Affinage

NELFE

Negative elongation factor E · UniProt P18615

Length
380 aa
Mass
43.2 kDa
Annotated
2026-06-10
39 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NELFE is the RNA-binding subunit of the Negative Elongation Factor complex that couples nascent transcript recognition to promoter-proximal RNA Polymerase II pausing (PMID:24453987). Its RNA Recognition Motif adopts a βαββαβ fold and binds RNA directly, undergoing a conformational change in which its C-terminal region folds into an α-helix upon engaging RNA (PMID:16898873, PMID:18303858); through this RRM it recognizes a defined consensus element (NBE, CUGAGGA(U)) that is enriched 20–30 nucleotides downstream of transcription start sites at paused genes, linking sequence-specific RNA binding to the pausing function (PMID:24453987). A C-terminal peptide of NELFE binds the nuclear cap-binding complex in a manner mutually exclusive with ARS2/PHAX, defining a distinct CBC–NELFE complex at capped nascent transcripts (PMID:29101316). Beyond steady-state transcription, NELFE is recruited to DNA double-strand breaks in a PARP1- and Pol II-dependent manner to shut off local transcription and enable repair (PMID:28336775). NELFE also acts oncogenically across multiple cancers, both by post-transcriptionally tuning target mRNA stability—destabilizing NDRG2 to activate Wnt/β-catenin signaling and EMT in pancreatic cancer (PMID:31638184) and stabilizing E2F2 via its 3'UTR in gastric cancer (PMID:34295816)—and by co-opting the EMT transcription factor SLUG as a chromatin partner to drive a KAT2B-dependent transcriptional program (PMID:37117180). In hepatocellular carcinoma, NELFE amplification enhances MYC signaling and reprograms the tumor transcriptome (PMID:28697339).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Established that NELFE's RRM is a bona fide RNA-binding module by determining its fold and demonstrating direct, quantifiable binding to a viral RNA element.

    Evidence NMR solution structure and fluorescence equilibrium titrations with labeled RNA oligonucleotides (HIV-1 TAR)

    PMID:16898873

    Open questions at the time
    • Did not define a physiological cellular RNA target
    • Binding measured only against TAR RNA in vitro
  2. 2008 High

    Revealed the structural mechanism of RNA recognition, showing that RNA binding drives a major conformational change including formation of a C-terminal helix.

    Evidence NMR chemical-shift perturbation mapping and solution structure of the RNA-bound RRM

    PMID:18303858

    Open questions at the time
    • Functional consequence of the conformational change in vivo not tested
    • Studied as isolated RRM, not within the NELF complex
  3. 2014 High

    Connected NELFE's RNA-binding specificity to its biological role by identifying a consensus element enriched at paused promoters genome-wide.

    Evidence In vitro SELEX, quantitative binding assays, and genome-wide bioinformatic analysis of NBE distribution

    PMID:24453987

    Open questions at the time
    • Direct demonstration that NBE engagement controls pausing at endogenous genes not shown
    • Consensus defined for Drosophila NELF-E
  4. 2017 High

    Extended NELFE function beyond steady-state transcription, showing it represses transcription at DNA double-strand breaks to facilitate repair.

    Evidence I-SceI and CRISPR DSB induction, live-cell recruitment imaging, PARP1 inhibition epistasis, and Pol II depletion with repair readouts

    PMID:28336775

    Open questions at the time
    • Molecular basis of PARP1-dependent recruitment unresolved
    • Whether RRM RNA binding is required at DSBs not established
  5. 2017 High

    Defined a structural interface linking NELFE to cap-bound transcripts, showing it binds the cap-binding complex mutually exclusively with ARS2/PHAX.

    Evidence Crystal structure of CBC–NELFE, cap-analogue co-crystallization, and competition binding

    PMID:29101316

    Open questions at the time
    • Functional outcome of CBC–NELFE versus CBC–ARS2–PHAX partitioning in cells not determined
    • Cap-dependent vs RRM-dependent recruitment not integrated
  6. 2017 Medium

    Implicated NELFE as an oncogenic driver, showing copy-number-driven activation enhances MYC signaling in hepatocellular carcinoma.

    Evidence Analysis of 1,225 clinical HCC samples, somatic copy-number analysis, and functional transcriptomic studies in HCC cells

    PMID:28697339

    Open questions at the time
    • Mechanism by which NELFE selects MYC-associated genes not defined
    • Single lab
  7. 2019 Medium

    Identified a post-transcriptional oncogenic mechanism in which NELFE destabilizes NDRG2 mRNA to activate Wnt/β-catenin signaling and EMT.

    Evidence shRNA knockdown, mRNA decay assays, RIP, luciferase reporters, and invasion assays in pancreatic cancer

    PMID:31638184

    Open questions at the time
    • RNA element on NDRG2 bound by NELFE not mapped
    • Single lab
  8. 2021 Medium

    Showed NELFE can also stabilize target mRNAs, binding the E2F2 3'UTR to promote gastric cancer growth, with E2F2 placed downstream by rescue.

    Evidence shRNA knockdown, mRNA stability assays, E2F2 overexpression rescue, and xenograft experiments

    PMID:33526068 PMID:34295816

    Open questions at the time
    • How NELFE switches between stabilizing and destabilizing outcomes unknown
    • Direct vs indirect 3'UTR binding not fully resolved
  9. 2023 High

    Connected NELFE to a chromatin-level oncogenic program, showing it partners with SLUG and drives KAT2B-dependent EMT gene expression.

    Evidence qPLEX-RIME chromatin interactomics, SLUG ChIP, NELFE loss-of-function, and genetic/pharmacological KAT2B inactivation in cell lines and organoids

    PMID:37117180

    Open questions at the time
    • Whether SLUG recruitment depends on NELFE's RRM or NELF complex integrity not dissected
    • Relationship to pausing function unclear
  10. 2025 Medium

    Placed NELFE in a translation-initiation regulatory network, with its mRNA as a 4EHP interactor and its loss affecting 40S/eIF3 levels and ATF4 output.

    Evidence TRIBE screen, quantitative proteomics, and genetic epistasis with ATF4 reporter in Drosophila fat body

    PMID:41436469

    Open questions at the time
    • Mechanism connecting NELF-E to ribosome subunit levels unknown
    • Conservation in mammals not established
  11. 2025 Low

    Proposed that NELFE phase-separates with SMARCB1 to remodel chromatin accessibility and Pol II pausing in HCC.

    Evidence LLPS assays, low-complexity sequence mapping, SMARCB1 interaction studies, and chromatin accessibility/Pol II pausing readouts (preprint)

    PMID:40313774

    Open questions at the time
    • Preprint; methods not fully specified and not independently confirmed
    • Physiological role of condensates versus complex-based pausing unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NELFE's well-defined RRM/NBE pausing function mechanistically integrates with its diverse cytoplasmic and oncogenic mRNA-stability and chromatin-partner roles remains unresolved.
  • No unifying model linking sequence-specific RNA binding to mRNA stability control
  • Whether mRNA-stability functions occur within or outside the NELF complex is unknown
  • Structural basis of target mRNA selection in cancers not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-73894 DNA Repair 1
Partners
ARS2NCBP1PARP1SLUGSMARCB1
Complex memberships
CBC-NELFE complexNELF complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 The RRM (RNA Recognition Motif) of NELF-E adopts a βαββαβ fold in solution and directly binds HIV-1 TAR RNA with Kd values in the low-micromolar range, demonstrated using NMR structure determination and fluorescence equilibrium titrations with fluorescently labeled single-stranded and double-stranded oligoribonucleotides. NMR solution structure determination; fluorescence equilibrium titration with fluorescently labeled RNA oligonucleotides The Biochemical Journal High 16898873
2008 RNA binding to NELF-E RRM induces a major conformational change: the C-terminal region, which is unstructured in the free protein, forms an α-helix upon TAR RNA binding, and large chemical shift perturbations also occur in the loop between β3 and α2, regions distant from the canonical RRM binding interface. The RNA-bound NELF-E RRM structure closely resembles RNA-bound U1A RRM. NMR spectroscopy (chemical shift perturbation mapping); solution structure determination of RNA-bound NELF-E RRM Biochemistry High 18303858
2014 NELF-E contains an RRM that recognizes a specific consensus RNA element (NBE: CUGAGGA(U) for Drosophila NELF-E) identified by in vitro SELEX. An NBE-like element is present in the loop region of HIV-1 TAR RNA and is required for high-affinity binding. NBE sequences are enriched +20 to +30 nucleotides downstream of transcription start sites genome-wide in paused genes, supporting a role for NELF-E RNA binding in promoter-proximal Pol II pausing. In vitro SELEX (systematic evolution of ligands by exponential enrichment); quantitative binding assays; genome-wide bioinformatic analysis of NBE distribution; nuclear run-on SELEX PLoS Genetics High 24453987
2017 NELF-E (and NELF-A) are rapidly recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner, preferentially at DSBs upstream of transcriptionally active genes where RNA Pol II is present. NELF-E recruitment and its repressive activity are required to switch off transcription at DSBs, and NELF-E is required for intact DSB repair. I-SceI endonuclease and CRISPR-Cas9 DSB induction systems; live-cell recruitment assays (imaging); PARP1 inhibition epistasis; RNA Pol II ChIP/depletion; loss-of-function (knockdown) with transcription and repair readouts EMBO Reports High 28336775
2017 The C-terminal peptide of NELF-E binds directly to the nuclear cap-binding complex (CBC) in a manner that is enhanced when CBC is bound to a cap analogue. The NELF-E C-terminal peptide and the homologous C-terminal peptide of ARS2 bind identically to CBC, forming mutually exclusive complexes. NELF-E binding to CBC is incompatible with PHAX binding, defining two mutually exclusive complexes: CBC-NELF-E and CBC-ARS2-PHAX. Crystal structure determination; biochemical binding assays; co-crystallization with cap analogue; competition binding experiments Nature Communications High 29101316
2017 Oncogenic activation of NELFE via somatic copy-number alterations enhances MYC signaling and promotes hepatocellular carcinoma (HCC) progression. NELFE selectively regulates MYC-associated genes, inducing a unique tumor transcriptome. Analysis of 1,225 clinical HCC samples; somatic copy-number alteration analysis; functional studies in HCC cells; transcriptomic analysis of NELFE-regulated genes Cancer Cell Medium 28697339
2019 NELFE promotes pancreatic cancer metastasis and epithelial-to-mesenchymal transition (EMT) by decreasing the mRNA stability of NDRG2, thereby activating the Wnt/β-catenin signaling pathway. NELFE directly binds the NDRG2 mRNA as shown by RNA immunoprecipitation. shRNA knockdown; mRNA decay assays; RNA immunoprecipitation (RIP); luciferase reporter assays; transwell invasion/migration assays; western blotting for β-catenin pathway components International Journal of Oncology Medium 31638184
2021 NELFE promotes gastric cancer growth and metastasis by binding the 3'UTR of E2F2 mRNA and increasing E2F2 mRNA stability. Overexpression of E2F2 rescues the proliferation and migration defects caused by NELFE knockdown, placing NELFE upstream of E2F2. shRNA knockdown; RNA binding to 3'UTR (RIP implied); mRNA stability assays; rescue experiments with E2F2 overexpression; xenograft in vivo experiments; transwell assays Frontiers in Oncology Medium 34295816
2021 NELFE activates CSNK2B expression through the Wnt/β-catenin signaling pathway in gastric cancer. Gain- and loss-of-function experiments demonstrated that NELFE potentiates gastric cancer cell proliferation and metastasis in vitro and in vivo, with CSNK2B identified as a downstream effector using a 10-pathway reporter array and dual-luciferase reporter assays. Gain- and loss-of-function (siRNA/overexpression); Cignal Finder 10-Pathway Reporter Array; dual-luciferase reporter assays; CCK-8, colony formation, transwell assays; nude mouse xenograft model; IHC on consecutive sections Journal of Experimental & Clinical Cancer Research Medium 33526068
2023 NELF-E co-opts the EMT transcription factor SLUG as a chromatin partner during breast cancer EMT, and NELF-E loss impairs SLUG binding on chromatin. The histone acetyltransferase KAT2B is identified as a key functional downstream target of the NELF-E–SLUG axis, with KAT2B regulating EMT marker expression. NELF complex inhibition downregulates EMT and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME); ChIP assays for SLUG binding; loss-of-function (NELF-E knockdown/knockout); genetic and pharmacological KAT2B inactivation; integrative transcriptomics and genomics; cancer cell lines and patient-derived tumor organoids Nature Communications High 37117180
2025 In Drosophila, NELF-E mRNA is a top interactor of the cap-binding protein 4EHP. Knockdown of NELF-E reduces multiple subunits of the 40S ribosome (RpS) and eIF3 translation initiation factor subunits, and NELF-E knockdown suppresses ATF4 expression and its target genes, placing NELF-E in an ATF4 regulatory network with 4EHP, 40S ribosome, and eIF3. TRIBE (Targets of RNA Binding through Editing) screen to identify 4EHP-NELF-E mRNA interaction; quantitative proteomics after NELF-E knockdown; genetic epistasis (knockdown of NELF-E, 4EHP, RpS12, eIF3l, eIF3h with ATF4 reporter readout); Drosophila larval fat body in vivo model Nature Communications Medium 41436469
2025 NELFE undergoes liquid-liquid phase separation (LLPS) mediated by two low-complexity sequences, forming distinct nuclear foci. NELFE phase-separates with SMARCB1 to modulate chromatin accessibility, downregulating pro-apoptotic genes through Pol II pausing while activating pro-growth signals, thereby promoting HCC progression. Phase separation assays (LLPS); identification of low-complexity sequences; co-IP/interaction studies with SMARCB1; ATAC-seq or equivalent chromatin accessibility assays; Pol II pausing analysis; loss-of-function with apoptotic and growth gene expression readouts Research Square (preprint)preprint Low 40313774

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 RDP: detection of recombination amongst aligned sequences. Bioinformatics (Oxford, England) 1205 10980155
2003 The Ribosomal Database Project (RDP-II): previewing a new autoaligner that allows regular updates and the new prokaryotic taxonomy. Nucleic acids research 951 12520046
2005 The Ribosomal Database Project (RDP-II): sequences and tools for high-throughput rRNA analysis. Nucleic acids research 947 15608200
1999 A new version of the RDP (Ribosomal Database Project). Nucleic acids research 646 9847171
1997 The RDP (Ribosomal Database Project). Nucleic acids research 628 9016515
1996 The Ribosomal Database Project (RDP). Nucleic acids research 391 8594608
2007 The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain : a journal of neurology 180 17282997
2011 Distribution of Na/K-ATPase alpha 3 isoform, a sodium-potassium P-type pump associated with rapid-onset of dystonia parkinsonism (RDP) in the adult mouse brain. The Journal of comparative neurology 132 21165980
2017 Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma. Cancer cell 126 28697339
2017 NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. EMBO reports 71 28336775
2014 Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions. PLoS genetics 56 24453987
2017 Structural basis for mutually exclusive co-transcriptional nuclear cap-binding complexes with either NELF-E or ARS2. Nature communications 42 29101316
1999 Substitution of Asp-309 by Asn in the Arg-Asp-Pro (RDP) motif of Acetobacter diazotrophicus levansucrase affects sucrose hydrolysis, but not enzyme specificity. The Biochemical journal 42 9895294
2012 Associations of the C2-CFB-RDBP-SKIV2L locus with age-related macular degeneration and polypoidal choroidal vasculopathy. Ophthalmology 40 23260260
2006 Structural studies on the RNA-recognition motif of NELF E, a cellular negative transcription elongation factor involved in the regulation of HIV transcription. The Biochemical journal 31 16898873
1998 Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 28 9799600
1990 A clonal prostaglandin-responsive cell line (RDP 4-1) derived from rat dental pulp. Bone and mineral 28 2176558
2018 Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-β signaling pathways in mice. Journal of ethnopharmacology 25 30342194
2009 Role of RDBP and SKIV2L variants in the major histocompatibility complex class III region in polypoidal choroidal vasculopathy etiology. Ophthalmology 23 19556007
1988 Rabbit MHC. II. Sequence analysis of the R-DP alpha- and beta-genes. Journal of immunology (Baltimore, Md. : 1950) 21 2834455
2021 Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression. Journal of experimental & clinical cancer research : CR 19 33526068
2019 NELFE promoted pancreatic cancer metastasis and the epithelial‑to‑mesenchymal transition by decreasing the stabilization of NDRG2 mRNA. International journal of oncology 19 31638184
2023 Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Nature communications 15 37117180
2014 History and impact of RDP: a legacy from Carl Woese to microbiology. RNA biology 15 24607969
2019 NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma. Scientific reports 14 30833661
2021 The RNA-Binding Protein NELFE Promotes Gastric Cancer Growth and Metastasis Through E2F2. Frontiers in oncology 13 34295816
2008 NELF-E RRM undergoes major structural changes in flexible protein regions on target RNA binding. Biochemistry 12 18303858
2015 A novel cell-permeable RDP-p53 fusion protein for specific inhibition on the growth of cancerous neural cells. Drug delivery 10 25765771
2025 CAF-derived exosomal LINC01711 promotes breast cancer progression by activating the miR-4510/NELFE axis and enhancing glycolysis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 40172996
2021 Renoprotective activity of Ribes diacanthum pall (RDP) against inflammation in cisplatin-stimulated mice model and human renal tubular epithelial cells. Journal of ethnopharmacology 5 34601083
2004 Refined linkage to the RDP/DYT12 locus on 19q13.2 and evaluation of GRIK5 as a candidate gene. Movement disorders : official journal of the Movement Disorder Society 5 15254951
1992 Polymorphism in the RD (D6S45) gene. Human genetics 4 1534063
2025 Recombination Analysis of Geminiviruses Using Recombination Detection Program (RDP). Methods in molecular biology (Clifton, N.J.) 3 40064777
2016 In vivo study of the role of α6-containing nicotinic acetylcholine receptor in retinal function using subtype-specific RDP-MII(E11R) toxin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 27682206
2025 Phase separation of NELFE modulates chromatin accessibility to promote dichotomous signaling pathways in hepatocellular carcinoma. Research square 1 40313774
2025 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila. Nature communications 1 41436469
2021 Comparison of in-vitro and in-vivo parameters of whole blood derived random donor platelets (RDP) after over-night hold with RDP prepared after 2-h hold: Single centre report from India. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 1 34538569
2025 AMCF-RDP: a self-attention-based multi-source and cascade framework for the identification of drug-protein relationships. Molecular diversity 0 40866752
2025 TCN-RDP: Predicting Drug-Induced Liver Injury from Time-Series Toxicogenomic Data. Journal of chemical information and modeling 0 41056366

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