact with PIN1. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. Interacts with MCM3AP isoform GANP.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Methylated by PRMT1/HRMT1L2 and PRMT5/SKB1. Methylation negatively regulates interaction with P-TEFb and RNA polymerase II. Phosphorylated by CDK7 and CDK9. Phosphorylation by P-TEFb (CDK9) at Thr residues of the C-terminal repeats alleviates transcriptional pausing and promotes transcription elongation. Dephosphorylated by the INTAC complex when transcripts are unfavorably configured for transcriptional elongation, leading to premature transcription termination: dephosphorylation is mediated by the PPP2CA component of the INTAC complex. Dephosphorylated by the PNUTS-PP1 complex in termination zones downstream of poly(A) sites, thereby promoting deceleration of RNA polymerase II transcription. Phosphorylation may also stimulate interaction with PIN1. Bulk phosphorylation occurs predominantly in mitosis. Phosphorylation by P-TEFb can stimulate transcriptional elongation from the HIV-1 LTR. P-TEFb dependent phosphorylation is stimulated by the HIV-1 Tat protein. Ubiquitinated by UBR5 when not assembled in the DSIF complex, leading to its degradation: UBR5 recognizes and binds a degron that is not accessible when SUPT5H is part of the DSIF complex.

Similarity. Belongs to the SPT5 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00267-1	1	yes
O00267-2	2

RefSeq proteins (6): NP_001104490, NP_001124296, NP_001124297, NP_001306919, NP_001306920, NP_003160 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005100	NGN-domain	Domain
IPR005824	KOW	Domain
IPR006645	NGN-like_dom	Domain
IPR008991	Translation_prot_SH3-like_sf	Homologous_superfamily
IPR014722	Rib_uL2_dom2	Homologous_superfamily
IPR017071	TF_Spt5_eukaryote	Family
IPR022581	Spt5_N	Domain
IPR024945	Spt5_C_dom	Domain
IPR036735	NGN_dom_sf	Homologous_superfamily
IPR039385	NGN_Euk	Domain
IPR039659	SPT5	Family
IPR041973	KOW_Spt5_1	Domain
IPR041975	KOW_Spt5_2	Domain
IPR041976	KOW_Spt5_3	Domain
IPR041977	KOW_Spt5_4	Domain
IPR041978	KOW_Spt5_5	Domain
IPR041980	KOW_Spt5_6_metazoa	Domain
IPR057934	KOW_Spt5_7	Domain
IPR057936	KOWx_Spt5	Domain

Pfam: PF00467, PF03439, PF11942, PF23037, PF23042, PF23284, PF23287, PF23288, PF23290, PF23291

UniProt features (179 total): strand 52, mutagenesis site 26, modified residue 21, repeat 19, turn 15, helix 14, compositionally biased region 9, region of interest 7, domain 5, sequence conflict 4, binding site 2, cross-link 2, chain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

55 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5OHQ	X-RAY DIFFRACTION	1.1
3H7H	X-RAY DIFFRACTION	1.55
5OHO	X-RAY DIFFRACTION	1.6
5U98	X-RAY DIFFRACTION	2
9HVQ	ELECTRON MICROSCOPY	2
9MLC	ELECTRON MICROSCOPY	2.4
4L1U	X-RAY DIFFRACTION	2.42
8UHG	ELECTRON MICROSCOPY	2.7
8UI0	ELECTRON MICROSCOPY	2.7
8UHD	ELECTRON MICROSCOPY	2.8
9EGX	ELECTRON MICROSCOPY	2.9
9EGY	ELECTRON MICROSCOPY	2.9
9EGZ	ELECTRON MICROSCOPY	2.9
7OL0	ELECTRON MICROSCOPY	3
7UNC	ELECTRON MICROSCOPY	3
7UND	ELECTRON MICROSCOPY	3
6GMH	ELECTRON MICROSCOPY	3.1
6TED	ELECTRON MICROSCOPY	3.1
9EH2	ELECTRON MICROSCOPY	3.1
9G0A	ELECTRON MICROSCOPY	3.1
8XRM	ELECTRON MICROSCOPY	3.13
6GML	ELECTRON MICROSCOPY	3.2
8UIS	ELECTRON MICROSCOPY	3.23
7OKX	ELECTRON MICROSCOPY	3.3
8A3Y	ELECTRON MICROSCOPY	3.3
9FYX	ELECTRON MICROSCOPY	3.3
9J0O	ELECTRON MICROSCOPY	3.3
9J0P	ELECTRON MICROSCOPY	3.3
9J0N	ELECTRON MICROSCOPY	3.4
8UHA	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00267-F1	69.21	0.37

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 (2): 579; 619

Post-translational modifications (23): 32, 36, 666, 681, 681, 686, 696, 696, 698, 698, 698, 718, 775, 784, 789, 791, 799, 804, 806, 814 …

Mutagenesis-validated functional residues (26):

Position	Phenotype
246	reduces the affinity for pol ii elongation complex; when associated with a-247, a-249, a-250 and a-251.
247	reduces the affinity for pol ii elongation complex; when associated with a-246, a-249, a-250 and a-251.
249	reduces the affinity for pol ii elongation complex; when associated with a-246, a-247, a-250 and a-251.
250	reduces the affinity for pol ii elongation complex; when associated with a-246, a-247, a-249 and a-251.
251	reduces the affinity for pol ii elongation complex; when associated with a-246, a-247, a-249 and a-250.
577	reduces the affinity for pol ii elongation complex; when associated with a-578, a-579 and a-582.
577	reduces the affinity for pol ii elongation complex; when associated with e-578, e-579 and e-582.
578	reduces the affinity for pol ii elongation complex; when associated with a-577, a-579 and a-582.
578	reduces the affinity for pol ii elongation complex; when associated with e-577, e-579 and e-582.
579	reduces the affinity for pol ii elongation complex; when associated with a-577, a-578 and a-582.
579	reduces the affinity for pol ii elongation complex; when associated with e-577, e-578 and e-582.
582	reduces the affinity for pol ii elongation complex; when associated with a-577, a-578 and a-579.
582	reduces the affinity for pol ii elongation complex; when associated with e-577, e-578 and e-579.
681	enhances interactions with cdk9 and rna polymerase ii and enhances transcriptional elongation; when associated with a-69
681	increases promoter association and enhances transcriptional elongation; when associated with k-696 and k-698.
696	enhances interactions with cdk9 and rna polymerase ii and enhances transcriptional elongation; when associated with a-68
696	increases promoter association and enhances transcriptional elongation; when associated with k-681 and k-698.
698	enhances transcriptional elongation. enhances interactions with cdk9 and rna polymerase ii and enhances transcriptional
698	increases promoter association and enhances transcriptional elongation; when associated with k-681 and k-696.
775	decreased ability to promote transcription elongation; when associated with a-784, a-791, a-799, a-806 and a-814.
784	decreased ability to promote transcription elongation; when associated with a-775, a-791, a-799, a-806 and a-814.
791	decreased ability to promote transcription elongation; when associated with a-775, a-784, a-799, a-806 and a-814.
799	decreased ability to promote transcription elongation; when associated with a-775, a-784, a-791, a-806 and a-814.
806	decreased ability to promote transcription elongation; when associated with a-775, a-784, a-791, a-799 and a-814.
814	decreased ability to promote transcription elongation; when associated with a-775, a-784, a-791, a-799 and a-806.

Function

Pathways and Gene Ontology

Reactome pathways

31 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-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-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-72086	mRNA Capping
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-77075	RNA Pol II CTD phosphorylation and interaction with CE
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-1643685	Disease
R-HSA-167169	HIV Transcription Elongation
R-HSA-167172	Transcription of the HIV genome
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 178 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, CAGCTG_AP4_Q5, GOBP_MACROAUTOPHAGY, REACTOME_HIV_INFECTION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, KOYAMA_SEMA3B_TARGETS_UP, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, BENPORATH_ES_CORE_NINE_CORRELATED, KUUSELO_PANCREATIC_CANCER_19Q13_AMPLIFICATION, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, SUZUKI_AMPLIFIED_IN_ORAL_CANCER, DANG_BOUND_BY_MYC, SCHLOSSER_SERUM_RESPONSE_AUGMENTED_BY_MYC, GOBP_POSITIVE_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), transcription elongation by RNA polymerase II (GO:0006368), positive regulation of macroautophagy (GO:0016239), negative regulation of DNA-templated transcription, elongation (GO:0032785), positive regulation of DNA-templated transcription, elongation (GO:0032786), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), regulation of transcription elongation by RNA polymerase II (GO:0034243), positive regulation of transcription by RNA polymerase II (GO:0045944), DNA-templated transcription elongation (GO:0006354), regulation of transcription by RNA polymerase II (GO:0006357), regulation of DNA-templated transcription elongation (GO:0032784), transcription elongation-coupled chromatin remodeling (GO:0140673)

GO Molecular Function (6): chromatin binding (GO:0003682), RNA binding (GO:0003723), mRNA binding (GO:0003729), enzyme binding (GO:0019899), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), DSIF complex (GO:0032044)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Transcription of the HIV genome	6
RNA Polymerase II Transcription	4
HIV Transcription Elongation	3
RNA Polymerase II Transcription Elongation	2
Tat-mediated elongation of the HIV-1 transcript	1
Transcriptional Regulation by TP53	1
Metabolism of RNA	1
HIV Infection	1
HIV Life Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	4
DNA-templated transcription elongation	4
regulation of DNA-templated transcription elongation	3
transcription elongation by RNA polymerase II	3
regulation of transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
regulation of DNA-templated transcription	2
binding	2
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
positive regulation of transcription by RNA polymerase II	1
DNA-templated transcription	1
RNA biosynthetic process	1
chromatin remodeling	1
nucleic acid binding	1
RNA binding	1
protein binding	1
protein dimerization activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
transcription elongation factor complex	1

Protein interactions and networks

STRING

3004 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUPT5H	SUPT4H1	P63272	999
SUPT5H	SUPT6H	Q7KZ85	996
SUPT5H	NELFE	P18615	960
SUPT5H	NELFB	Q8WX92	950
SUPT5H	RTF1	Q92541	894
SUPT5H	SUPT16H	Q9Y5B9	893
SUPT5H	POLR2A	P24928	887
SUPT5H	NELFCD	Q8IXH7	881
SUPT5H	NELFA	Q9H3P2	878
SUPT5H	TCEA2	Q15560	870
SUPT5H	POLR2B	P30876	870
SUPT5H	TCEA3	O75764	868
SUPT5H	TCEA1	P23193	867
SUPT5H	CDK9	P50750	845
SUPT5H	CTR9	Q6PD62	831

IntAct

194 interactions, top by confidence:

A	B	Type	Score
SUPT5H	SUPT4H1	psi-mi:“MI:0915”(physical association)	0.960
SUPT4H1	SUPT5H	psi-mi:“MI:0915”(physical association)	0.960
SUPT5H	SUPT4H1	psi-mi:“MI:0407”(direct interaction)	0.960
SUPT4H1	SUPT5H	psi-mi:“MI:0407”(direct interaction)	0.960
SUPT5H	POLR2A	psi-mi:“MI:0915”(physical association)	0.840
POLR2A	SUPT5H	psi-mi:“MI:0914”(association)	0.840
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
POLR2D	POLR2K	psi-mi:“MI:0915”(physical association)	0.730
SUPT5H	PIN1	psi-mi:“MI:0915”(physical association)	0.670
PIN1	SUPT5H	psi-mi:“MI:0915”(physical association)	0.670
POLR2C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
POLR2E	POLR2B	psi-mi:“MI:0915”(physical association)	0.640
PPP4C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
NELFA	SUPT5H	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
LEO1	SUPT5H	psi-mi:“MI:0914”(association)	0.530

BioGRID (578): SUPT5H (Affinity Capture-Western), BRCA1 (Affinity Capture-Western), POLR2A (Affinity Capture-Western), SUPT5H (Affinity Capture-RNA), SUPT5H (Affinity Capture-RNA), SUPT5H (Affinity Capture-RNA), SUPT5H (Affinity Capture-RNA), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS), SUPT5H (Affinity Capture-MS)

ESM2 similar proteins: A1L2H9, B8AZ14, B9FKM7, F4JSG3, O00267, O55201, O97472, P15927, P22336, P26754, P27894, P34552, Q09236, Q10Q08, Q13156, Q19537, Q21338, Q22307, Q23697, Q26454, Q43704, Q5F310, Q5R405, Q5RC43, Q5ZI08, Q62193, Q63528, Q65XV7, Q6DFS2, Q6FQE9, Q6H7J5, Q6IP18, Q6K9U2, Q6YZ49, Q84K16, Q8LFJ8, Q92372, Q92373, Q99128, Q9DDT5

Diamond homologs: O00267, O13936, O55201, O80770, P0CR70, P0CR71, Q21338, Q2UGU3, Q4I5I4, Q4PIC4, Q4WP96, Q5ALX3, Q5BCN2, Q5R405, Q5ZI08, Q6BZG0, Q6CC84, Q6CWW9, Q7S3C4, Q8TZK1, Q9DDT5, Q9STN3, Q9V460, P27692, Q6FRZ5, Q759T6, F4JW79, P27341, P96036, Q46494, Q57818, Q5JH33, Q9Y9W3

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CDK9	up-regulates	SUPT5H	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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	9	55.3×	2e-13
Signaling by FGFR2 IIIa TM	10	48.5×	4e-14
Abortive elongation of HIV-1 transcript in the absence of Tat	12	48.0×	8e-17
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	13	42.8×	2e-17
RNA Pol II CTD phosphorylation and interaction with CE	13	42.8×	2e-17
Pausing and recovery of Tat-mediated HIV elongation	14	41.6×	3e-18
Tat-mediated HIV elongation arrest and recovery	14	41.6×	3e-18
HIV Transcription Elongation	15	40.6×	6e-19

GO biological processes:

GO term	Partners	Fold	FDR
transcription initiation at RNA polymerase II promoter	7	17.0×	8e-05
transcription elongation by RNA polymerase II	5	14.4×	6e-03
transcription by RNA polymerase II	14	6.4×	4e-05
Wnt signaling pathway	9	5.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	91
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3936 predictions. Top by Δscore:

Variant	Effect	Δscore
19:39445635:GAG:G	donor_gain	1.0000
19:39445638:G:GA	donor_loss	1.0000
19:39445953:C:T	donor_gain	1.0000
19:39445957:G:GT	donor_gain	1.0000
19:39445961:CCGAG:C	donor_loss	1.0000
19:39445962:CGAG:C	donor_loss	1.0000
19:39445964:AGG:A	donor_loss	1.0000
19:39445966:G:GA	donor_loss	1.0000
19:39445967:T:A	donor_loss	1.0000
19:39453458:G:GT	donor_gain	1.0000
19:39453517:GGCTG:G	donor_gain	1.0000
19:39453518:GCTG:G	donor_gain	1.0000
19:39453518:GCTGG:G	donor_gain	1.0000
19:39457667:C:A	acceptor_gain	1.0000
19:39457669:TTTTA:T	acceptor_loss	1.0000
19:39457670:TTTA:T	acceptor_loss	1.0000
19:39457671:TTA:T	acceptor_loss	1.0000
19:39457672:TA:T	acceptor_loss	1.0000
19:39457673:A:AG	acceptor_gain	1.0000
19:39457673:A:C	acceptor_loss	1.0000
19:39457673:AGAT:A	acceptor_gain	1.0000
19:39457674:G:GA	acceptor_gain	1.0000
19:39457674:GA:G	acceptor_gain	1.0000
19:39457674:GAT:G	acceptor_gain	1.0000
19:39457674:GATG:G	acceptor_gain	1.0000
19:39457736:GAAAG:G	donor_gain	1.0000
19:39457740:GG:G	donor_loss	1.0000
19:39458813:TTCAG:T	acceptor_loss	1.0000
19:39458816:A:AG	acceptor_gain	1.0000
19:39458816:A:C	acceptor_loss	1.0000

AlphaMissense

7173 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:39453503:T:C	F75L	1.000
19:39453504:T:C	F75S	1.000
19:39453504:T:G	F75C	1.000
19:39453505:C:A	F75L	1.000
19:39453505:C:G	F75L	1.000
19:39453507:T:A	I76N	1.000
19:39453507:T:C	I76T	1.000
19:39453507:T:G	I76S	1.000
19:39453518:G:C	A80P	1.000
19:39453519:C:A	A80D	1.000
19:39459237:T:C	L171P	1.000
19:39459239:C:T	P172S	1.000
19:39459240:C:A	P172Q	1.000
19:39459570:T:A	L179Q	1.000
19:39459570:T:C	L179P	1.000
19:39459570:T:G	L179R	1.000
19:39459572:T:A	W180R	1.000
19:39459572:T:C	W180R	1.000
19:39459573:G:C	W180S	1.000
19:39459574:G:C	W180C	1.000
19:39459574:G:T	W180C	1.000
19:39459579:T:A	V182D	1.000
19:39459584:T:C	C184R	1.000
19:39459585:G:A	C184Y	1.000
19:39459585:G:T	C184F	1.000
19:39459586:T:G	C184W	1.000
19:39459896:G:A	G187E	1.000
19:39459929:G:C	R198P	1.000
19:39464813:T:C	S214P	1.000
19:39464840:G:C	G223R	1.000

dbSNP variants (sampled 300 via entrez): RS1000035407 (19:39444067 CCT>C), RS1000094731 (19:39471970 C>T), RS1000139640 (19:39443744 C>A), RS1000207127 (19:39449222 G>A), RS1000275443 (19:39447020 C>G), RS1000361125 (19:39465641 A>G), RS1000470637 (19:39461134 A>G), RS1000554567 (19:39454754 A>G), RS1000578802 (19:39448860 C>G), RS1000624804 (19:39453754 A>T), RS1000731398 (19:39460950 G>T), RS1000903239 (19:39454581 C>A), RS1001006418 (19:39445163 T>C), RS1001216437 (19:39444788 C>T), RS1001286615 (19:39450237 C>A)

Disease associations

OMIM: gene MIM:602102 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002398_87	Neutrophil count	1.000000e-13
GCST90002407_374	White blood cell count	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004833	neutrophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Smoke	decreases expression, affects expression, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
geraniol	increases expression	1
sodium arsenate	decreases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Atrazine	increases expression	1
Caffeine	increases phosphorylation	1
Dactinomycin	increases secretion, affects cotreatment	1
Dimethyl Sulfoxide	increases expression	1
Gallic Acid	increases expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1

Clinical trials (associated diseases)

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