CNOT3 Gene

Name	CCR4-NOT transcription complex, subunit 3
Description	Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Mar 2025]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CNOT3 is a non‐catalytic subunit of the CCR4–NOT complex that plays multifaceted roles in the regulation of gene expression at the post‐transcriptional level. Structural studies have demonstrated that CNOT3, in conjunction with CNOT1 and CNOT2, forms a scaffold (the “NOT module”) that is essential for the assembly and proper function of the entire complex, thereby facilitating mRNA deadenylation and subsequent decay."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functionally, CNOT3 has been implicated in diverse biological processes. It can act as a transcriptional repressor; for example, by directly binding to specific promoter regions, CNOT3 modulates gene expression and has been identified as a key modifier of disease penetrance in conditions such as autosomal dominant retinitis pigmentosa through its repression of PRPF31 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, CNOT3 plays a critical role in metabolic homeostasis. In liver and adipose tissues, its regulated expression enables the CCR4–NOT complex to be recruited to the 3′ end of specific mRNAs, promoting their deadenylation. Reduced CNOT3 levels (for instance, during fasting) are associated with longer poly(A) tails and increased stability of mRNAs involved in energy metabolism, thereby contributing to lean phenotypes and improved glucose tolerance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n CNOT3 is also indispensable for cell survival and proper developmental decisions. Depletion of CNOT3 in mouse embryonic fibroblasts results in the stabilization of mRNAs encoding pro-necroptotic proteins such as RIPK1 and RIPK3, making cells prone to necroptotic death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, in bone homeostasis, CNOT3 modulates osteoclastogenesis by targeting the mRNA of RANK, thus controlling its stability and ensuring balanced bone resorption; loss or reduction of CNOT3 leads to elevated RANK mRNA levels and contributes to osteoporosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, CNOT3-dependent deadenylation has been shown to be essential for the maintenance of pluripotency in embryonic stem cells. By promoting the degradation of differentiation-related transcripts, CNOT3 helps sustain the pluripotent state."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CNOT3 serves as a central regulator that integrates structural assembly of the CCR4–NOT complex with targeted mRNA turnover. Through its roles in transcriptional repression and deadenylation-mediated mRNA decay, CNOT3 influences a wide range of fundamental cellular processes—including developmental decisions, metabolic control, bone remodeling, and cell survival—thereby modifying disease phenotypes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andreas Boland, Ying Chen, Tobias Raisch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and assembly of the NOT module of the human CCR4-NOT complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.2681"}], "href": "https://doi.org/10.1038/nsmb.2681"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24121232"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24121232"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alain-Pierre Petit, Lara Wohlbold, Praveen Bawankar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The structural basis for the interaction between the CAF1 nuclease and the NOT1 scaffold of the human CCR4-NOT deadenylase complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gks883"}], "href": "https://doi.org/10.1093/nar/gks883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22977175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22977175"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Giulia Venturini, Anna M Rose, Amna Z Shah, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003040"}], "href": "https://doi.org/10.1371/journal.pgen.1003040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23144630"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23144630"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Masahiro Morita, Yuichi Oike, Takeshi Nagashima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/- mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.320"}], "href": "https://doi.org/10.1038/emboj.2011.320"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21897366"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21897366"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Toru Suzuki, Chisato Kikuguchi, Sahil Sharma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep14779"}], "href": "https://doi.org/10.1038/srep14779"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26437789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26437789"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Chiho Watanabe, Masahiro Morita, Tadayoshi Hayata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stability of mRNA influences osteoporotic bone mass via CNOT3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1316932111"}], "href": "https://doi.org/10.1073/pnas.1316932111"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24550297"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24550297"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xiaofeng Zheng, Pengyi Yang, Brad Lackford, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Reports (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stemcr.2016.09.007"}], "href": "https://doi.org/10.1016/j.stemcr.2016.09.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27746116"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27746116"}]}]}]}
Synonyms	LENG2, NOT3H, NOT3
Proteins	CNOT3_HUMAN
NCBI Gene ID	4849
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CNOT3 has 7,060 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 126 datasets.

Click the + buttons to view associations for CNOT3 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CNOT3 Gene

Functional Associations

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

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 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 CNOT3 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CNOT3 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 CNOT3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CNOT3 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CNOT3 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CNOT3 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CNOT3 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 CNOT3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with CNOT3 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of CNOT3 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing CNOT3 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CNOT3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CNOT3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing CNOT3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CNOT3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing CNOT3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CNOT3 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 CNOT3 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 CNOT3 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CNOT3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CNOT3 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CNOT3 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DGIdb Drug Targets 2026	interacting drugs for CNOT3 protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CNOT3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CNOT3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CNOT3 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 CNOT3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CNOT3 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 CNOT3 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 CNOT3 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CNOT3 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.