SUB1

Summary

SUB1 (SUB1 regulator of transcription, HGNC:19985) is a protein-coding gene on chromosome 5p13.3, encoding Activated RNA polymerase II transcriptional coactivator p15 (P53999). General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery.

Enables several functions, including DNA binding activity; identical protein binding activity; and transcription coactivator activity. Involved in RNA polymerase II promoter clearance; protein homooligomerization; and regulation of nucleobase-containing compound metabolic process. Located in nucleolus and nucleoplasm. Part of transcription regulator complex.

Source: NCBI Gene 10923 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006713

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19985
Approved symbol	SUB1
Name	SUB1 regulator of transcription
Location	5p13.3
Locus type	gene with protein product
Status	Approved
Aliases	PC4, p15, p14
Ensembl gene	ENSG00000113387
Ensembl biotype	protein_coding
OMIM	600503
Entrez	10923

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 25 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000265073, ENST00000502453, ENST00000502897, ENST00000504016, ENST00000504789, ENST00000506237, ENST00000510442, ENST00000511175, ENST00000511615, ENST00000511988, ENST00000512913, ENST00000513013, ENST00000515355, ENST00000879054, ENST00000879055, ENST00000879056, ENST00000879057, ENST00000879058, ENST00000879059, ENST00000879060, ENST00000879061, ENST00000879062, ENST00000922096, ENST00000922097, ENST00000922098, ENST00000922099, ENST00000922100, ENST00000922101, ENST00000922102, ENST00000954957, ENST00000954958, ENST00000954959

RefSeq mRNA: 1 — MANE Select: NM_006713 NM_006713

CCDS: CCDS3897

Canonical transcript exons

ENST00000265073 — 5 exons

Exon	Start	End
ENSE00001164444	32585557	32585625
ENSE00001563086	32601005	32604079
ENSE00003522003	32591563	32591685
ENSE00003618865	32598961	32599069
ENSE00003628443	32588512	32588584

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 398.9053 / max 20586.4502, expressed in 1826 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56007	390.8748	1826
56005	3.0025	483
56004	2.5599	505
56012	1.3639	656
56006	0.6685	183
56008	0.3326	143
56009	0.1031	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	99.43	gold quality
nasopharynx	UBERON:0001728	99.41	gold quality
cortical plate	UBERON:0005343	99.32	gold quality
mammary duct	UBERON:0001765	99.24	gold quality
colonic epithelium	UBERON:0000397	99.23	gold quality
ganglionic eminence	UBERON:0004023	99.22	gold quality
gingival epithelium	UBERON:0001949	99.20	gold quality
parotid gland	UBERON:0001831	99.18	gold quality
cervix squamous epithelium	UBERON:0006922	99.17	gold quality
adrenal tissue	UBERON:0018303	99.16	gold quality
bone marrow cell	CL:0002092	99.10	gold quality
germinal epithelium of ovary	UBERON:0001304	99.09	gold quality
gingiva	UBERON:0001828	99.08	gold quality
endometrium	UBERON:0001295	99.05	gold quality
ventricular zone	UBERON:0003053	99.04	gold quality
epithelium of mammary gland	UBERON:0003244	99.03	gold quality
oral cavity	UBERON:0000167	99.02	gold quality
upper leg skin	UBERON:0004262	99.02	gold quality
oocyte	CL:0000023	99.01	gold quality
endothelial cell	CL:0000115	99.01	gold quality
embryo	UBERON:0000922	99.01	gold quality
tonsil	UBERON:0002372	99.00	gold quality
lymph node	UBERON:0000029	98.97	gold quality
epithelial cell of pancreas	CL:0000083	98.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.96	gold quality
tongue squamous epithelium	UBERON:0006919	98.95	gold quality
penis	UBERON:0000989	98.92	gold quality
pylorus	UBERON:0001166	98.92	gold quality
skin of hip	UBERON:0001554	98.88	gold quality
mammary gland	UBERON:0001911	98.88	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	3887.37
E-MTAB-9221	yes	2821.35
E-HCAD-1	yes	2250.60
E-CURD-55	yes	1613.52
E-MTAB-9841	yes	1587.77
E-CURD-77	yes	1491.64
E-HCAD-4	yes	45.16
E-HCAD-9	yes	27.28
E-CURD-122	yes	25.25
E-CURD-46	yes	24.26
E-HCAD-13	yes	21.51
E-MTAB-6701	yes	19.17
E-MTAB-10042	yes	17.42
E-CURD-88	yes	4.26
E-HCAD-32	no	2410.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2C, RCOR2, RELA, TBP, TP53

miRNA regulators (miRDB)

191 targeting SUB1, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 38)

• General transcription factor IIH protects promoters from PC4-mediated repression by relieving the topological constraint imposed by PC4 through the ERCC3 helicase activity rather than by reducing the repressive activity of PC4 via its phosphorylation. (PMID:12590132)
• These results establish the first physiological role of PC4 as a transcriptional coactivator. (PMID:14966284)
• structure explains high-affinity binding of PC4 to the complementary strands of unwinding duplex DNA. (PMID:16415882)
• These results establish PC4 as a new member of chromatin-associated protein family, which plays an important role in chromatin organization. (PMID:16982701)
• p38 MAP kinase mediated HNF4 Ser158 phosphorylation (P-HNF4-S158), binding of PC4 to P-HNF4-S158 and characterize the functional domain of PC4 required for P-HNF4-S158 binding. (PMID:17317687)
• PC4 interacts with the DNA binding and C-terminal domains of p53 through its DNA binding domain, which is essential for the stimulation of p53 DNA binding. (PMID:17785449)
• PC4 activates double-strand break (DSB) repair activity through stimulation of DSB rejoining in vivo (PMID:19038270)
• Report recruitment of RNA polymerase II cofactor PC4 to DNA damage sites. (PMID:19047459)
• analysis of the interaction between the transactivation domain of p53 and PC4 (PMID:19525231)
• PC4 interacts with heterochromatin protein 1alpha, REST/NRSF (RE1-silencing transcription factor/neuron-restrictive silencer factor) and CoREST to establish the repressed state of neural genes in nonneuronal cells. (PMID:20080105)
• Sub1/PC4 a chromatin associated protein with multiple functions in transcription. (PMID:20305379)
• findings demonstrated a critical aspect of LHR modulation whereby PC4 acts as a coactivator of Sp1 to contribute to the human of LHR transcription (PMID:21193408)
• acetylation of lysine 382/381 of p53 may play an important role in modulating p53-PC4 interaction and as a consequence PC4 mediated activation of p53 target genes. (PMID:21586571)
• expression of PC4 in astrocytoma was upregulated as assessed by western blot and immunohistochemical staining. Moreover, elevated PC4 expression was strongly correlated with the progression of astrocytoma and overall survival. (PMID:25262015)
• PC4 protects esophageal squamous cell carcinoma cells from IR-induced death by enhancing the nonhomologous end joining-promoting activity of XLF. (PMID:25321468)
• Sub1, and its human homolog PC4, bind preferentially to G-quadruplexes (PMID:25813861)
• PC4 has similar functions to RPA in binding ssDNA to promote genome stability, especially at sites of replication-transcription collisions. (PMID:25961912)
• SMYD3 interacts with the human positive coactivator 4 (PC4) and that such interaction potentiates a group of genes whose expression is linked to cell proliferation and invasion. (PMID:26350217)
• PC4 associates with Aurora A and Aurora B and undergoes phosphorylation, following which PC4 activates both Aurora A and B to sustain optimal kinase activity to maintain the phosphorylation gradient for the proper functioning of the mitotic machinery. (PMID:26777301)
• Results show elevated expression of SUB1 in aggressive prostate cancer. Knockdown of SUB1 in prostate cancer cells resulted in reduced cell proliferation, invasion and migration. (PMID:27270442)
• Yeast Sub1 and human PC4 are G-quadruplex binding proteins that suppress genome instability at co-transcriptionally formed G4 DNA. (PMID:28369605)
• these data provide a novel mode of PC4 binding to a DNA secondary structure that remains within the framework of the model for binding to ssDNA. Additionally, consideration of the PC4-G4DNA interaction could provide insight into the biological functions of PC4, which remain incompletely understood. (PMID:28416612)
• Evolutionarily conserved role for Sub1 and PC4 in the maintenance of yeast and human genome stability has been summarized. (Review) (PMID:28567479)
• REVIEW: many evidences showed that Sub1 influences processes downstream during mRNA biogenesis, such as elongation, termination, and RNAPII phosphorylation. The recent discovery that Sub1 directly interacts with the RNAPII stalk adds new insights into how it achieves all these tasks. (PMID:28853990)
• PC4 expression correlated with radiosensitivity and was an independent prognostic factor of progression-free survival (PFS) in patients with NSCLC. (PMID:29522271)
• Study shows that PC4 might repress RNA pol II recruitment and transcription of replication-dependent histone genes in order to maintain the balance between histone gene expression and DNA synthesis. Moreover, PC4 might promote the interaction of cleavage and polyadenylation complex with histone pre-mRNAs, that might impede with the recruitment of histone cleavage complex. (PMID:30053800)
• this study reveals for the first time that PC4 promotes breast cancer progression by directly regulating c-Myc transcription to promote Warburg effect, implying a novel therapeutic target for breast cancer. (PMID:30992017)
• PC4 is essential for genomic integrity and autophagy regulation. (PMID:31169983)
• PC4 emerges as a global co-regulator of p53 and a therapeutic target against pathogeneses where the p53-dependent cell death process plays a crucial role. (PMID:31236588)
• Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4. (PMID:33357426)
• Knockdown of PC4 increases chemosensitivity of Oxaliplatin in triple negative breast cancer by suppressing mTOR pathway. (PMID:33524870)
• The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis. (PMID:34378353)
• CircVCAN/SUB1 up-regulates MYC/HSP90beta to enhance the proliferation and migration of glioma cells. (PMID:34534637)
• Phosphorylation-dependent association of human chromatin protein PC4 to linker histone H1 regulates genome organization and transcription. (PMID:35670677)
• SUB1 promotes colorectal cancer metastasis by activating NF-kappaB signaling via UBR5-mediated ubiquitination of UBXN1. (PMID:38240906)
• Periodic changes of cyclin D1 mRNA stability are regulated by PC4 modifications in the cell cycle. (PMID:38349334)
• PC4 promotes bladder cancer progression and stemness by directly interacting with Sp1 to transcriptionally activate the Wnt5a/beta-catenin pathway. (PMID:38820928)
• HMGB3 and SUB1 Bind to and Facilitate the Repair of N[2]-Alkylguanine Lesions in DNA. (PMID:39101269)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sub1b	ENSDARG00000007720
danio_rerio	sub1a	ENSDARG00000053446
mus_musculus	Sub1	ENSMUSG00000022205
rattus_norvegicus	LOC103693281	ENSRNOG00000063454
rattus_norvegicus	Sub1	ENSRNOG00000067555
caenorhabditis_elegans		WBGENE00011743

Protein

Protein identifiers

Activated RNA polymerase II transcriptional coactivator p15 — P53999 (reviewed: P53999)

Alternative names: Positive cofactor 4, SUB1 homolog, p14

All UniProt accessions (4): P53999, D6R970, D6RC37, Q6IBA2

UniProt curated annotations — full annotation on UniProt →

Function. General coactivator that functions cooperatively with TAFs and mediates functional interactions between upstream activators and the general transcriptional machinery. May be involved in stabilizing the multiprotein transcription complex. Binds single-stranded DNA. Also binds, in vitro, non-specifically to double-stranded DNA (ds DNA).

Subunit / interactions. Homodimer. Interacts with CSTF2.

Subcellular location. Nucleus.

Post-translational modifications. Activity is controlled by protein kinases that target the regulatory region. Phosphorylation inactivates both ds DNA-binding and cofactor function, but does not affect binding to ssDNA. Seems to be phosphorylated in vivo by CK2 in at least 7 sites in the N-terminal Ser-rich region.

Similarity. Belongs to the transcriptional coactivator PC4 family.

RefSeq proteins (1): NP_006704* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003173	PC4_C	Domain
IPR009044	ssDNA-bd_transcriptional_reg	Homologous_superfamily
IPR045125	Sub1/Tcp4-like	Family

Pfam: PF02229

UniProt features (39 total): modified residue 16, mutagenesis site 5, strand 5, region of interest 3, compositionally biased region 3, cross-link 2, initiator methionine 1, chain 1, sequence variant 1, helix 1, site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1PCF	X-RAY DIFFRACTION	1.74
2C62	X-RAY DIFFRACTION	1.74
4USG	X-RAY DIFFRACTION	1.97
7E4W	X-RAY DIFFRACTION	2.9
6YCS	X-RAY DIFFRACTION	3.05
2PHE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53999-F1	77.03	0.54

Functional residue map

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

Catalytic / active sites (1): 50–51 (cleavage)

Post-translational modifications (18): 9, 10, 11, 13, 15, 17, 19, 35, 53, 55, 56, 57, 58, 68, 118, 68, 68, 4

Mutagenesis-validated functional residues (5):

Position	Phenotype
68	reduced ssdna binding.
75	reduced ssdna binding.
77–80	loss of ssdna binding.
86	loss of ssdna binding.
101	loss of ssdna binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 301 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, TACAATC_MIR508, SHAFFER_IRF4_TARGETS_IN_PLASMA_CELL_VS_MATURE_B_LYMPHOCYTE, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, GOZGIT_ESR1_TARGETS_UP, SCHLOSSER_SERUM_RESPONSE_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, NADLER_HYPERGLYCEMIA_AT_OBESITY, TIEN_INTESTINE_PROBIOTICS_24HR_UP, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_DENDRITIC_CELL, ACEVEDO_LIVER_CANCER_UP

GO Biological Process (6): RNA polymerase II promoter clearance (GO:0001111), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of DNA metabolic process (GO:0051053), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), regulation of DNA-templated transcription (GO:0006355), protein homooligomerization (GO:0051260)

GO Molecular Function (10): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), identical protein binding (GO:0042802), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), protein binding (GO:0005515), DNA-binding transcription factor binding (GO:0140297)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
DNA binding	2
nucleic acid binding	2
nuclear lumen	2
promoter clearance during DNA-templated transcription	1
regulation of DNA-templated transcription	1
DNA metabolic process	1
negative regulation of macromolecule metabolic process	1
negative regulation of nucleobase-containing compound metabolic process	1
regulation of DNA metabolic process	1
transcription initiation at RNA polymerase II promoter	1
positive regulation of transcription by RNA polymerase II	1
regulation of transcription initiation by RNA polymerase II	1
positive regulation of DNA-templated transcription initiation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
protein complex oligomerization	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
protein binding	1
helicase activity	1
ATP-dependent activity, acting on DNA	1
binding	1
transcription factor binding	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
protein-containing complex	1
intracellular membraneless organelle	1
extracellular vesicle	1

Protein interactions and networks

STRING

2314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUB1	GTF2B	Q00403	786
SUB1	TBP	P20226	746
SUB1	CSTF2	P33240	716
SUB1	TOP1	P11387	650
SUB1	MED19	A0JLT2	640
SUB1	SUPT5H	O00267	605
SUB1	MED10	Q9BTT4	599
SUB1	AFF1	P51825	584
SUB1	MED11	Q9P086	581
SUB1	LDHA	P00338	580
SUB1	MED18	Q9BUE0	567
SUB1	AFF3	P51826	556
SUB1	LDHC	P07864	547
SUB1	CSNK2A1	P19138	540
SUB1	TP53	P04637	531

IntAct

211 interactions, top by confidence:

A	B	Type	Score
CDKN2A	CDK4	psi-mi:“MI:0914”(association)	0.960
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
EMC7	EMC8	psi-mi:“MI:0914”(association)	0.790
SUB1	SUB1	psi-mi:“MI:0915”(physical association)	0.750
SUB1	SUB1	psi-mi:“MI:0407”(direct interaction)	0.750
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730
NHP2	DKC1	psi-mi:“MI:0914”(association)	0.730
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
COMMD6	VPS26C	psi-mi:“MI:0914”(association)	0.640
SUB1	CSNK2A1	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
CSNK2A1	SUB1	psi-mi:“MI:0217”(phosphorylation reaction)	0.620
tat	SUB1	psi-mi:“MI:0915”(physical association)	0.590
tat	SUB1	psi-mi:“MI:0407”(direct interaction)	0.590
SDCBP	SUB1	psi-mi:“MI:0915”(physical association)	0.560
ABCD3	SUB1	psi-mi:“MI:0915”(physical association)	0.560
PABIR3	SUB1	psi-mi:“MI:0915”(physical association)	0.560
SMC1A	PDS5B	psi-mi:“MI:0914”(association)	0.530
TMEM63B	SLC19A2	psi-mi:“MI:0914”(association)	0.530
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
GNL3	IPO5	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
Kif1c	KIF1C	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (295): SUB1 (Affinity Capture-MS), SUB1 (Two-hybrid), SUB1 (Biochemical Activity), SUB1 (Affinity Capture-MS), SUB1 (Affinity Capture-MS), SUB1 (Affinity Capture-RNA), ABCF1 (Co-fractionation), CHD5 (Co-fractionation), EIF1AX (Co-fractionation), EIF2S2 (Co-fractionation), EIF2S3 (Co-fractionation), NACA (Co-fractionation), NOLC1 (Co-fractionation), POLR3C (Co-fractionation), SART1 (Co-fractionation)

ESM2 similar proteins: A4IGK3, A6H6W9, O08609, O14639, O43741, O60519, O88508, P53999, P60762, P97875, Q0VD32, Q12800, Q1LZ53, Q32M00, Q3SZ60, Q4R947, Q4W5Z4, Q5BJU6, Q5NVP9, Q5R6D0, Q5RBB8, Q5RCB7, Q5SQY2, Q5XIT1, Q5XJK1, Q5ZJV7, Q5ZK63, Q642H2, Q6AYJ2, Q6AYU1, Q6I9Y2, Q6PAM0, Q6PER3, Q78E65, Q7Z422, Q8BR65, Q8C8M1, Q8CCI5, Q8N488, Q8VE65

Diamond homologs: O65154, O65155, P11031, P53999, P54000, P87294, Q4R947, Q5R6D0, Q5ZK63, Q63396, Q872F4, Q94045, Q9VLR5, Q9FHX8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SUB1	“up-regulates activity”	REST-CoREST	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 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
mRNA Polyadenylation	9	5.5×	9e-03
Processing of Capped Intron-Containing Pre-mRNA	9	5.1×	9e-03
mRNA Splicing - Major Pathway	13	4.9×	2e-03
Dengue Virus-Host Interactions	12	3.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
telomere maintenance via telomerase	5	20.7×	2e-03
amyloid fibril formation	5	17.0×	4e-03
positive regulation of interferon-beta production	5	11.1×	9e-03
mRNA export from nucleus	6	10.0×	6e-03
positive regulation of fibroblast proliferation	6	10.0×	6e-03
rhythmic process	6	8.5×	8e-03
cytoplasmic translation	7	7.3×	8e-03
rRNA processing	8	6.4×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2140 predictions. Top by Δscore:

Variant	Effect	Δscore
5:32531872:G:GT	donor_gain	1.0000
5:32588510:AG:A	acceptor_gain	1.0000
5:32588511:GG:G	acceptor_gain	1.0000
5:32591560:TAGTT:T	acceptor_loss	1.0000
5:32591561:A:AG	acceptor_gain	1.0000
5:32591562:G:GT	acceptor_gain	1.0000
5:32591562:GTTAA:G	acceptor_gain	1.0000
5:32599065:AAAAG:A	donor_loss	1.0000
5:32599068:AGG:A	donor_loss	1.0000
5:32599070:GTG:G	donor_loss	1.0000
5:32599071:T:A	donor_loss	1.0000
5:32531912:TACAG:T	donor_loss	0.9900
5:32531913:ACAGG:A	donor_loss	0.9900
5:32531914:CAGGT:C	donor_loss	0.9900
5:32531915:AG:A	donor_loss	0.9900
5:32531916:G:GC	donor_loss	0.9900
5:32531918:T:C	donor_loss	0.9900
5:32531919:GAG:G	donor_loss	0.9900
5:32538265:G:GT	donor_gain	0.9900
5:32588506:TTTCA:T	acceptor_loss	0.9900
5:32588507:TTCA:T	acceptor_loss	0.9900
5:32588508:TCAG:T	acceptor_loss	0.9900
5:32588509:CA:C	acceptor_loss	0.9900
5:32588510:A:AG	acceptor_gain	0.9900
5:32588510:A:C	acceptor_loss	0.9900
5:32588511:G:GG	acceptor_gain	0.9900
5:32588581:AAAGG:A	donor_loss	0.9900
5:32588583:AG:A	donor_loss	0.9900
5:32588584:GG:G	donor_loss	0.9900
5:32588585:GTGA:G	donor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000147655 (5:32598821 C>T), RS1000148010 (5:32587835 C>A,G,T), RS1000186102 (5:32585166 T>C), RS1000345412 (5:32587383 A>G), RS1000415679 (5:32587645 T>C), RS1000498955 (5:32588021 A>T), RS1000573991 (5:32592411 G>A), RS1000676750 (5:32588371 C>T), RS1000748912 (5:32583889 T>C), RS1000925463 (5:32592668 A>G,T), RS1001026553 (5:32594268 T>C), RS1001061728 (5:32603759 C>G), RS1001305725 (5:32584102 G>T), RS1001407854 (5:32597772 T>A), RS1001465498 (5:32592413 A>T)

Disease associations

OMIM: gene MIM:600503 | 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
GCST009391_211	Metabolite levels	2.000000e-06
GCST010320_145	PR interval	2.000000e-11
GCST010321_214	PR interval	5.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725063 (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

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.96	Kd	110	nM	MOLIBRESIB
6.51	IC50	310	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 9 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179111: Binding affinity against SUB1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.1100	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	3
bisphenol A	decreases expression	2
bisphenol S	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Smoke	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
bufotalin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
geraniol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
CD 437	increases expression	1
K 7174	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
jinfukang	decreases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases 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
CHEMBL5652564	Binding	Binding affinity to human SUB1 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

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6V7	SEES3-1V human SUB1, clone1	Embryonic stem cell	Male
CVCL_A6V8	SEES3-1V human SUB1, clone2	Embryonic stem cell	Male
CVCL_A6V9	SEES3-1V human SUB1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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