CNOT7

Summary

CNOT7 (CCR4-NOT transcription complex subunit 7, HGNC:14101) is a protein-coding gene on chromosome 8p22, encoding CCR4-NOT transcription complex subunit 7 (Q9UIV1). Has 3’-5’ poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. It is a selective cancer dependency (DepMap: 12.5% of cell lines).

The protein encoded by this gene binds to an anti-proliferative protein, B-cell translocation protein 1, which negatively regulates cell proliferation. Binding of the two proteins, which is driven by phosphorylation of the anti-proliferative protein, causes signaling events in cell division that lead to changes in cell proliferation associated with cell-cell contact. The encoded protein downregulates the innate immune response and therefore provides a therapeutic target for enhancing its antimicrobial activity against foreign agents. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 1 and X.

Source: NCBI Gene 29883 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 36 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 12.5% of screened cell lines
• MANE Select transcript: NM_013354

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14101
Approved symbol	CNOT7
Name	CCR4-NOT transcription complex subunit 7
Location	8p22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198791
Ensembl biotype	protein_coding
OMIM	604913
Entrez	29883

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 31 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000361272, ENST00000518021, ENST00000518541, ENST00000518885, ENST00000519918, ENST00000519954, ENST00000519998, ENST00000520178, ENST00000522062, ENST00000523649, ENST00000523917, ENST00000524358, ENST00000776869, ENST00000851024, ENST00000851025, ENST00000880739, ENST00000880740, ENST00000880741, ENST00000880742, ENST00000880743, ENST00000880744, ENST00000880745, ENST00000880746, ENST00000880747, ENST00000880748, ENST00000931011, ENST00000931012, ENST00000931013, ENST00000931014, ENST00000931015, ENST00000931016, ENST00000931017, ENST00000931018, ENST00000931019, ENST00000931020, ENST00000931021, ENST00000931022, ENST00000931023

RefSeq mRNA: 16 — MANE Select: NM_013354 NM_001322087, NM_001322088, NM_001322089, NM_001322090, NM_001322091, NM_001322092, NM_001322093, NM_001322094, NM_001322095, NM_001322096, NM_001322097, NM_001322098, NM_001322099, NM_001322100, NM_013354, NM_054026

CCDS: CCDS55202, CCDS6000

Canonical transcript exons

ENST00000361272 — 7 exons

Exon	Start	End
ENSE00000681987	17232427	17232537
ENSE00001321978	17224966	17230848
ENSE00002137788	17246675	17246857
ENSE00003484474	17242992	17243185
ENSE00003484785	17245036	17245247
ENSE00003517163	17234716	17234860
ENSE00003575496	17237212	17237373

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.9649 / max 174.3585, expressed in 1816 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91986	24.8466	1812
91984	3.5240	1570
91985	1.4226	1055
91983	0.7814	523
91982	0.3903	199

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.07	gold quality
buccal mucosa cell	CL:0002336	99.05	gold quality
corpus epididymis	UBERON:0004359	98.69	gold quality
secondary oocyte	CL:0000655	98.59	gold quality
germinal epithelium of ovary	UBERON:0001304	98.50	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.44	gold quality
biceps brachii	UBERON:0001507	98.43	gold quality
caput epididymis	UBERON:0004358	98.42	gold quality
parotid gland	UBERON:0001831	98.13	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.05	gold quality
cauda epididymis	UBERON:0004360	97.78	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.67	gold quality
ganglionic eminence	UBERON:0004023	97.62	gold quality
pigmented layer of retina	UBERON:0001782	97.55	gold quality
superficial temporal artery	UBERON:0001614	97.53	gold quality
ventricular zone	UBERON:0003053	97.51	gold quality
jejunal mucosa	UBERON:0000399	97.34	gold quality
palpebral conjunctiva	UBERON:0001812	97.33	gold quality
jejunum	UBERON:0002115	97.31	gold quality
nipple	UBERON:0002030	97.30	gold quality
adrenal tissue	UBERON:0018303	97.29	gold quality
islet of Langerhans	UBERON:0000006	97.27	gold quality
skin of hip	UBERON:0001554	97.24	gold quality
oral cavity	UBERON:0000167	97.22	gold quality
colonic mucosa	UBERON:0000317	97.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.17	gold quality
embryo	UBERON:0000922	97.12	gold quality
upper leg skin	UBERON:0004262	97.03	gold quality
trabecular bone tissue	UBERON:0002483	96.95	gold quality
bronchial epithelial cell	CL:0002328	96.90	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
CXCL8	Repression
ICAM1	Repression
MSMB	Unknown
PMP22	Unknown

miRNA regulators (miRDB)

174 targeting CNOT7, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• CNOT7 is not the target tumor suppressor gene in the 8p22-23.1 colorectal cancer suppressor region. (PMID:12845644)
• CAF1 is a new regulator of PRMT1-dependent arginine methylation. (PMID:17264152)
• antiproliferative region of human Tob (residues 1-138) and intact hCaf1 were co-expressed in Escherichia coli, purified and successfully cocrystallized (PMID:18084094)
• Data show that Ccr4-Not function in RNA splicing and nuclear export, and that CNOT7 binds strongly with CNOT6. (PMID:19558367)
• Data show that efficient cell proliferation requires both CNOT7 and CNOT8, although combined knockdown of both subunits further reduces cell proliferation indicating partial redundancy between these proteins. (PMID:19605561)
• The anti-proliferative activity of BTG/TOB proteins is mediated via the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits of the Ccr4-not complex. (PMID:23236473)
• CNOT7 is an antimicrobial protein and a regulator of the innate immune response. (PMID:23386060)
• CNOT7/hCAF1 is involved in ICAM-1 and IL-8 regulation by TTP in HPMEC. (PMID:25038453)
• MEX3C associates with the cytoplasmic deadenylation complexes and ubiquitinates CNOT7. (PMID:26471122)
• Findings suggest a preferential involvement of CNOT7 variant 2 (CNOT7v2) in nuclear processes, such as arginine methylation and alternative splicing, rather than mRNA turnover (PMID:28591869)
• Active 1-hydroxy-xanthines inhibit both isolated Caf1 (CNOT7) enzyme and human Caf1-containing complexes that also contain the second nuclease subunit Ccr4 (CNOT6L) to a similar extent, indicating that the active site of the Caf1 nuclease subunit does not undergo substantial conformational change when bound to other Ccr4-Not subunits. (PMID:30984545)
• Data show that incorporation of ATP-dependent RNA helicase eIF4A-2 (eIF4A2) into the CCR4-NOT complex inhibits CCR4-NOT transcription complex subunit 7 (CNOT7) deadenylation activity. (PMID:31180491)
• CNOT7 depletion reverses natural killer cell resistance by modulating the tumor immune microenvironment of hepatocellular carcinoma. (PMID:32160402)
• Frequent loss of BTG1 activity and impaired interactions with the Caf1 subunit of the Ccr4-Not deadenylase in non-Hodgkin lymphoma. (PMID:33021411)
• CNOT7 modulates biological functions of ovarian cancer cells via AKT signaling pathway. (PMID:33412213)
• Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer’s pathophysiology. (PMID:33757599)
• Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex. (PMID:34038562)
• CNOT7 regulates lipid deposition in nonalcoholic fatty liver disease. (PMID:38772212)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnot7	ENSDARG00000032116
mus_musculus	Cnot7	ENSMUSG00000031601
rattus_norvegicus	Cnot7	ENSRNOG00000012263
drosophila_melanogaster	Pop2	FBGN0036239
caenorhabditis_elegans		WBGENE00000369

Paralogs (1): CNOT8 (ENSG00000155508)

Protein

Protein identifiers

CCR4-NOT transcription complex subunit 7 — Q9UIV1 (reviewed: Q9UIV1)

Alternative names: BTG1-binding factor 1, CCR4-associated factor 1, Caf1a

All UniProt accessions (7): Q9UIV1, E5RGA8, E5RGH2, E5RHV9, E5RJE0, H0YAV9, H0YBT3

UniProt curated annotations — full annotation on UniProt →

Function. Has 3’-5’ poly(A) exoribonuclease activity for synthetic poly(A) RNA substrate. Its function seems to be partially redundant with that of CNOT8. Catalytic component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. During miRNA-mediated repression the complex also seems to act as translational repressor during translational initiation. Additional complex functions may be a consequence of its influence on mRNA expression. Associates with members of the BTG family such as TOB1 and BTG2 and is required for their anti-proliferative activity.

Subunit / interactions. Component of the CCR4-NOT complex; distinct complexes seem to exist that differ in the participation of probably mutually exclusive catalytic subunits; the complex contains two deadenylase subunits, CNOT6 or CNOT6L, and CNOT7 or CNOT8. In the complex, interacts directly with CNOT1. Interacts with AGO2. Interacts with TOB1; recruited by TOB1 to a ternary complex with CPEB3 which is required for mRNA deadenylation and decay. Interacts with BTG1. Interacts with BTG2. Interacts with NANOS2. Interacts with ZFP36, ZFP36L1 and ZFP36L2; these interactions are inhibited in response to phorbol 12-myristate 13-acetate (PMA) treatment in a p38 MAPK-dependent manner. Interacts with TARDBP. Interacts with BTG4. Interacts with EIF4E; this interaction is increased by CNOT7 interaction with BTG4.

Subcellular location. Nucleus. Cytoplasm. P-body. Cytoplasmic ribonucleoprotein granule.

Cofactor. Binds 2 divalent metal cations per subunit with RNAase activity being higher in presence of Mn(2+) than of Mg(2+) or Co(2+).

Similarity. Belongs to the CAF1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UIV1-1	1	yes
Q9UIV1-2	2

RefSeq proteins (16): NP_001309016, NP_001309017, NP_001309018, NP_001309019, NP_001309020, NP_001309021, NP_001309022, NP_001309023, NP_001309024, NP_001309025, NP_001309026, NP_001309027, NP_001309028, NP_001309029, NP_037486, NP_473367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006941	RNase_CAF1	Family
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily
IPR039637	CNOT7/CNOT8/Pop2	Family

Pfam: PF04857

Enzyme classification (BRENDA):

• EC 3.1.13.4 — poly(A)-specific ribonuclease (BRENDA: 15 organisms, 67 substrates, 89 inhibitors, 9 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
POLY(A) RNA	—	7
POLY(A)	0.0051	1

UniProt features (44 total): helix 13, mutagenesis site 10, strand 9, binding site 6, sequence conflict 2, turn 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2D5R	X-RAY DIFFRACTION	2.5
4GMJ	X-RAY DIFFRACTION	2.7
9E7T	ELECTRON MICROSCOPY	2.8
7AX1	X-RAY DIFFRACTION	3.3
7VOI	X-RAY DIFFRACTION	4.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UIV1-F1	91.28	0.87

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 (6): 40; 40; 42; 161; 230; 278

Mutagenesis-validated functional residues (10):

Position	Phenotype
138	abolishes interaction with cnot1; when associated with y-142 and k-149.
141	abolishes interaction with cnot1.
142	abolishes interaction with cnot1; when associated with k-138 and k-149.
149	abolishes interaction with cnot1; when associated with k-138 and y-142.
161	abolishes rna deadenylase activity. drastically reduces the rate of deadenylation and decay of cbep3-tethered mrna.
203	abolishes interaction with tob1.
225	abolishes rna deadenylase activity.
230	abolishes rna deadenylase activity.
40	abolishes rna deadenylase activity.
42	abolishes rna deadenylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-429947	Deadenylation of mRNA
R-HSA-6804115	TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain
R-HSA-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors

MSigDB gene sets: 360 (showing top): GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_P_BODY_ASSEMBLY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, TGCACTT_MIR519C_MIR519B_MIR519A, GOMF_NUCLEASE_ACTIVITY, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT

GO Biological Process (20): nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), deadenylation-dependent decapping of nuclear-transcribed mRNA (GO:0000290), regulation of translation (GO:0006417), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), negative regulation of gene expression (GO:0010629), regulatory ncRNA-mediated gene silencing (GO:0031047), P-body assembly (GO:0033962), miRNA-mediated gene silencing by mRNA destabilization (GO:0035279), regulation of tyrosine phosphorylation of STAT protein (GO:0042509), positive regulation of viral genome replication (GO:0045070), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), defense response to virus (GO:0051607), positive regulation of nuclear-transcribed mRNA poly(A) tail shortening (GO:0060213), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), positive regulation of mRNA catabolic process (GO:0061014), piRNA-mediated gene silencing by mRNA destabilization (GO:0140991), positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900153)

GO Molecular Function (13): 3’-5’-RNA exonuclease activity (GO:0000175), transcription corepressor activity (GO:0003714), RNA exonuclease activity (GO:0004532), poly(A)-specific ribonuclease activity (GO:0004535), piRNA binding (GO:0034584), metal ion binding (GO:0046872), DNA-binding transcription factor binding (GO:0140297), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): P-body (GO:0000932), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604), nuclear speck (GO:0016607), CCR4-NOT complex (GO:0030014), CCR4-NOT core complex (GO:0030015), cytoplasmic ribonucleoprotein granule (GO:0036464)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1
TP53 Regulates Transcription of Cell Cycle Genes	1
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear-transcribed mRNA catabolic process	3
mRNA destabilization	3
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	3
cellular anatomical structure	3
cell population proliferation	2
regulation of cell population proliferation	2
positive regulation of mRNA catabolic process	2
binding	2
cytoplasm	2
intracellular protein-containing complex	2
mRNA methylguanosine-cap decapping	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
positive regulation of cellular process	1
negative regulation of cellular process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
negative regulation of gene expression	1
membraneless organelle assembly	1
miRNA-mediated post-transcriptional gene silencing	1
tyrosine phosphorylation of STAT protein	1
regulation of peptidyl-tyrosine phosphorylation	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
defense response	1
response to virus	1
nuclear-transcribed mRNA poly(A) tail shortening	1
regulation of nuclear-transcribed mRNA poly(A) tail shortening	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1

Protein interactions and networks

STRING

1434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNOT7	CNOT1	A5YKK6	998
CNOT7	CNOT2	Q9NZN8	997
CNOT7	CNOT6L	Q96LI5	997
CNOT7	CNOT6	Q9ULM6	997
CNOT7	CNOT3	O75175	995
CNOT7	CNOT9	Q92600	990
CNOT7	CNOT4	O95628	968
CNOT7	CNOT10	Q9H9A5	959
CNOT7	CNOT8	Q9UFF9	936
CNOT7	BTG4	Q9NY30	910
CNOT7	CNOT11	Q9UKZ1	854
CNOT7	TOB2	Q14106	792
CNOT7	ZFP36L2	P47974	761
CNOT7	TOB1	P50616	735
CNOT7	BTG2	P78543	691

IntAct

177 interactions, top by confidence:

A	B	Type	Score
CNOT7	TOB1	psi-mi:“MI:0914”(association)	0.930
TOB1	CNOT7	psi-mi:“MI:0915”(physical association)	0.930
CNOT7	TOB1	psi-mi:“MI:0915”(physical association)	0.930
CNOT7	TOB1	psi-mi:“MI:0407”(direct interaction)	0.930
TOB1	CNOT7	psi-mi:“MI:0407”(direct interaction)	0.930
CNOT7	CNOT6L	psi-mi:“MI:0915”(physical association)	0.880
CNOT6L	CNOT7	psi-mi:“MI:0915”(physical association)	0.880
CNOT7	CNOT1	psi-mi:“MI:0914”(association)	0.880
CNOT7	CNOT6L	psi-mi:“MI:0914”(association)	0.880
CNOT7	CNOT1	psi-mi:“MI:0915”(physical association)	0.880
CNOT1	CNOT7	psi-mi:“MI:0407”(direct interaction)	0.880
CNOT7	CNOT1	psi-mi:“MI:0407”(direct interaction)	0.880
TOB2	CNOT7	psi-mi:“MI:0915”(physical association)	0.830
CNOT7	TOB2	psi-mi:“MI:0915”(physical association)	0.830
CNOT6L	CNOT1	psi-mi:“MI:0914”(association)	0.810
BTG2	CNOT7	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (282): TOB1 (Affinity Capture-Western), CNOT7 (Affinity Capture-MS), CNOT7 (Two-hybrid), CNOT7 (Two-hybrid), CNOT7 (Two-hybrid), CNOT7 (Reconstituted Complex), CNOT7 (Affinity Capture-Western), CNOT7 (Affinity Capture-MS), CNOT7 (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), CNOT1 (Affinity Capture-MS), CNOT3 (Affinity Capture-MS), TNKS1BP1 (Affinity Capture-MS), CNOT10 (Affinity Capture-MS), RAVER1 (Affinity Capture-MS)

ESM2 similar proteins: A4II96, A7SLW1, A7YW45, A9RBS1, O14744, O23617, O48538, O64773, O74856, O80738, O80765, O81209, O81210, P07805, P46513, Q06429, Q08BM8, Q0WUI9, Q17345, Q17819, Q2HXK9, Q3KQ85, Q3ZC01, Q4R5M3, Q556Y2, Q5R698, Q5ZJV9, Q60809, Q6NUA1, Q8BLR2, Q8CIG8, Q8GWT4, Q90ZA1, Q948U0, Q96A23, Q9D8X5, Q9FMS6, Q9LEU4, Q9LMI0, Q9LRA7

Diamond homologs: A4II96, O64773, O74856, P39008, Q08BM8, Q17345, Q3KQ85, Q3ZC01, Q5ZJV9, Q60809, Q9C6M9, Q9D8X5, Q9FMS6, Q9LEU4, Q9LXM2, Q9LXM4, Q9S9P2, Q9SAI2, Q9SFX6, Q9SHJ0, Q9SKZ2, Q9UFF9, Q9UIV1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CNOT7	“form complex”	“CCR4-NOT complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 88 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
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	8	88.4×	3e-12
Deadenylation of mRNA	8	74.8×	9e-12
Regulation of RUNX1 Expression and Activity	5	71.5×	2e-07
M-decay: degradation of maternal mRNAs by maternally stored factors	10	69.4×	4e-14
Regulation of MITF-M-dependent genes involved in apoptosis	5	67.5×	3e-07
TGFBR3 expression	5	48.6×	1e-06
Regulation of MECP2 expression and activity	6	47.0×	9e-08
MTOR signalling	6	33.9×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	7	109.2×	2e-11
nuclear-transcribed mRNA poly(A) tail shortening	7	78.0×	3e-10
regulatory ncRNA-mediated gene silencing	8	74.9×	2e-11
miRNA-mediated gene silencing by inhibition of translation	5	61.6×	1e-06
negative regulation of translation	7	19.1×	6e-06
regulation of translation	5	15.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1733 predictions. Top by Δscore:

Variant	Effect	Δscore
8:17230739:T:TA	donor_gain	1.0000
8:17232451:T:TA	donor_gain	1.0000
8:17233270:A:AC	donor_gain	1.0000
8:17233271:C:CC	donor_gain	1.0000
8:17234714:A:AC	donor_gain	1.0000
8:17234715:C:CC	donor_gain	1.0000
8:17234748:TC:T	donor_gain	1.0000
8:17234857:ACCG:A	acceptor_gain	1.0000
8:17234857:ACCGC:A	acceptor_loss	1.0000
8:17234858:CCG:C	acceptor_gain	1.0000
8:17234858:CCGC:C	acceptor_gain	1.0000
8:17234859:CG:C	acceptor_gain	1.0000
8:17234859:CGC:C	acceptor_gain	1.0000
8:17234860:GCTAT:G	acceptor_loss	1.0000
8:17234861:C:CC	acceptor_gain	1.0000
8:17234861:CT:C	acceptor_loss	1.0000
8:17234862:T:G	acceptor_loss	1.0000
8:17234863:A:C	acceptor_gain	1.0000
8:17234872:T:C	acceptor_gain	1.0000
8:17234872:T:TC	acceptor_gain	1.0000
8:17237370:CTCC:C	acceptor_gain	1.0000
8:17237372:CC:C	acceptor_gain	1.0000
8:17237373:CC:C	acceptor_gain	1.0000
8:17237374:CTG:C	acceptor_loss	1.0000
8:17237375:T:A	acceptor_loss	1.0000
8:17243030:T:TA	donor_gain	1.0000
8:17245067:TG:T	donor_gain	1.0000
8:17246673:A:AC	donor_gain	1.0000
8:17246674:C:CC	donor_gain	1.0000
8:17246687:G:C	donor_gain	1.0000

AlphaMissense

1889 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:17230796:C:T	G261D	1.000
8:17230797:C:G	G261R	1.000
8:17230840:A:C	F246L	1.000
8:17230840:A:T	F246L	1.000
8:17230842:A:G	F246L	1.000
8:17232442:A:C	F238L	1.000
8:17232442:A:T	F238L	1.000
8:17232444:A:G	F238L	1.000
8:17232452:C:T	G235E	1.000
8:17232453:C:G	G235R	1.000
8:17232453:C:T	G235R	1.000
8:17232458:A:G	L233P	1.000
8:17232458:A:T	L233H	1.000
8:17232465:A:G	S231P	1.000
8:17232466:A:C	D230E	1.000
8:17232466:A:T	D230E	1.000
8:17232467:T:A	D230V	1.000
8:17232467:T:C	D230G	1.000
8:17232467:T:G	D230A	1.000
8:17232468:C:A	D230Y	1.000
8:17232468:C:G	D230H	1.000
8:17232470:G:A	S229F	1.000
8:17232471:A:G	S229P	1.000
8:17232473:C:A	G228V	1.000
8:17232473:C:T	G228E	1.000
8:17232474:C:G	G228R	1.000
8:17232474:C:T	G228R	1.000
8:17232476:G:A	A227V	1.000
8:17232476:G:T	A227E	1.000
8:17232477:C:T	A227T	1.000

dbSNP variants (sampled 300 via entrez): RS1000024559 (8:17245390 A>T), RS1000124923 (8:17240681 A>G), RS1000135745 (8:17248735 G>A), RS1000303513 (8:17234353 AAC>A), RS1000466520 (8:17245546 A>T), RS1000545191 (8:17226422 C>A,T), RS1000579477 (8:17226681 C>T), RS1000760237 (8:17239717 T>C), RS1000763516 (8:17232915 T>C), RS1001038208 (8:17235678 A>G), RS1001070941 (8:17246416 C>T), RS1001120557 (8:17230524 G>A), RS1001143054 (8:17241622 T>C), RS1001201820 (8:17244862 G>A), RS1001223154 (8:17246840 C>A,T)

Disease associations

OMIM: gene MIM:604913 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3616361 (SINGLE PROTEIN)

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

ChEMBL bioactivities

11 potent at pChembl≥5 of 25 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.23	IC50	590	nM	CHEMBL3616525
5.82	IC50	1500	nM	CHEMBL3616514
5.77	IC50	1700	nM	CHEMBL3616520
5.68	IC50	2100	nM	CHEMBL3616517
5.44	IC50	3600	nM	CHEMBL3616512
5.40	IC50	4000	nM	CHEMBL3616515
5.32	IC50	4800	nM	CHEMBL3616519
5.18	IC50	6600	nM	CHEMBL3616508
5.06	IC50	8700	nM	CHEMBL3616526
5.03	IC50	9300	nM	CHEMBL3616516
5.00	IC50	9900	nM	CHEMBL3616521

PubChem BioAssay actives

11 with measured affinity, of 32 total; 11 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
3-[3-(dimethylamino)propyl]-1-hydroxy-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	0.5900	uM
1-hydroxy-7-(2-phenylethyl)-3H-purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	1.5000	uM
1-hydroxy-3-(4-methylpentyl)-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	1.7000	uM
1-hydroxy-7-(2-phenylethyl)-3-(3-phenylpropyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	2.1000	uM
1-hydroxy-7-(2-thiophen-2-ylethyl)-3H-purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	3.6000	uM
1-hydroxy-7-(2-pyridin-2-ylethyl)-3H-purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	4.0000	uM
1-hydroxy-3-pentyl-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	4.8000	uM
1-hydroxy-7-(pyridin-3-ylmethyl)-3H-purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	6.6000	uM
1-hydroxy-3-(2-morpholin-4-ylethyl)-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	8.7000	uM
1-hydroxy-3-methyl-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	9.3000	uM
1-hydroxy-3-nonyl-7-(2-phenylethyl)purine-2,6-dione	1247253: Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	increases expression	1
sodium arsenite	increases abundance, increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Amiodarone	increases expression	1
Arsenic	increases expression, increases abundance	1
Coal	decreases expression, increases abundance	1
Succimer	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Gallic Acid	increases expression	1
Gold	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Progesterone	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3619397	Binding	Inhibition of human poly(A)-selective ribonuclease Caf1 by fluorescence-based assay	Discovery, synthesis and biochemical profiling of purine-2,6-dione derivatives as inhibitors of the human poly(A)-selective ribonuclease Caf1. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1NQ	Abcam HeLa CNOT7 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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