CNOT4 Gene

HGNC Family	RNA binding motif containing (RBM)
Name	CCR4-NOT transcription complex, subunit 4
Description	The protein encoded by this gene is a subunit of the CCR4-NOT complex, a global transcriptional regulator. The encoded protein interacts with CNOT1 and has E3 ubiquitin ligase activity. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CNOT4 is a multifunctional protein that provides intrinsic E3 ubiquitin ligase activity within or in parallel to the CCR4‐NOT regulatory network. Its RING domain selectively binds to specific E2 ubiquitin‐conjugating enzymes – a specificity that has been structurally and functionally characterized – to mediate substrate ubiquitination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In several settings, CNOT4 targets key regulatory proteins for polyubiquitination and subsequent proteasomal degradation. For example, it ubiquitinates RBM15, an RNA‐binding protein involved in alternative splicing and cell‐fate determination, thereby modulating megakaryocyte differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Similarly, CNOT4 promotes the polyubiquitination of the histone H3K4 demethylase JARID1C/SMCX, which underscores a conserved mechanism to balance histone methylation and gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, in the context of influenza virus infection, CNOT4 ubiquitinates the viral nucleoprotein (NP), thereby influencing viral RNA levels, protein production, and replication complex activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " CNOT4 has also been implicated in the regulated turnover of transcription-related factors such as PAF1, linking it to control of RNA polymerase II–dependent transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition to its roles in protein quality control and transcriptional regulation, altered CNOT4 levels have been associated with cancer biology: aberrant expression in the normal colonic mucosa may contribute to RNA stabilization events that precede malignant transformation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", whereas in non‐small cell lung cancer CNOT4 appears to act as a tumor suppressor and can enhance the efficacy of anti–PD‑1 immunotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Collectively, these findings reveal that CNOT4 functions as a versatile E3 ligase, coordinating post‐translational modifications that are critical for the regulation of mRNA metabolism, chromatin modification, viral replication, and cellular signaling pathways.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Sebastiaan Winkler, Thomas K Albert, Cyril Dominguez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An altered-specificity ubiquitin-conjugating enzyme/ubiquitin-protein ligase pair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2004.01.031"}], "href": "https://doi.org/10.1016/j.jmb.2004.01.031"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15001359"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15001359"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Li Zhang, Ngoc-Tung Tran, Hairui Su, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.07938"}], "href": "https://doi.org/10.7554/eLife.07938"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26575292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26575292"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Douglas P Mersman, Hai-Ning Du, Ian M Fingerman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polyubiquitination of the demethylase Jhd2 controls histone methylation and gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1769209"}], "href": "https://doi.org/10.1101/gad.1769209"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19346402"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19346402"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yu-Chen Lin, King-Song Jeng, Michael M C Lai "}, {"type": "b", "children": [{"type": "t", "text": "CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mBio.00597-17"}], "href": "https://doi.org/10.1128/mBio.00597-17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28536288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28536288"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hwa-Young Sun, Nari Kim, Cheol-Sang Hwang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protein Degradation of RNA Polymerase II-Association Factor 1(PAF1) Is Controlled by CNOT4 and 26S Proteasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0125599"}], "href": "https://doi.org/10.1371/journal.pone.0125599"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25933433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25933433"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Masumi Tsuda, Misa Noguchi, Tsuyoshi Kurai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15157"}], "href": "https://doi.org/10.1111/cas.15157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34626022"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34626022"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Biao Zhang, Song Han, Haitao Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNOT4 enhances the efficacy of anti-PD-1 immunotherapy in a model of non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Open Bio (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/2211-5463.12998"}], "href": "https://doi.org/10.1002/2211-5463.12998"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33034149"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33034149"}]}]}]}
Synonyms	NOT4, CLONE243, NOT4H
Proteins	CNOT4_HUMAN
NCBI Gene ID	4850
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CNOT4 has 8,346 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 120 datasets.

Click the + buttons to view associations for CNOT4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CNOT4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by CNOT4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CNOT4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CNOT4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CNOT4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CNOT4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CNOT4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CNOT4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CNOT4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CNOT4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CNOT4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CNOT4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CNOT4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CNOT4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CNOT4 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CNOT4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CNOT4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CNOT4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of CNOT4 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CNOT4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CNOT4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CNOT4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CNOT4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CNOT4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CNOT4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with CNOT4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CNOT4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CNOT4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CNOT4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CNOT4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CNOT4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CNOT4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CNOT4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CNOT4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CNOT4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CNOT4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with CNOT4 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CNOT4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with CNOT4 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing CNOT4 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of CNOT4 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.