Affinage

CNOT3

CCR4-NOT transcription complex subunit 3 · UniProt O75175

Length
753 aa
Mass
81.9 kDa
Annotated
2026-06-09
38 papers in source corpus 26 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNOT3 is a scaffold subunit of the CCR4-NOT complex that controls cell fate and proliferation principally by targeting specific mRNAs for deadenylation and decay, while also acting at the transcriptional level at select promoters (PMID:27746116, PMID:21897366). As part of an ancient negative regulatory module, CNOT3 was first defined as a member of a discrete nuclear NOT complex (NOT1-NOT4) that globally represses RNA polymerase II transcription (PMID:7926748). Its post-transcriptional function operates by recruiting the CCR4-NOT deadenylase to the 3′-UTRs of target transcripts — directly binding mRNAs (e.g., RANK, RIPK1/RIPK3) or acting through RNA-binding protein intermediaries such as Roquin and ZFP36L1 — so that loss of CNOT3 elongates poly(A) tails, extends mRNA half-lives, and elevates target levels (PMID:24550297, PMID:26437789, PMID:42118148, PMID:27746116). Through this activity CNOT3 enforces stem and lineage identity by degrading differentiation-promoting transcripts: it maintains ESC/epiblast pluripotency by repressing differentiation genes including Cdx2 (PMID:22367759, PMID:27746116), sustains spermatogonial stem cell and β-cell identity (PMID:40814964, PMID:37873304, PMID:32859966), and preserves ILC2 identity by destabilizing the lineage-deviating transcripts Tbx21 and Rorc (PMID:42118148). It restrains proliferation and cell death by destabilizing cell-cycle and effector mRNAs — MAD1 (spindle checkpoint), KLF2/p21, and RIPK1/RIPK3 (necroptosis) (PMID:22342980, PMID:30531840, PMID:26437789) — and controls B-cell development, metabolic homeostasis, and inflammation, including dual transcriptional and post-transcriptional suppression of Il1b via PU.1 (PMID:26238124, PMID:28032897, PMID:39161681). Beyond mRNA decay, CNOT3 binds and represses the PRPF31 promoter directly (PMID:23144630), is phosphorylated by Aurora B near its NLS to govern nuclear localization and FGF2-induced ERK signaling during mesendoderm differentiation (PMID:34613789), and promotes codon-usage-dependent translation of targets such as c-MYC through association with ribosomal proteins and elongation factors in myeloid leukemia (PMID:38491013). Recurrent CNOT3 mutations in adult T-ALL and a conserved oncosuppressive phenotype establish a tumor-suppressor role in some contexts (PMID:23263491).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1994 High

    Established that CNOT3's ancestor (yeast NOT3) is a subunit of a discrete nuclear complex that negatively regulates RNA polymerase II transcription, defining the complex membership and its repressive function.

    Evidence Two-hybrid, allele-specific suppressor genetics, and biochemical co-fractionation in yeast

    PMID:7926748

    Open questions at the time
    • Did not address the mRNA deadenylation function later attributed to the complex
    • Yeast complex; human CNOT3 activities not yet tested
  2. 2002 Medium

    Identified a specific protein partner (TIP120B) and mapped the interacting C-terminal domain of human NOT3, beginning the molecular characterization of the human protein's interactions.

    Evidence GST pull-down and yeast two-hybrid with domain mapping

    PMID:12207886

    Open questions at the time
    • Functional consequence of the TIP120B interaction not established
    • Single-lab interaction without in vivo validation
  3. 2010 High

    Demonstrated an in vivo physiological requirement for CNOT3/CCR4-NOT in cardiac muscle integrity and linked the defect to HDAC-dependent chromatin remodeling.

    Evidence Cardiac-specific RNAi in Drosophila, heterozygous knockout mice, HDAC inhibitor rescue

    PMID:20371351

    Open questions at the time
    • Did not identify specific mRNA or transcriptional targets in heart
    • Mechanistic link between CNOT3 and HDAC activity not resolved
  4. 2011 High

    Established the core post-transcriptional mechanism: CNOT3 recruits the CCR4-NOT deadenylase to specific 3′ ends to control mRNA stability of metabolic transcripts in vivo.

    Evidence Poly(A) tail-length assay and expression profiling in Cnot3+/- hepatocytes

    PMID:21897366

    Open questions at the time
    • How CNOT3 confers target specificity not defined
    • Direct mRNA binding versus adaptor-mediated recruitment unresolved
  5. 2012 High

    Showed CNOT3 also acts as a direct transcriptional repressor by binding the PRPF31 promoter, distinguishing a chromatin-level activity from its mRNA-decay role.

    Evidence ChIP and siRNA knockdown with mRNA/protein quantification

    PMID:23144630

    Open questions at the time
    • Cofactors mediating promoter recruitment not identified
    • Generality of direct promoter binding across genes unknown
  6. 2012 Medium

    Placed CNOT3-mediated mRNA destabilization upstream of cell-cycle control by identifying MAD1 mRNA as a target governing the spindle assembly checkpoint and mitotic progression.

    Evidence siRNA knockdown, mRNA stability assay, and MAD1 epistasis (double knockdown) with mitotic index

    PMID:22342980

    Open questions at the time
    • Direct CNOT3–MAD1 mRNA binding not demonstrated
    • Single-lab study
  7. 2012 Medium

    Defined CNOT3 as a tumor suppressor through recurrent human T-ALL mutations and a conserved Drosophila loss-of-function tumor phenotype.

    Evidence Exome sequencing of adult T-ALL and Drosophila RNAi tumor model

    PMID:23263491

    Open questions at the time
    • Specific oncosuppressive target transcripts not resolved
    • Functional impact of individual patient mutations not tested
  8. 2012 Medium

    Established that CNOT1/2/3 act together as a complex to maintain ESC identity by repressing trophectoderm transcription factors, independent of known self-renewal pathways.

    Evidence siRNA/shRNA knockdown and genetic epistasis in mouse and human ESCs

    PMID:22367759

    Open questions at the time
    • Did not distinguish transcriptional from post-transcriptional repression of Cdx2
    • Direct targets beyond Cdx2 not mapped
  9. 2014 High

    Demonstrated direct 3′-UTR binding and bidirectional control of a specific mRNA (RANK), linking CNOT3 deadenylase activity to osteoclastogenesis and bone mass in vivo.

    Evidence RNA immunoprecipitation, bidirectional luciferase 3′-UTR reporter, and Cnot3+/- mouse model

    PMID:24550297

    Open questions at the time
    • RNA-binding adaptors mediating RANK 3′-UTR recognition not identified
  10. 2015 High

    Established CNOT3 as a survival factor that restrains necroptosis by destabilizing RIPK1 and RIPK3 mRNAs, placing it upstream of the necroptotic execution machinery.

    Evidence Knockdown, RIP, poly(A) tail assay, and necroptosis inhibitor/genetic rescue in MEFs

    PMID:26437789

    Open questions at the time
    • Whether CNOT3 binds RIPK mRNAs directly or via an adaptor not resolved
  11. 2015 High

    Revealed a multifaceted role in B-cell development, coupling p53 mRNA destabilization with control of Igh locus accessibility and rearrangement during the pro-to-pre-B transition.

    Evidence Conditional B-cell knockout with Igh FISH/3C, p53 knockout and pre-rearranged Igh transgene rescues

    PMID:26238124

    Open questions at the time
    • Mechanism linking CNOT3 to Igh locus compaction not defined
    • Whether Igh effect is transcriptional or post-transcriptional unresolved
  12. 2016 High

    Confirmed that deadenylation, requiring the C-terminus for CCR4-NOT association, is the mechanism by which CNOT3 maintains pluripotency by degrading differentiation gene mRNAs.

    Evidence Conditional knockout, PAL-seq, mRNA half-life measurement, and domain deletion/rescue

    PMID:27746116

    Open questions at the time
    • Sequence/structural features directing target selection not defined
  13. 2017 Medium

    Showed context-dependent control of proliferation: in cardiomyocytes CNOT3 enables CCR4-NOT to degrade anti-proliferation transcripts, promoting proliferation.

    Evidence Knockdown in hESC-derived cardiomyocytes, OE in infarcted mouse hearts, RIP, mRNA stability assay

    PMID:28473716

    Open questions at the time
    • Specific cell-cycle inhibitor target transcripts not individually validated
    • Single-lab study
  14. 2017 Medium

    Established a requirement for CNOT3 in adipose tissue homeostasis, with its loss causing lipodystrophy, inflammation, and systemic insulin resistance.

    Evidence Adipocyte-specific conditional knockout with metabolic phenotyping and expression analysis

    PMID:28032897

    Open questions at the time
    • Direct mRNA targets in adipocytes not identified
    • Single-lab study
  15. 2018 Medium

    Identified the KLF2–p21 axis as a proliferation-control target, with CNOT3 degrading KLF2 mRNA to suppress p21 in lung cancer cells.

    Evidence siRNA knockdown, mRNA stability assay, and epistatic pathway placement

    PMID:30531840

    Open questions at the time
    • Direct CNOT3–KLF2 mRNA binding not shown
    • Single-lab study
  16. 2019 Medium

    Linked CNOT3 to chemoresistance by showing it promotes cisplatin resistance through suppression of RIPK3-mediated, caspase-8-dependent apoptosis.

    Evidence Knockdown, apoptosis and caspase-8 assays, RIPK3 rescue in resistant lung cancer cells

    PMID:31177396

    Open questions at the time
    • Whether RIPK3 regulation is via mRNA deadenylation here not confirmed
    • Single-lab study
  17. 2019 Medium

    Demonstrated in vivo functional differences among CNOT3 variants, identifying E70K as a loss-of-function allele in intestinal development.

    Evidence Zebrafish cnot3a morpholino knockdown with variant mRNA rescue in apc-deficient background

    PMID:31231471

    Open questions at the time
    • Molecular basis of E70K dysfunction not defined
    • Relationship to deadenylase activity not tested
  18. 2020 High

    Extended the identity-maintenance role to pancreatic β-cells, showing CNOT3-mediated deadenylation suppresses progenitor and disallowed genes to preserve β-cell function.

    Evidence β-cell-specific conditional knockout with glucose tolerance, mRNA stability/poly(A) analysis, transcriptomics

    PMID:32859966

    Open questions at the time
    • Direct mRNA targets and adaptors in β-cells not individually validated
  19. 2021 High

    Uncovered regulation of CNOT3 itself by Aurora B phosphorylation near its NLS, controlling its nuclear localization and crosstalk with FGF2/ERK signaling during mesendoderm differentiation.

    Evidence Co-IP, domain mapping, phospho-site mutagenesis, fractionation/imaging, ESC differentiation, ERK phosphorylation assay

    PMID:34613789

    Open questions at the time
    • How nuclear CNOT3 mechanistically alters ERK signaling not resolved
    • Whether phosphorylation affects deadenylase function untested
  20. 2021 Medium

    Identified CAPN4 as a direct partner promoting CNOT3 protein degradation within a miR-124–CAPN4–CNOT3 axis modulating cisplatin-induced necroptosis.

    Evidence Co-IP, qPCR, western blot, miRNA mimic, xenograft in renal cancer cells

    PMID:34733662

    Open questions at the time
    • Mechanism of CAPN4-mediated CNOT3 turnover not defined
    • Single-lab study
  21. 2023 Medium

    Defined reciprocal EGFR/c-Jun–CNOT3 regulation, with CNOT3 translationally repressing c-Jun and contributing to gefitinib resistance via TSC1/mTOR.

    Evidence Knockdown, EGFR/HER2 inhibitors, reporter assays, gefitinib-resistance models in vitro and in vivo

    PMID:37919290

    Open questions at the time
    • Mechanism of CNOT3-mediated translational repression of c-Jun not detailed here
    • Single-lab study
  22. 2024 High

    Revealed a translation-promoting activity distinct from deadenylation: CNOT3 enhances codon-usage-dependent translation of targets including c-MYC via association with ribosomal proteins and elongation factors in AML.

    Evidence Transcriptomics, proteomics, ribosome profiling, and MS interactome with depletion phenotype

    PMID:38491013

    Open questions at the time
    • How CNOT3 reconciles mRNA-destabilizing and translation-promoting roles unresolved
    • Direct contacts with ribosome/elongation machinery not structurally defined
  23. 2024 Medium

    Demonstrated dual-layer suppression of inflammation: CNOT3 destabilizes Il1b/Nos2 mRNAs and additionally represses Il1b transcription by limiting PU.1 expression.

    Evidence Cnot3 heterozygous KO mice, nascent pre-mRNA decay assay in LPS-stimulated MEFs, lung injury model

    PMID:39161681

    Open questions at the time
    • Whether PU.1 elevation is a direct or indirect CNOT3 effect not resolved
    • Single-lab study
  24. 2025 High

    Established CNOT3 as essential for spermatogonial stem cell maintenance, degrading differentiation-promoting transcripts to preserve the stem cell pool.

    Evidence Conditional germ-cell knockout, scRNA-seq, and cultured SSC assays

    PMID:37873304 PMID:40814964

    Open questions at the time
    • RNA-binding adaptors directing SSC target selection not identified
  25. 2026 High

    Defined the adaptor logic of CNOT3 target selection in immune identity, showing it recruits deadenylation to Tbx21 and Rorc via the RNA-binding proteins Roquin and ZFP36L1 to maintain ILC2 identity.

    Evidence Conditional ILC2 knockout, 3′-UTR interaction assays, airway allergy and helminth models

    PMID:42118148

    Open questions at the time
    • Whether Roquin/ZFP36L1 bridging is direct to CNOT3 not structurally defined
    • Generality of RBP-adaptor model across other CNOT3 targets unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CNOT3 reconciles its three distinct activities — CCR4-NOT-mediated mRNA deadenylation, direct transcriptional repression at promoters, and codon-dependent translational enhancement — and how target specificity is encoded across these modes remains unresolved.
  • No unifying structural or regulatory model integrating decay, transcription, and translation roles
  • Determinants of context-specific target selection not defined
  • Conditions under which CNOT3 destabilizes versus promotes translation of a given transcript unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0140110 transcription regulator activity 2 GO:0045182 translation regulator activity 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2
Partners
AURKBCAPN4CNOT1CNOT2RC3H1TIP120BZFP36L1
Complex memberships
CCR4-NOT deadenylase complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 In yeast, NOT1, NOT2, NOT3, and NOT4 form a discrete ~500 kDa nuclear complex that acts as a global negative regulator of RNA polymerase II transcription, preferentially repressing TC TATA element-dependent transcription. Allele-specific suppression, two-hybrid interaction, and biochemical co-fractionation established complex association; NOT4 interacts with NOT1 and NOT3 in two-hybrid assays, and overexpression of NOT3 or NOT4 suppresses not1/not2 mutations. Two-hybrid interaction, allele-specific suppressor screen, biochemical co-fractionation, overexpression epistasis Genes & development High 7926748
2002 Human NOT3 (hNOT3L, an isoform with an extra 144 aa at the C-terminus) physically interacts with TIP120B (a muscle-specific TBP-interacting protein) but not with TIP120A. The C-terminal 92 aa of hNOT3L were identified as the TIP120B-interacting domain, and the N-terminal 209 aa of TIP120B mediate this binding. GST pull-down assay, yeast two-hybrid Biochemical and biophysical research communications Medium 12207886
2010 NOT3 (Drosophila ortholog) is required for cardiac muscle integrity; cardiac-specific RNAi silencing of CCR4-NOT components causes myofibrillar disarray and dilated cardiomyopathy. Heterozygous not3 knockout mice show spontaneous impairment of cardiac contractility and increased susceptibility to heart failure. These heart defects were reversed by HDAC inhibition, establishing a mechanistic link to epigenetic chromatin remodeling. Cardiac-specific RNAi in Drosophila, heterozygous knockout mouse model, HDAC inhibitor rescue Cell High 20371351
2011 CNOT3, as a subunit of the CCR4-NOT deadenylase complex, regulates mRNA stability of specific metabolic transcripts (e.g., PDK4, IGFBP1) by recruiting the CCR4-NOT deadenylase to their 3′ ends. In Cnot3+/- hepatocytes these mRNAs have elongated poly(A) tails and elevated levels, indicating CNOT3-dependent deadenylation controls their decay. Poly(A) tail-length assay, gene expression profiling, Cnot3+/- mouse model The EMBO journal High 21897366
2012 CNOT3 directly binds to a specific PRPF31 promoter sequence and transcriptionally represses PRPF31 expression. siRNA-mediated silencing of CNOT3 in cultured cells causes an increase in PRPF31 mRNA and protein, confirming CNOT3 as a transcriptional repressor of PRPF31. Chromatin immunoprecipitation (ChIP), siRNA knockdown with mRNA/protein quantification PLoS genetics High 23144630
2012 CNOT3 depletion increases the mitotic index and specifically stabilizes MAD1 mRNA, elevating MAD1 protein levels and activating the spindle assembly checkpoint. MAD1 knockdown attenuates the CNOT3-depletion-induced mitotic arrest, placing CNOT3-mediated MAD1 mRNA destabilization upstream of the spindle checkpoint. siRNA knockdown, mRNA stability assay, MAD1 rescue knockdown, mitotic index measurement Biochemical and biophysical research communications Medium 22342980
2012 CNOT3 functions as a tumor suppressor in T-ALL; its knockdown in a sensitized Drosophila model causes tumors, supporting a conserved oncosuppressive role. Mutations in CNOT3 were identified in 7/89 (7.9%) adult T-ALL cases by exome sequencing. Exome sequencing of patient samples, Drosophila RNAi tumor model Nature genetics Medium 23263491
2012 Cnot1, Cnot2, and Cnot3 function as a protein complex to maintain mouse and human ESC identity by repressing early trophectoderm transcription factors such as Cdx2. Genetic analysis showed they do not act through known self-renewal pathways or core transcription factors. siRNA/shRNA knockdown in mouse and human ESCs, gene expression analysis, genetic epistasis Stem cells (Dayton, Ohio) Medium 22367759
2014 CNOT3 destabilizes RANK mRNA by binding to its 3′-UTR. Anti-CNOT3 antibody immunoprecipitates RANK mRNA; Cnot3 deficiency stabilizes RANK 3′-UTR-linked luciferase reporter ~2-fold, and Cnot3 overexpression destabilizes the same reporter. This post-transcriptional regulation of RANK mRNA controls osteoclastogenesis and bone mass. RNA immunoprecipitation (RIP), luciferase 3′-UTR reporter assay, Cnot3+/- mouse model, Cnot3 overexpression Proceedings of the National Academy of Sciences of the United States of America High 24550297
2015 CNOT3 depletion in MEFs causes necroptotic cell death by stabilizing mRNAs encoding RIPK1 and RIPK3; these mRNAs bind CNOT3 and exhibit elongated poly(A) tails in its absence. Inhibition of RIPK1-RIPK3 signaling (shRNA or necrostatin-1) rescues viability of CNOT3-depleted MEFs, placing CNOT3-mediated mRNA destabilization upstream of necroptosis execution. siRNA/shRNA knockdown, RNA immunoprecipitation, poly(A) tail assay, necroptosis inhibitor rescue, gene expression profiling Scientific reports High 26437789
2015 B cell-specific deletion of CNOT3 blocks pro-to-pre-B cell transition. CNOT3 regulates generation of germline transcripts in the VH region of the Igh locus, locus compaction, and Igh gene rearrangement, and destabilizes p53 mRNA. Partial rescue by p53 ablation or pre-rearranged Igh transgene places CNOT3 upstream of both p53 mRNA stability and Igh locus accessibility. Conditional Cnot3 knockout in B cells, Igh locus FISH/3C, p53 knockout epistasis, pre-rearranged Igh transgene rescue The Journal of experimental medicine High 26238124
2016 CNOT3-dependent mRNA deadenylation is required for mouse epiblast maintenance. CNOT3 C-terminus is required for its interaction with the CCR4-NOT complex and its function in ESCs. Cnot3 deletion increases poly(A) tail lengths, half-lives, and steady-state levels of differentiation gene mRNAs, demonstrating that CNOT3 maintains pluripotency by promoting deadenylation and degradation of differentiation gene transcripts. Conditional Cnot3 knockout (embryo/ESC), poly(A) tail length sequencing (PAL-seq), mRNA half-life measurement, domain deletion/rescue experiments Stem cell reports High 27746116
2017 Cnot3 promotes cardiomyocyte proliferation by enabling CCR4-NOT complex interaction with anti-proliferation gene transcripts in a Cnot3-dependent manner, promoting their degradation. The CCR4-NOT complex preferentially associated with cell cycle inhibitor mRNAs when Cnot3 was present, as shown by RNA immunoprecipitation. siRNA knockdown in human ESC-derived cardiomyocytes, Cnot3 overexpression in infarcted mouse hearts, RNA immunoprecipitation, mRNA stability assay Scientific reports Medium 28473716
2017 Adipocyte-specific disruption of Cnot3 in mice causes lipodystrophy with decreased WAT, enhanced inflammation, increased brown adipose tissue with larger lipid droplets, hyperinsulinemia, hyperglycemia, and insulin resistance, demonstrating that CNOT3-mediated mRNA regulation in adipocytes is required for normal adipose tissue homeostasis. Adipocyte-specific Cnot3 conditional knockout mouse (Cnot3ad-/-), metabolic phenotyping, gene expression analysis FEBS letters Medium 28032897
2018 CNOT3 depletion in A549 non-small cell lung cancer cells suppresses proliferation by stabilizing KLF2 mRNA, which in turn induces p21 (CDKN1A) expression. CNOT3 targets KLF2 mRNA for degradation, placing CNOT3 upstream of the KLF2–p21 axis in cell cycle control. siRNA knockdown, mRNA stability assay, gene expression analysis Oncogene Medium 30531840
2019 CNOT3 depletion in A549/DDP (cisplatin-resistant) lung cancer cells up-regulates RIPK3 expression and sensitizes cells to apoptosis via Caspase-8 activation, establishing that CNOT3 promotes cisplatin resistance by suppressing RIPK3-mediated apoptotic signaling. siRNA knockdown, apoptosis assay, caspase-8 activation measurement, RIPK3 rescue experiment Apoptosis : an international journal on programmed cell death Medium 31177396
2019 In zebrafish FAP model, CTBP1 regulates cnot3a expression. CNOT3 E70K mutation (but not E20K) fails to rescue cnot3a knockdown lordosis phenotype and does not initiate gut differentiation in apc-deficient zebrafish, identifying E70K as a loss-of-function variant affecting intestinal developmental function. Zebrafish cnot3a morpholino knockdown, mRNA rescue injection, apc zebrafish model, in vivo gut differentiation assay Oncotarget Medium 31231471
2020 β-cell-specific Cnot3 deletion (Cnot3βKO) causes impaired glucose tolerance, decreased β-cell mass, and gradual diabetes. Cnot3βKO islets show increased mRNA stability and altered deadenylation, leading to elevated expression of progenitor markers and β-cell-disallowed genes, demonstrating that CNOT3-mediated mRNA deadenylation is required for β-cell identity and function. β-cell-specific conditional Cnot3 knockout, glucose tolerance testing, mRNA stability and poly(A) analysis, transcriptomic profiling Communications biology High 32859966
2021 CNOT3 interacts with Aurora B kinase via sequences in the NOT box domain. Aurora B phosphorylates CNOT3 at two sites near a nuclear localization signal, promoting nuclear localization of CNOT3 in mouse ESCs and metastatic lung cancer cells. ESCs with both phosphorylation sites mutated produce embryoid bodies largely devoid of mesoderm/endoderm and show reduced survival of mesendoderm progenitors. The double mutation alters the balance of CNOT3 interaction with Aurora B versus ERK and reduces ERK phosphorylation in response to FGF2. Co-immunoprecipitation, site-directed mutagenesis, subcellular fractionation/imaging, ESC differentiation assay, kinase assay, ERK phosphorylation measurement Molecular biology of the cell High 34613789
2021 CAPN4 directly interacts with CNOT3 (confirmed by co-immunoprecipitation) and promotes CNOT3 protein degradation. In the miR-124–CAPN4–CNOT3 axis, miR-124 suppresses CAPN4, which stabilizes CNOT3 and thereby reduces cisplatin-induced necroptosis in renal cancer cells. Co-immunoprecipitation, qPCR, western blotting, miRNA mimic transfection, xenograft model Translational andrology and urology Medium 34733662
2023 In lung cancer cells, EGFR signaling upregulates CNOT3 expression via the transcription factor c-Jun. Reciprocally, CNOT3 inversely regulates c-Jun expression at the translational level. CNOT3 reduction post-EGFR blockade inhibits cell proliferation partly via the TSC1/mTOR axis. Elevated CNOT3 in gefitinib-resistant cells is driven by bypass HER2/c-Jun signaling. siRNA knockdown, EGFR/HER2 inhibitor treatment, reporter assay, in vitro and in vivo gefitinib resistance models, western blotting Cell death discovery Medium 37919290
2024 CNOT3 acts as a modulator of translation efficiency in myeloid leukemia. CNOT3 selectively promotes translation of target genes in a codon-usage-dependent manner and associates with a protein network comprising ribosomal proteins and translation elongation factors. c-MYC is identified as a critical downstream target translationally regulated by CNOT3. CNOT3 depletion induces AML cell differentiation and apoptosis. Transcriptomic and proteomic profiling, ribosome profiling, mass spectrometry interactome, CNOT3 depletion with defined cellular phenotype Nature communications High 38491013
2024 CNOT3 haploinsufficiency stabilizes both Il1b and Nos2 mRNAs post-transcriptionally and also represses Il1b transcription. PU.1 (Spi1) was identified as a transcription factor whose elevated expression under Cnot3 haploinsufficiency promotes Il1b transcription, revealing dual transcriptional and post-transcriptional mechanisms by which CNOT3 suppresses pro-inflammatory gene expression. Cnot3 heterozygous conditional KO mice, mRNA decay (nascent pre-mRNA) assay in LPS-stimulated MEFs, acid aspiration ALI model Journal of inflammation research Medium 39161681
2025 CNOT3 is essential for spermatogonial stem cell (SSC) maintenance and spermatogenesis in mice. Cnot3 deletion in spermatogonia causes de-repression of transcripts encoding differentiation factors (including glutathione redox pathway genes), depletion of the SSC pool, and infertility. CNOT3 functions via the CCR4-NOT complex to degrade differentiation-promoting transcripts and maintain the stem cell state. Conditional Cnot3 knockout in adult germ cells and spermatogonia, single-cell RNA sequencing, cell proliferation/viability assay of cultured SSCs, SSC marker quantification Development (Cambridge, England) High 37873304 40814964
2026 CNOT3 maintains ILC2 identity by destabilizing Tbx21 and Rorc mRNAs through interactions with RNA-binding proteins Roquin (for Tbx21 3′-UTR) and ZFP36L1 (for Rorc 3′-UTR). Loss of CNOT3 in ILC2s causes aberrant T-bet and RORγt expression, suppression of GATA-3, and impaired type 2 immune responses. Conditional Cnot3 deletion in ILC2s, 3′-UTR interaction assays, airway allergy and helminth infection models, gene expression analysis The Journal of experimental medicine High 42118148

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nature genetics 336 23263491
2010 A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. Cell 186 20371351
1994 NOT1(CDC39), NOT2(CDC36), NOT3, and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes & development 183 7926748
2012 CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS genetics 110 23144630
2011 Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3+/- mice. The EMBO journal 80 21897366
2012 Cnot1, Cnot2, and Cnot3 maintain mouse and human ESC identity and inhibit extraembryonic differentiation. Stem cells (Dayton, Ohio) 65 22367759
2019 The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genetics in medicine : official journal of the American College of Medical Genetics 52 31474762
2015 CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability. The Journal of experimental medicine 49 26238124
2015 CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins. Scientific reports 36 26437789
2016 CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State. Stem cell reports 33 27746116
2013 Dominant PRPF31 mutations are hypostatic to a recessive CNOT3 polymorphism in retinitis pigmentosa: a novel phenomenon of "linked trans-acting epistasis". Annals of human genetics 31 24116917
2014 Stability of mRNA influences osteoporotic bone mass via CNOT3. Proceedings of the National Academy of Sciences of the United States of America 28 24550297
2019 De novo variants in CNOT3 cause a variable neurodevelopmental disorder. European journal of human genetics : EJHG 25 31201375
2016 Transcriptional Regulator CNOT3 Defines an Aggressive Colorectal Cancer Subtype. Cancer research 22 27899379
2018 CNOT3 targets negative cell cycle regulators in non-small cell lung cancer development. Oncogene 19 30531840
2017 Adipocyte-specific disruption of mouse Cnot3 causes lipodystrophy. FEBS letters 18 28032897
2012 Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression. Biochemical and biophysical research communications 17 22342980
2020 Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation. Communications biology 16 32859966
2012 A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis. Annals of the rheumatic diseases 15 22294640
2002 TBP-interacting protein 120B, which is induced in relation to myogenesis, binds to NOT3. Biochemical and biophysical research communications 15 12207886
2019 CNOT3 contributes to cisplatin resistance in lung cancer through inhibiting RIPK3 expression. Apoptosis : an international journal on programmed cell death 13 31177396
2021 MiRNA-124 regulates the sensitivity of renal cancer cells to cisplatin-induced necroptosis by targeting the CAPN4-CNOT3 axis. Translational andrology and urology 11 34733662
2017 Cnot3 enhances human embryonic cardiomyocyte proliferation by promoting cell cycle inhibitor mRNA degradation. Scientific reports 11 28473716
2024 Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis. Nature communications 10 38491013
2021 Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype. Genes 10 34208845
2023 Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients. Neurogenetics 7 36802310
2021 A Genetic Study of Cerebral Atherosclerosis Reveals Novel Associations with NTNG1 and CNOT3. Genes 7 34073619
2019 Functional characterization of CNOT3 variants identified in familial adenomatous polyposis adenomas. Oncotarget 5 31231471
2021 CNOT3 interacts with the Aurora B and MAPK/ERK kinases to promote survival of differentiating mesendodermal progenitor cells. Molecular biology of the cell 4 34613789
2025 Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization. European journal of human genetics : EJHG 3 40562808
2025 Cnot3 is required for male germ cell development and spermatogonial stem cell maintenance. Development (Cambridge, England) 3 40814964
2024 Novel In-Frame Deletion CNOT3 Variant in a Family With Intellectual Developmental Disorder With Speech Delay and Dysmorphic Facies. Neurology. Genetics 3 38179413
2023 Cnot3 is required for male germ cell development and spermatogonial stem cell maintenance. bioRxiv : the preprint server for biology 3 37873304
2023 Targeting the up-regulated CNOT3 reverses therapeutic resistance and metastatic progression of EGFR-mutant non-small cell lung cancer. Cell death discovery 2 37919290
2025 Knockdown of CNOT3, a subunit of the CCR4-NOT deadenylase complex, sensitizes A549 human non-small cell lung cancer cells to senescence-inducing stimuli. Biochemical and biophysical research communications 1 39823890
2024 Haploinsufficiency of Cnot3 Aggravates Acid-Induced Acute Lung Injury Likely Through Transcriptional and Post-Transcriptional Upregulation of Pro-Inflammatory Genes. Journal of inflammation research 1 39161681
2026 CNOT3 resists ovarian aging by accelerating oocyte maturation and promoting ESCs differentiation. Stem cell research & therapy 0 41547942
2026 CNOT3 supports ILC2 differentiation and function by destabilizing Tbx21 and Rorc transcripts. The Journal of experimental medicine 0 42118148

Missed literature

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