Affinage

NSMF

NMDA receptor synaptonuclear signaling and neuronal migration factor · UniProt Q6X4W1

Length
530 aa
Mass
60.1 kDa
Annotated
2026-06-10
76 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The NSMF locus encodes two functionally distinct proteins built on transcriptional and genome-protective roles. The dominant product is NELF-A, a subunit of the metazoan negative elongation factor (NELF) complex of five polypeptides (A–E) that, together with DSIF, represses RNA polymerase II elongation in a manner reversed by P-TEFb-mediated CTD phosphorylation (PMID:10199401, PMID:12612062). NELF establishes promoter-proximal pausing of Pol II 30–50 nt downstream of transcription start sites genome-wide, requiring a nascent transcript longer than 18 nt and orchestrated recruitment by sequence-specific factors such as GAF (PMID:12782658, PMID:18332113, PMID:20534440, PMID:23746353). Structurally, NELF binds the polymerase funnel and trigger loop to restrain Pol II mobility, exclude TFIIS, and stabilize a paused state with a tilted DNA-RNA hybrid that impairs NTP binding (PMID:30135580). Pause release is triggered by enhancer RNAs that allosterically contact NELF-A and NELF-E to detach the complex, and by ERK-mediated NELF-A phosphorylation (counteracted by PP2A) at immediate-early genes (PMID:35508485, PMID:36463234). Beyond canonical pausing, NELF couples to RNA processing machineries—the cap-binding complex and SLBP for histone mRNA 3'-end processing, and Integrator for snRNA processing and termination (PMID:17499042, PMID:24968874, PMID:25410209)—and recent rapid-depletion studies redefine NELF as a factor that focuses initiation sites, maintains promoter chromatin architecture, and controls termination to prevent transcription-replication conflicts (PMID:38197272, PMID:41721097). Under stress, NELF forms nuclear condensates dependent on NELF-A dephosphorylation and SUMOylation of its intrinsically disordered region to drive transcriptional downregulation, with condensate dynamics regulated by the HSPA1A/DNAJB1 chaperone system (PMID:33548202, PMID:41653920). In the DNA damage response, NELF-E is recruited to double-strand breaks via PARP1 to repress local transcription and promote BRCA1/RAD51-dependent homologous recombination (PMID:28336775, PMID:33248388). Separately, the NSMF/Jacob protein from the same locus functions as a synapto-nuclear messenger transducing NMDAR/BDNF signals to activate CREB and sustain Bdnf transcription during hippocampal dendritogenesis (PMID:26977770), and acts as a scaffold at stalled replication forks that modulates RPA binding modes on ssDNA to potentiate ATR-mediated RPA32 phosphorylation and the replication stress response (PMID:33963872, PMID:37378431).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Established that a multisubunit factor cooperates with DSIF to repress Pol II elongation, defining the existence of negative elongation control reversible by P-TEFb.

    Evidence Purification from HeLa nuclear extract with in vitro transcription elongation assays

    PMID:10199401

    Open questions at the time
    • Subunit composition and individual subunit roles not yet resolved
    • Mechanism of Pol II contact unknown
  2. 2003 High

    Defined NELF as a five-subunit complex and assigned NELF-A as the critical Pol II-binding subunit, enabling functional reconstitution.

    Evidence Subunit identification, recombinant coexpression in insect cells, mutant in vitro transcription assays

    PMID:12612062

    Open questions at the time
    • Structural basis of subunit assembly not determined
    • How NELF-A contacts Pol II at atomic level unresolved
  3. 2003 High

    Demonstrated in vivo that NELF drives promoter-proximal pausing at an inducible gene and dissociates upon activation, linking the factor to gene regulation.

    Evidence Immunodepletion, RNAi in salivary glands, ChIP and polytene immunofluorescence in Drosophila

    PMID:12782658 PMID:15741180

    Open questions at the time
    • Signal triggering NELF dissociation not defined
    • Genome-wide scope of pausing not yet assessed
  4. 2008 High

    Showed NELF-mediated pausing is a genome-wide phenomenon affecting thousands of genes, including highly expressed ones, expanding NELF beyond a simple repressor.

    Evidence ChIP-chip and permanganate genomic footprinting in Drosophila

    PMID:18332113

    Open questions at the time
    • Determinants of which genes are paused not fully defined
    • Functional consequence of pausing at active genes unclear
  5. 2010 High

    Resolved how NELF is loaded onto the elongation complex, showing DSIF binds nascent RNA >18 nt and recruits NELF, while NELF RNA binding is dispensable for pausing.

    Evidence Reconstituted Drosophila Pol II elongation complex with protein-RNA cross-linking and defined RNA lengths

    PMID:20534440 PMID:23746353

    Open questions at the time
    • Role of NELF-E RNA binding in vivo remained ambiguous
    • Timing of loading relative to pause position needed structural context
  6. 2014 High

    Defined NELF-E's RNA-binding specificity (NBE consensus) and identified eRNAs as physiological ligands that release NELF during activation, connecting enhancers to pause control.

    Evidence SELEX, quantitative binding, genome-wide NBE analysis; RNA-IP, ChIP, and eRNA knockdown in neurons

    PMID:24453987 PMID:25263592

    Open questions at the time
    • Structural basis of eRNA-induced NELF release not yet shown
    • Generality of eRNA mechanism across gene classes unclear
  7. 2007 High

    Extended NELF function beyond pausing to RNA processing, coupling it to CBC/SLBP for histone mRNA 3'-end formation and revealing NELF nuclear bodies.

    Evidence Co-IP, RNAi, ChIP, RT-PCR, immunofluorescence

    PMID:17499042

    Open questions at the time
    • Mechanism linking pausing to processing not defined
    • Composition and function of NELF bodies unresolved
  8. 2014 High

    Established NELF/DSIF–Integrator coupling for correct snRNA processing and termination, broadening NELF's role to non-coding RNA fate.

    Evidence Co-IP, ChIP, RNAi with snRNA processing readouts; reciprocal Integrator interaction studies

    PMID:24968874 PMID:25410209

    Open questions at the time
    • How NELF directs processing versus pausing not mechanistically separated
    • Catalytic interplay with INTS11 incompletely defined
  9. 2018 High

    Provided the atomic mechanism of pausing, showing NELF binds the polymerase funnel and trigger loop to restrain Pol II and exclude TFIIS.

    Evidence Cryo-EM structure of Pol II-DSIF-NELF at 3.2 Å

    PMID:30135580 PMID:37591184

    Open questions at the time
    • Dynamics of pause-to-release transition not captured
    • Conformational basis of eRNA-triggered detachment unresolved
  10. 2022 High

    Identified ERK phosphorylation of NELF-A (opposed by PP2A) and allosteric eRNA contacts as triggers of NELF dissociation, linking signaling to pause release at immediate-early genes.

    Evidence In vitro kinase assays, MS site mapping, ChIP, PP2A inhibition; in vitro eRNA binding with cross-linking MS

    PMID:28336775 PMID:35508485 PMID:36463234

    Open questions at the time
    • Integration of multiple release signals in vivo not resolved
    • Quantitative contribution of each pathway per gene unknown
  11. 2021 High

    Revealed stress-induced NELF condensation governed by dephosphorylation and NELF-A IDR SUMOylation as a mechanism for transcriptional downregulation and stress survival.

    Evidence Live imaging, FRAP, SUMOylation/dephosphorylation assays, IDR domain swaps, ChIP under stress

    PMID:33548202 PMID:41653920

    Open questions at the time
    • Which target genes are silenced by condensates not fully mapped
    • How condensation alters Pol II engagement mechanistically incomplete
  12. 2020 High

    Connected NELF-E to genome maintenance through PARP1-dependent recruitment to DSBs, BRCA1 interaction, and promotion of homologous recombination.

    Evidence I-SceI/CRISPR DSB systems, laser microirradiation, Co-IP, IRIF and HDR assays, PARP inhibitor synthetic lethality

    PMID:28336775 PMID:33248388

    Open questions at the time
    • Whether transcriptional repression and HR promotion are separable not resolved
    • Mechanism of BRCA1 recruitment by NELF-E undefined
  13. 2016 High

    Defined the distinct NSMF/Jacob protein as a synapto-nuclear messenger transducing NMDAR/BDNF signals to CREB to sustain Bdnf transcription and dendritogenesis.

    Evidence Nsmf knockout mice, nuclear translocation imaging, CREB phosphorylation, electrophysiology, BDNF rescue

    PMID:26977770

    Open questions at the time
    • Relationship between Jacob and nuclear NELF function unclear
    • Carrier mechanism of long-distance nuclear import not detailed here
  14. 2023 High

    Defined NSMF's biophysical role at stalled forks, showing it scaffolds RPA and selectively shifts RPA to the stable 30-nt binding mode to potentiate ATR-mediated RPA32 phosphorylation.

    Evidence Co-IP, single-molecule DNA binding assays, purified-protein RPA binding mode analysis; KO mouse genomic instability assays

    PMID:33963872 PMID:37378431

    Open questions at the time
    • Structural basis of RPA-mode displacement unresolved
    • How NSMF is recruited to forks not defined
  15. 2024 High

    Rapid-depletion studies redefined NELF's primary role as focusing initiation sites and controlling termination/chromatin architecture rather than canonical pause-release, with loss driving transcription-replication conflict.

    Evidence Auxin-inducible degradation of NELF-B/C, PRO-seq, TT-seq/NET-seq, DFF-ChIP, termination factor ChIP

    PMID:32155413 PMID:38197272 PMID:40

    Open questions at the time
    • Reconciliation of pause-release versus initiation/termination models incomplete
    • Subunit-specific contributions to each function not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same NSMF locus partitions into the nuclear NELF complex versus the synapto-nuclear/replication-fork Jacob protein, and whether their genome-protective functions mechanistically intersect, remains unresolved.
  • Isoform/protein product relationship between NELF-A and Jacob/NSMF undefined in the corpus
  • No unified structural or regulatory model spanning both functions
  • Tissue-specific expression switching not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-112316 Neuronal System 1
Partners
ATRBRCA1DSIFINTEGRATORNELFBNELFEPARP1RPA
Complex memberships
NELF complex (NELF-A/B/C/D/E)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NELF (negative elongation factor) is a multisubunit complex that cooperates with DSIF to strongly repress RNA polymerase II elongation; this repression is reversed by P-TEFb-dependent phosphorylation of the Pol II C-terminal domain. The smallest subunit of NELF is identical to RD, a putative RNA-binding protein. Purification from HeLa nuclear extract, in vitro transcription elongation assays with DRB, biochemical reconstitution Cell High 10199401
2003 NELF contains five polypeptides (A–E): NELF-A has similarity to hepatitis delta antigen and is critical for RNAPII binding and transcriptional pausing; NELF-B is identical to COBRA1 (a BRCA1-associated protein); NELF-C and NELF-D are related to TH1; NELF-B and NELF-C/D are integral subunits that bring NELF-A and NELF-E together. Coexpression of all four proteins in insect cells reconstitutes functionally active NELF. The HDAg-homology region of NELF-A is critical for RNAPII binding. Subunit identification, recombinant coexpression in insect cells, in vitro transcription assays with mutant complexes Molecular and cellular biology High 12612062
2003 NELF and DSIF cause promoter-proximal pausing of RNA Pol II on the Drosophila hsp70 gene. Immunodepletion of NELF from Drosophila nuclear extract reduced paused polymerase levels. In vivo cross-linking showed NELF and DSIF associate with the hsp70 promoter region before heat shock. After heat shock induction, DSIF and Pol II but not NELF were recruited to chromosomal puffs at hsp70 genes, suggesting NELF dissociates upon activation. Immunodepletion from nuclear extract, RNA interference in salivary glands, in vivo protein-DNA cross-linking (ChIP), immunofluorescence on polytene chromosomes Genes & development High 12782658
2000 DSIF and NELF associate with the RNA Pol II elongation complex during early transcription elongation and travel with elongation complexes as nascent RNA is synthesized. HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of DSIF and RNA Pol II during elongation to overcome NELF/DSIF repression. Stepwise RNA Pol II walking approach, Western blotting, in vitro kinase assay The Journal of biological chemistry High 11112772
2000 FACT functions with P-TEFb to relieve DSIF/NELF-mediated transcriptional repression. TFIIH kinase activity is dispensable for this relief, demonstrating that TFIIH-mediated CTD phosphorylation is not involved in regulating FACT and DSIF/NELF activities. FACT acts on naked DNA templates independently of its chromatin activities. In vitro transcription elongation assay with purified factors, kinase inhibition experiments Molecular cell High 10912001
2005 Drosophila NELF has four subunits analogous to human NELF subunits. Immunodepletion of NELF from Drosophila nuclear extract impairs promoter-proximal pausing on the hsp70 promoter without affecting transcription initiation. ChIP detects NELF at hsp70 and beta1-tubulin promoters; heat shock induction causes marked decrease of NELF at the hsp70 promoter. Immunodepletion, in vitro transcription, chromatin immunoprecipitation (ChIP), immunofluorescence on polytene chromosomes Nucleic acids research High 15741180
2006 NELF-E RRM adopts a betaalphabetabetaalphabeta fold and binds to HIV TAR RNA. NMR solution structure of the RRM was determined. The RRM binds single-stranded TAR RNA oligoribonucleotides with Kd values in the low-micromolar range. NMR solution structure determination, fluorescence equilibrium titration binding assays The Biochemical journal High 16898873
2006 NELF-mediated transcriptional pausing has a dual role at the human junB gene: before IL-6 induction, RNAPII, DSIF, and NELF accumulate at ~+50 from TSS; after induction, depletion of NELF enhances junB mRNA both before and after induction, indicating NELF-mediated pausing contributes to negative regulation at both stages. Chromatin immunoprecipitation, RNA interference (siRNA knockdown), RT-PCR Molecular and cellular biology Medium 16880520
2007 NELF interacts with the nuclear cap-binding complex (CBC) and together they participate in 3'-end processing of replication-dependent histone mRNAs through association with SLBP. Absence of NELF and CBC causes aberrant production of polyadenylated histone mRNAs. NELF is physically associated with histone gene loci and forms distinct intranuclear foci (NELF bodies) that overlap with Cajal bodies and cleavage bodies. Co-immunoprecipitation, RNA interference, RT-PCR, chromatin immunoprecipitation, immunofluorescence microscopy Molecular cell High 17499042
2007 NELF is associated with the HIV LTR and pauses RNA Pol II at the LTR in a repressed state. NELF depletion increased processive HIV transcription and replication, released paused Pol II, displaced a positioned nucleosome, and increased histone H4 acetylation, linking transcription elongation to chromatin remodeling. Chromatin immunoprecipitation, NELF depletion (RNAi), Pol II mapping on LTR, nucleosome positioning analysis The Journal of biological chemistry High 17442680
2008 NELF-E RRM undergoes major conformational changes upon RNA binding: the flexible C-terminal region and loop between beta3 and alpha2 show large chemical shift perturbations. RNA binding induces formation of a helix in the C-terminus, resulting in an RNA-bound structure similar to U1A RRM. NMR solution structure of RNA-bound NELF-E RRM, chemical shift perturbation analysis Biochemistry High 18303858
2008 NELF is concentrated at the 5' ends of ~2,111 genes genome-wide in Drosophila cells (ChIP-chip), and 46 of 56 tested NELF-associated genes display paused Pol II 30–50 nt downstream of TSS. NELF associates with ~39% of GAGA factor-bound genes. NELF associates with ~half of the most highly expressed genes, indicating it is not necessarily a repressor. ChIP-chip (genome-wide location analysis), permanganate genomic footprinting for paused Pol II detection Molecular and cellular biology High 18332113
2009 NELF-E is predominantly nuclear in GnRH neurons. Mutagenesis of a putative nuclear localization signal results in impaired nuclear expression. NELF knockdown impairs GnRH neuronal migration of NLT cells in vitro. Immunofluorescence, NLS mutagenesis, siRNA knockdown with migration assay Molecular and cellular endocrinology Medium 20025934
2009 NELF subunits exhibit distinct subcellular localizations including NELF bodies and midbodies; some subunits shuttle actively between nucleus and cytoplasm. Loss of NELF from cells leads to enlarged and/or multiple nuclei. Live imaging of GFP-fusion proteins, FRAP, subcellular fractionation, fluorescence microscopy Experimental cell research Medium 19245807
2010 DSIF and NELF require a nascent transcript longer than 18 nt to stably associate with the Pol II elongation complex. Spt5 (DSIF) contacts nascent RNA as it emerges from the elongation complex via protein-RNA cross-linking, suggesting DSIF binds via the nascent transcript and subsequently recruits NELF. No NELF-RNA contact was detected when the nascent transcript was between 22–31 nt (the pausing region), suggesting RNA binding by NELF is not required for promoter-proximal pausing. Reconstituted Drosophila Pol II elongation complex, protein-RNA cross-linking, DSIF/NELF binding assays with defined RNA lengths Proceedings of the National Academy of Sciences of the United States of America High 20534440
2013 The timing between NELF loading onto Pol II and Pol II escape from the promoter determines the location of the promoter-proximal pause. GAF (sequence-specific transcription factor) orchestrates efficient pausing by recruiting NELF to promoters before transcription initiation and by assisting in loading NELF onto Pol II after initiation. Permanganate-ChIP-seq (genome-wide), biochemical reconstitution system for promoter-proximal pausing Molecular cell High 23746353
2013 NELF interacts with the Integrator complex subunits (INTScom) in an RNA- and DNA-independent manner. Integrator subunits control NELF-mediated RNAPII pause/release at coding genes; INTS11 catalytic subunit is required for RNAPII processivity. NELF-target genes are enriched in TAR/NBE-like elements and 3'-box sequences. Co-immunoprecipitation, siRNA knockdown, ChIP, nascent RNA analysis, genome-wide studies Nature communications High 25410209
2013 NELF interacts with Pcf11 (a transcription termination factor) to couple RNAP II pausing to premature transcription termination at the HIV LTR. NELF also interacts with the corepressor complex NCoR1-GPS2-HDAC3, which is associated with repressed HIV LTRs. Depleting NELF or Pcf11 in primary CD4+ T cells induces HIV transcription elongation. Co-immunoprecipitation, ChIP, siRNA knockdown in primary T cells, HIV transcription assays The Journal of biological chemistry Medium 23884411
2013 BRD4 coordinates recruitment of both the pause release factor P-TEFb and the pausing complex NELF/DSIF to IFN-stimulated genes. A BRD4 small-molecule inhibitor blocks IFN-induced recruitment of P-TEFb and NELF/DSIF. NELF knockdown revealed it negatively regulates Pol II passage across ISGs during elongation. ChIP, shRNA knockdown, small-molecule BRD4 inhibitor treatment Molecular and cellular biology Medium 23589332
2014 NELF-E contains an RNA Recognition Motif (RRM) that binds a consensus NELF-E binding element (NBE: CUGAGGA(U) for Drosophila). An NBE-like element is present in the loop of HIV-1 TAR RNA and is required for high-affinity binding (not the lower stem as previously claimed). NBEs are enriched +20 to +30 nt downstream of TSS genome-wide in paused genes. In vitro SELEX, quantitative biochemical binding assays, genome-wide NBE analysis in Drosophila PLoS genetics High 24453987
2014 eRNAs interact with the NELF complex and facilitate transient release of NELF from specific target promoters (immediate early genes) during transcriptional activation in neurons. Knockdown of enhancer-specific eRNAs impairs NELF release from promoters and decreases target mRNA induction. Enhancer-promoter chromatin looping enables local eRNA action. RNA immunoprecipitation, eRNA knockdown (siRNA), ChIP, chromatin conformation capture Molecular cell High 25263592
2014 DSIF and NELF associate with Integrator to specify the correct post-transcriptional fate of snRNA genes. Knockdown of NELF results in misprocessing of U1, U2, U4, and U5 snRNAs, disruption of transcription termination, and induction of polyadenylated U1 transcripts via enhanced recruitment of cleavage stimulation factor. DSIF is required for proper transcription of these snRNA genes. Co-immunoprecipitation, RNA interference (siRNA), ChIP, RT-PCR for snRNA processing Nature communications High 24968874
2017 The C-terminal peptides of NELF-E and ARS2 bind identically to the nuclear cap-binding complex (CBC), and affinity is enhanced when CBC is bound to a cap analogue. NELF-E and ARS2 compete for the same CBC binding site, forming mutually exclusive complexes: CBC-NELF-E (likely earlier transcription phase) and CBC-ARS2-PHAX (later phase). NELF-E binding to CBC is incompatible with PHAX binding. Biochemical binding assays, crystal structure determination of CBC-NELF-E peptide complex Nature communications High 29101316
2017 NELF-E and NELF-A are rapidly recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner. NELF-E is preferentially recruited to DSBs upstream of transcriptionally active genes; RNA Pol II presence is a prerequisite. NELF-E recruitment and its repressive activity are required for switching off transcription at DSBs and for intact repair of DSBs. I-SceI endonuclease and CRISPR-Cas9 DSB systems, ChIP, live imaging, transcription and repair assays EMBO reports High 28336775
2018 Cryo-EM structure of the paused transcription elongation complex (Pol II-DSIF-NELF) at 3.2 Å. NELF binds the polymerase funnel, bridges two mobile polymerase modules, and contacts the trigger loop, restraining Pol II mobility required for pause release. NELF prevents TFIIS binding. NELF has two flexible 'tentacles' that can contact DSIF and exiting RNA. The paused complex features a tilted DNA-RNA hybrid that impairs NTP substrate binding. Cryo-electron microscopy structure determination at 3.2 Å, structural analysis of complex interfaces Nature High 30135580
2020 Upon rapid NELF depletion, RNA Pol II fails to be released into gene bodies, stalling instead around the +1 nucleosomal dyad-associated region in a manner independent of P-TEFb. NELF depletion results in global loss of cap-binding complex (CBC) from chromatin without global reduction of nascent transcript 5' cap stability, implicating NELF in early elongation complexes distinct from canonical pause-release. Auxin-inducible degron (rapid NELF depletion), PRO-seq, ChIP-seq Molecular cell High 32155413
2021 NELF rapidly forms nuclear condensates upon stress (heat, oxidative, osmotic stress) in human cells. Condensate formation requires NELF dephosphorylation and SUMOylation induced by stress. The intrinsically disordered region (IDR) in NELFA is necessary for nuclear NELF condensation and can be functionally replaced by IDRs of FUS or EWSR1. Biomolecular condensation facilitates enhanced recruitment of NELF to promoters upon stress to drive transcriptional downregulation. NELF condensation is required for cellular viability under stressful conditions. Live cell imaging, FRAP, SUMOylation assays, dephosphorylation assays, IDR domain swap experiments, ChIP upon stress Molecular cell High 33548202
2021 NSMF (Jacob/NSMF protein) localizes rapidly to stalled replication forks and acts as a scaffold to modulate RPA complex formation with CDC5L and ATR/ATRIP. Depletion of NSMF compromises phosphorylation and ubiquitination of RPA2 and the ATR signaling cascade, resulting in genomic instability. NSMF knockout mice exhibited increased genomic instability and hypersensitivity to genotoxic stress. Co-immunoprecipitation, immunofluorescence at stalled forks, siRNA knockdown, NSMF knockout mice, ATR signaling assays (phosphorylation, ubiquitination) Nucleic acids research High 33963872
2022 eRNAs stimulate Pol II pause release by making multiple allosteric contacts with NELF subunits -A and -E to trigger efficient NELF detachment from paused Pol II. eRNA function requires length >200 nucleotides and unpaired guanosines; it does not require common structural or sequence motifs. In vitro NELF-eRNA binding assays, cross-linking mass spectrometry, eRNA length/structure mutants, pause release functional assays Nature communications High 35508485
2022 ERK phosphorylates NELF-A upon growth factor stimulation, causing dissociation of NELF from paused Pol II at promoter-proximal regions of immediate-early genes to allow productive elongation. PP2A efficiently dephosphorylates NELF-A, preventing aberrant IEG expression. In cancer cells, decreased PP2A activity combined with oncogene-mediated ERK activation induces NELF-A phosphorylation and IEG upregulation. In vitro kinase assay (ERK→NELF-A), phosphorylation site identification (MS), ChIP, growth factor stimulation experiments, PP2A inhibitor treatment Nature communications High 36463234
2023 NSMF physically interacts with RPA at DNA damage sites. NSMF selectively displaces RPA in weakly bound 8- and 20-nucleotide binding modes from ssDNA, allowing retention of stable RPA molecules in the 30-nt binding mode. The 30-nt binding mode of RPA enhances RPA32 phosphorylation by ATR, and phosphorylated RPA becomes stabilized on ssDNA. Co-immunoprecipitation, single-molecule DNA binding assays, purified protein biochemical assays, RPA binding mode analysis Nucleic acids research High 37378431
2023 NELF-depleted Drosophila cells recapitulate NELF-independent pausing observed in fission yeast. Only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for Pol II pause release into productive elongation. In NELF-depleted cells, Cdk9 inhibition fails to shut down transcription efficiently, allowing non-productive transcription to continue. NELF depletion in Drosophila cells, Cdk9 inhibition, PRO-seq, genetic epistasis analysis Nature communications High 37179384
2023 Crystal structure of the human NELF-B/C/E ternary complex was solved at high resolution. Detailed interaction interfaces between subunits were characterized, and residues important for the NELF-B and NELF-E association were identified. X-ray crystallography Biochemical and biophysical research communications High 37591184
2024 NELF depletion increased utilization of downstream transcription start sites and caused genome-wide loss of H3K4me3-marked nucleosomes. NELF depletion had minimal effect on paused transcript levels and almost no effect on productive elongation control, redefining NELF as a factor that focuses initiation sites and maintains promoter chromatin architecture rather than primarily controlling pause-release. Auxin-inducible degradation of NELFB, PRO-seq (nascent RNA), DFF-ChIP (chromatin architecture) Nucleic acids research High 38197272
2016 Jacob (encoded by the Nsmf gene) mediates BDNF-induced NMDAR-dependent nuclear translocation in early development. Nuclear import of Jacob results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout mice show reduced hippocampal Bdnf mRNA and protein, reduced pCREB, hippocampal dysplasia with fewer synapses, simplified dendrites, reduced LTP, and deficits in hippocampus-dependent learning. BDNF application rescues morphological deficits in Jacob-deficient hippocampal neurons. Nsmf knockout mouse generation, immunofluorescence for nuclear translocation, CREB phosphorylation assays, Bdnf mRNA/protein quantification, electrophysiology (LTP), BDNF rescue experiments PLoS genetics High 26977770
2020 NELF-E interacts with BRCA1 and promotes BRCA1 recruitment to laser-microirradiated DSB sites. NELF-E deficiency reduces BRCA1 and RAD51 IRIF formation, impairs homology-directed repair (HDR) of chromosomal DSBs, and sensitizes HCC cells to PARP inhibition (synthetic lethality). Co-immunoprecipitation, laser microirradiation with live imaging, IRIF assays, CRISPR-Cas9 HDR assay, PARP inhibitor sensitivity assay DNA repair High 33248388
2012 Haploinsufficiency of NELF-A (WHSC2) in Wolf-Hirschhorn syndrome patient cells contributes to: delayed progression from S-phase into M-phase, reduced DNA replication in asynchronous culture, and altered chromatin assembly (reduced histone-chromatin association, elevated soluble chaperone-bound histone H3, increased MNase sensitivity). Cells also show increased sensitivity to camptothecin-induced inhibition of DNA replication. Patient-derived cell lines with differing 4p deletions, cell cycle analysis, DNA replication assays, chromatin fractionation, MNase digestion, drug sensitivity assays Human molecular genetics Medium 22328085
2021 NELF-A subunit interacts with the ecdysone receptor (EcR) in Drosophila and the NELF complex is recruited to promoters and enhancers of 20E-dependent genes. NELF depletion causes significant decrease in 20E-induced transcription, disruption of Pol II elongation complexes, and a considerable reduction in promoter-bound Spt5 (DSIF subunit), suggesting NELF stabilizes the Pol II-DSIF complex. Co-immunoprecipitation (NELF-A/EcR), ChIP at 20E-dependent promoters, NELF depletion with nascent RNA analysis Scientific reports Medium 33420323
2015 CTCF knockdown abrogates RNAP II pausing at c-myc by affecting DSIF recruitment. CTCF knockdown causes a termination defect on U2 snRNA genes by affecting NELF recruitment. CTCF is also required for recruitment of P-TEFb, which phosphorylates NELF, DSIF, and Ser2 of RNAP II CTD. ChIP, CTCF siRNA knockdown, RNAP II pausing and termination assays Transcription Medium 26399478
2013 NELF-A and NELF-B independently act as competitive decelerators at steps downstream of glucocorticoid receptor (GR) action to attenuate GR-mediated gene induction and reduce partial agonist activity. A conserved motif in NELF-A and NELF-B is required for full modulatory activity. ChIP assays show NELF-B diminishes GR recruitment to promoter regions of endogenous genes. Competition transcription assays, ChIP, stable NELF-B knockdown, domain mutagenesis The Journal of biological chemistry Medium 24097989
2024 Acute loss of NELF-C globally redistributes termination factors and perturbs Pol II transcription termination independently of promoter-proximal Pol II pausing. This drives pervasive Pol II transcription into DNA replication initiation zones, causing transcription-replication conflict that blocks cell cycle transition into S phase. Auxin-dependent NELF-C degradation, nascent transcript sequencing (TT-seq/NET-seq), termination factor ChIP EMBO reports High 41721097
2026 NSMF deficiency impairs replication fork progression under stress conditions in colorectal cancer cells, resulting in DNA damage accumulation, growth arrest, and senescence. NSMF overexpression provides resistance to oncogene-induced replication stress, enabling cancer cells to evade senescence. In ApcMin/+ mice, Nsmf knockout selectively induces replication-dependent DNA damage in tumor tissues. NSMF knockout in ApcMin/+ mice, replication fork progression assays, DNA damage markers, senescence assays, NSMF overexpression experiments Nucleic acids research Medium 41533586
2026 HSPA1A and DNAJB1 regulate NELF condensate dynamics during heat shock recovery. DNAJB1 recognizes NELFA's tentacle domain and facilitates HSPA1A recruitment, preventing aberrant NELF aggregation and enabling timely condensate disassembly. Disruption of NELF condensate dynamics causes persistent NELFA phosphorylation, impaired chromatin association, destabilized Pol II pausing, and premature release of non-productive Pol II complexes. Nanobody-based proximity labeling (NbPro), Co-IP, live imaging, domain mapping, ChIP, nascent RNA analysis Molecular cell High 41653920

Source papers

Stage 0 corpus · 76 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 680 10199401
2014 Enhancer RNA facilitates NELF release from immediate early genes. Molecular cell 355 25263592
2018 Structure of paused transcription complex Pol II-DSIF-NELF. Nature 292 30135580
2003 NELF and DSIF cause promoter proximal pausing on the hsp70 promoter in Drosophila. Genes & development 267 12782658
2007 NELF interacts with CBC and participates in 3' end processing of replication-dependent histone mRNAs. Molecular cell 197 17499042
2003 Human transcription elongation factor NELF: identification of novel subunits and reconstitution of the functionally active complex. Molecular and cellular biology 194 12612062
2008 NELF and GAGA factor are linked to promoter-proximal pausing at many genes in Drosophila. Molecular and cellular biology 175 18332113
2000 DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and DSIF during transcription elongation. The Journal of biological chemistry 172 11112772
2014 Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nature communications 151 25410209
2013 BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Molecular and cellular biology 144 23589332
2012 Transcription elongation factors DSIF and NELF: promoter-proximal pausing and beyond. Biochimica et biophysica acta 142 23202475
2020 NELF Regulates a Promoter-Proximal Step Distinct from RNA Pol II Pause-Release. Molecular cell 137 32155413
2010 Interactions between DSIF (DRB sensitivity inducing factor), NELF (negative elongation factor), and the Drosophila RNA polymerase II transcription elongation complex. Proceedings of the National Academy of Sciences of the United States of America 136 20534440
2021 Stress-induced nuclear condensation of NELF drives transcriptional downregulation. Molecular cell 115 33548202
2013 Kinetic competition between elongation rate and binding of NELF controls promoter-proximal pausing. Molecular cell 100 23746353
2006 Transcriptional pausing caused by NELF plays a dual role in regulating immediate-early expression of the junB gene. Molecular and cellular biology 93 16880520
2000 FACT relieves DSIF/NELF-mediated inhibition of transcriptional elongation and reveals functional differences between P-TEFb and TFIIH. Molecular cell 93 10912001
2007 Negative elongation factor NELF represses human immunodeficiency virus transcription by pausing the RNA polymerase II complex. The Journal of biological chemistry 92 17442680
2004 Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). Journal of human genetics 89 15362570
2014 DSIF and NELF interact with Integrator to specify the correct post-transcriptional fate of snRNA genes. Nature communications 85 24968874
2017 NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. EMBO reports 71 28336775
2013 Negative elongation factor (NELF) coordinates RNA polymerase II pausing, premature termination, and chromatin remodeling to regulate HIV transcription. The Journal of biological chemistry 58 23884411
2014 Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions. PLoS genetics 56 24453987
2022 Enhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF. Nature communications 52 35508485
2005 Molecular characterization of Drosophila NELF. Nucleic acids research 48 15741180
2011 Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertility and sterility 45 21300340
2017 Structural basis for mutually exclusive co-transcriptional nuclear cap-binding complexes with either NELF-E or ARS2. Nature communications 42 29101316
2012 Characterizing the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirschhorn syndrome. Human molecular genetics 39 22328085
2005 Molecular analysis of KAL-1, GnRH-R, NELF and EBF2 genes in a series of Kallmann syndrome and normosmic hypogonadotropic hypogonadism patients. The Journal of endocrinology 36 16423815
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
2016 A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. PLoS genetics 30 26977770
2010 NELF potentiates gene transcription in the Drosophila embryo. PloS one 28 20634899
2023 The NELF pausing checkpoint mediates the functional divergence of Cdk9. Nature communications 24 37179384
2001 Nasal embryonic LHRH factor (NELF) expression within the CNS and PNS of the rodent. Brain research. Gene expression patterns 24 15018815
2009 NELF is a nuclear protein involved in hypothalamic GnRH neuronal migration. Molecular and cellular endocrinology 20 20025934
2015 CTCF regulates NELF, DSIF and P-TEFb recruitment during transcription. Transcription 19 26399478
2008 Negative elongation factor NELF controls transcription of immediate early genes in a stimulus-specific manner. Experimental cell research 18 19014935
2021 The negative elongation factor NELF promotes induced transcriptional response of Drosophila ecdysone-dependent genes. Scientific reports 17 33420323
2022 ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II. Nature communications 16 36463234
2009 The transcription elongation factors NELF, DSIF and P-TEFb control constitutive transcription in a gene-specific manner. FEBS letters 16 19654008
2024 NELF focuses sites of initiation and maintains promoter architecture. Nucleic acids research 15 38197272
2023 Dependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis. Nature communications 15 37117180
2022 RNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity. Nature communications 15 35444206
2020 NELF complex fosters BRCA1 and RAD51 recruitment to DNA damage sites and modulates sensitivity to PARP inhibition. DNA repair 15 33248388
2015 NELF knockout is associated with impaired pubertal development and subfertility. Molecular and cellular endocrinology 13 25731822
2021 NSMF promotes the replication stress-induced DNA damage response for genome maintenance. Nucleic acids research 12 33963872
2008 NELF-E RRM undergoes major structural changes in flexible protein regions on target RNA binding. Biochemistry 12 18303858
2016 What do we learn from the murine Jacob/Nsmf gene knockout for human disease? Rare diseases (Austin, Tex.) 11 27803842
2013 A conserved protein motif is required for full modulatory activity of negative elongation factor subunits NELF-A and NELF-B in modifying glucocorticoid receptor-regulated gene induction properties. The Journal of biological chemistry 11 24097989
2023 Alteration of replication protein A binding mode on single-stranded DNA by NSMF potentiates RPA phosphorylation by ATR kinase. Nucleic acids research 10 37378431
2021 NELF-A controls Drosophila healthspan by regulating heat-shock protein-mediated cellular protection and heterochromatin maintenance. Aging cell 10 33788376
2022 Negative Elongation Factor (NELF) Inhibits Premature Granulocytic Development in Zebrafish. International journal of molecular sciences 9 35409193
2017 Dynamic Change of Transcription Pausing through Modulating NELF Protein Stability Regulates Granulocytic Differentiation. Blood advances 9 28868519
2013 CTR9, a component of PAF complex, controls elongation block at the c-Fos locus via signal-dependent regulation of chromatin-bound NELF dissociation. PloS one 9 23593388
2021 Epithelial NELF guards intestinal barrier function to ameliorate colitis by maintaining junctional integrity. Mucosal immunology 8 34697434
2015 Striatal NELF-mediated RNA polymerase II stalling controls L-dopa induced dyskinesia. Neurobiology of disease 8 26480869
2009 Cellular dynamics of the negative transcription elongation factor NELF. Experimental cell research 8 19245807
2024 NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness. Oncogene 6 38182897
2024 NELF coordinates Pol II transcription termination and DNA replication initiation. bioRxiv : the preprint server for biology 5 38352431
2023 Structural basis of the human negative elongation factor NELF-B/C/E ternary complex. Biochemical and biophysical research communications 5 37591184
2013 Differential expression of nasal embryonic LHRH factor (NELF) variants in immortalized GnRH neuronal cell lines. Molecular and cellular endocrinology 5 24316376
2023 A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death. Molecular brain 3 36774487
2014 N-methyl D-aspartate receptor synaptonuclear signaling and neuronal migration factor (Nsmf) plays a novel role in myoblast proliferation. In vitro cellular & developmental biology. Animal 3 25248434
2025 CRISPR with Transcriptional Readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response. bioRxiv : the preprint server for biology 2 39605461
2025 Copy Number Variations of the NSMF Gene and Their Associations with Growth Traits in Three Chinese Sheep Breeds. Genes 2 40004547
2021 Struggle for survival: new insights into NELF condensation for adaptive transcriptional reprogramming. Molecular cell 2 33667379
2021 Role of NELF-B in supporting epithelial-mesenchymal transition and cell proliferation during hepatocellular carcinoma progression. Oncology letters 2 34539865
2014 eRNAs lure NELF from paused polymerases. Molecular cell 2 25280099
2026 NELF prevents transcriptional readthrough into DNA replication zones in cancer cells. EMBO reports 1 41721097
2025 CRISPR with Transcriptional Readout reveals influenza transcription is modulated by NELF and can precipitate an interferon response. Proceedings of the National Academy of Sciences of the United States of America 1 40864651
2025 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila. Nature communications 1 41436469
2026 NSMF modulates replication stress to facilitate colorectal cancer progression. Nucleic acids research 0 41533586
2026 HSPA1A and DNAJB1 regulate NELF condensate dynamics to safeguard transcriptional recovery under heat stress. Molecular cell 0 41653920
2026 Diagnosis and treatment analysis of a case of idiopathic hypogonadotropic hypogonadism caused by NSMF gene mutation. Yi chuan = Hereditas 0 42145198
2024 Changing structures, changing paradigms: NELF helps regulate paused or elongating RNA polymerase II. Molecular cell 0 38579674
2023 Investigation of subfertility in the female Nsmf knockout mouse. F&S science 0 37516276

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