CNOT3: CCR4-NOT Transcription Complex Subunit 3
A key regulator of mRNA deadenylation, gene expression, and cellular homeostasis; implicated in hematological malignancies and developmental disorders.
Gene Information Card
| Symbol | CNOT3 |
|---|---|
| Full Name | CCR4-NOT transcription complex subunit 3 |
| Gene Type | protein-coding |
| Chromosomal Location | 19q13.42 |
| NCBI Gene ID | 4849 ncbi.nlm.nih.gov/gene/4849 |
| Ensembl ID | ENSG00000188010 |
| UniProt ID | O75175 |
| OMIM ID | 604910 |
| HGNC ID | 7879 |
| Aliases | NOT3, NOT3H, CDC39, LENG9, CCR4-associated factor 3 |
Description
CNOT3 encodes a subunit of the CCR4-NOT complex, a major regulator of mRNA deadenylation and turnover. The complex controls gene expression post-transcriptionally by shortening poly(A) tails, thereby influencing mRNA stability and translation. CNOT3 is also involved in transcription initiation and elongation, DNA damage response, and cellular differentiation. Mutations in CNOT3 are recurrent in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers, and germline variants are associated with developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| T-cell acute lymphoblastic leukemia (T-ALL) | Somatic loss-of-function mutations in CNOT3 impair mRNA deadenylation, leading to altered expression of oncogenes and tumor suppressors. | COSMIC; PMID: 24670627 |
| Adult T-cell leukemia/lymphoma (ATLL) | Recurrent somatic mutations in CNOT3 contribute to leukemogenesis through dysregulation of the CCR4-NOT complex. | COSMIC; PMID: 25326802 |
| Intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF) | Heterozygous germline missense and truncating variants in CNOT3 cause a neurodevelopmental syndrome via haploinsufficiency. | ClinVar; PMID: 31006513 |
| Breast cancer | Somatic CNOT3 alterations (amplifications/mutations) may affect mRNA stability of cell cycle regulators. | COSMIC; PMID: 21798893 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 25.3 | High |
| Bone marrow | 18.7 | High |
| Lymph node | 15.2 | Medium |
| Brain (cerebellum) | 12.1 | Medium |
| Heart | 10.5 | Medium |
| Liver | 8.9 | Low |
| Pancreas | 7.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (leukemia) | 22.1 | High expression |
| HEK293 (embryonic kidney) | 18.5 | High expression |
| HeLa (cervical carcinoma) | 15.3 | Medium expression |
| HepG2 (liver carcinoma) | 9.8 | Low expression |
| MCF7 (breast carcinoma) | 11.2 | Medium expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1072C>T (p.Arg358*) | Nonsense | 0.5% in T-ALL | Loss-of-function; truncation of CNOT3 protein |
| c.1246G>A (p.Gly416Arg) | Missense | 0.2% in T-ALL | Loss-of-function; impaired complex assembly |
| c.1A>G (p.Met1?) | Start-loss | <0.1% | Loss-of-function; abolished translation initiation |
| c.1450_1451del (p.Leu484Glufs*12) | Frameshift | 0.3% in ATLL | Loss-of-function; premature stop |
| c.832C>T (p.Arg278Cys) | Missense | Germline (IDDSDF) | Likely loss-of-function; reduced protein stability |
Mutation functional classification
Loss of Function (LOF)
The majority of CNOT3 mutations in T-ALL and ATLL are loss-of-function (nonsense, frameshift, missense affecting complex integrity), leading to reduced deadenylation activity and altered mRNA stability.
Gain of Function (GOF)
No gain-of-function mutations have been reported for CNOT3 in the curated databases.
Dominant Negative (DN)
Some missense mutations (e.g., p.Gly416Arg) may exert dominant-negative effects by disrupting CCR4-NOT complex assembly, though haploinsufficiency is the primary mechanism.
View complete mutation data：
Gene Ontology (GO)
| • nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289) | • protein binding (GO:0005515) |
| • nucleus (GO:0005634) | • cytoplasm (GO:0005737) |
| • CCR4-NOT complex (GO:0030014) | • circadian regulation of gene expression (GO:0032922) |
| • negative regulation of mRNA splicing (GO:0048025) | • regulation of defense response to virus (GO:1900150) |
Pathways
• mRNA deadenylation (REACT_1762)
• CCR4-NOT complex mediated mRNA decay (R-HSA-429958)
• Gene expression (Transcription) (R-HSA-74160)
• Cell cycle (R-HSA-1640170)
Protein Summary
CNOT3 is a 753-amino acid protein (UniProt O75175) that serves as a scaffold subunit of the CCR4-NOT complex. It contains a NOT-box domain essential for complex assembly and interacts with other subunits (CNOT1, CNOT2) to regulate deadenylation. The protein is ubiquitously expressed, with highest levels in testis and hematopoietic tissues. Post-translational modifications include phosphorylation, which may modulate complex activity. CNOT3 is critical for maintaining mRNA homeostasis, and its disruption leads to oncogenic transformation and neurodevelopmental phenotypes.
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