{"gene":"NELFE","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1999,"finding":"NELF (Negative Elongation Factor) is a multisubunit complex that cooperates with DSIF to repress RNA polymerase II elongation; this repression is reversed by P-TEFb-dependent phosphorylation of the Pol II CTD. NELFE (then called RD) was identified as the smallest subunit of NELF, a putative RNA-binding protein.","method":"Biochemical purification from HeLa nuclear extract, in vitro transcription elongation assay with DRB, functional reconstitution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — original purification and reconstituted in vitro transcription assay; foundational paper with 679 citations","pmids":["10199401"],"is_preprint":false},{"year":2006,"finding":"The RRM (RNA-recognition motif) of NELF-E adopts a βαββαβ fold and binds to HIV-1 TAR RNA; the RRM binds single-stranded TAR RNA with Kd values in the low-micromolar range, and the interaction is with the single-stranded portions rather than the stem.","method":"NMR solution structure determination of recombinant NELF-E RRM; fluorescence equilibrium titrations with fluorescently labeled RNA oligonucleotides","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1 — NMR structure plus quantitative binding assays","pmids":["16898873"],"is_preprint":false},{"year":2014,"finding":"NELF-E contains a conserved RRM that recognizes a specific consensus RNA sequence (NBE: CUGAGGA(U) for Drosophila); an NBE-like element is present in the TAR loop of HIV-1 RNA and is required for high-affinity binding. NBE motifs are enriched +20 to +30 nt downstream of transcription start sites in paused genes genome-wide, supporting a direct role for NELF-E RNA binding in promoter-proximal pausing.","method":"In vitro SELEX, quantitative RNA-binding biochemistry, genome-wide bioinformatic analysis of NBE distribution, nuclear run-on SELEX","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro selection plus quantitative biochemistry plus genome-wide functional correlation; multiple orthogonal methods","pmids":["24453987"],"is_preprint":false},{"year":2017,"finding":"The C-terminal peptide of NELF-E binds directly to the nuclear cap-binding complex (CBC) at the same site as the homologous C-terminal peptide of ARS2; CBC–NELF-E and CBC–ARS2–PHAX are mutually exclusive co-transcriptional complexes, and cap-analogue binding to CBC enhances affinity for both peptides. NELF-E binding to CBC is incompatible with PHAX binding.","method":"Crystal structure of CBC–NELF-E peptide complex; biochemical binding assays; direct interaction mapping","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus biochemical validation of mutually exclusive complex formation","pmids":["29101316"],"is_preprint":false},{"year":2017,"finding":"NELFE-E and NELF-A are rapidly recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner; NELF-E recruitment and its repressive activity are required for transcriptional silencing at DSBs, and NELF-E is preferentially recruited to DSBs upstream of transcriptionally active genes. RNA Pol II presence is a prerequisite for NELF-E recruitment. NELF-E is required for intact DSB repair.","method":"I-SceI endonuclease and CRISPR-Cas9 DSB induction; live-cell recruitment assays; PARP1 inhibition; Pol II ChIP; transcription repression assays at break sites; repair efficiency measurement","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (two DSB systems, inhibitor studies, Pol II dependence) in a single study","pmids":["28336775"],"is_preprint":false},{"year":2017,"finding":"Oncogenic copy-number amplification of NELFE enhances MYC signaling and promotes hepatocellular carcinoma (HCC) progression; NELFE selectively regulates MYC-associated gene transcription and induces a unique tumor transcriptome.","method":"Somatic copy-number alteration analysis of 1,225 clinical HCC samples; loss-of-function and gain-of-function experiments; transcriptome profiling","journal":"Cancer Cell","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional KD/OE with transcriptomic readout but pathway placement relies partly on correlative analysis","pmids":["28697339"],"is_preprint":false},{"year":2019,"finding":"NELFE destabilizes NDRG2 mRNA in pancreatic cancer cells, thereby activating Wnt/β-catenin signaling; NELFE knockdown inhibits EMT by suppressing β-catenin expression and nuclear accumulation.","method":"RNA immunoprecipitation; mRNA decay assays; luciferase reporter assays; shRNA knockdown with invasion/migration phenotypic readout","journal":"International Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP and mRNA decay assays support direct mRNA binding/destabilization mechanism; single lab","pmids":["31638184"],"is_preprint":false},{"year":1998,"finding":"NELFE (RD) is located in the HLA class III region, 205 bp downstream of complement factor B (Bf), and its gene is arranged head-to-head with SKIV2L in a pair sharing a common CpG-containing 5′ regulatory region; NELFE is ubiquitously expressed, consistent with a housekeeping function.","method":"Genomic sequencing, exon-intron mapping, expression analysis","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 — genomic/expression characterization only, no direct functional mechanism tested","pmids":["9799600"],"is_preprint":false}],"current_model":"NELFE (NELF-E/RD) is the RNA-binding subunit of the four-subunit Negative Elongation Factor (NELF) complex; its conserved RRM binds nascent RNA at a specific consensus sequence (NBE) enriched at promoter-proximal pause sites, tethering NELF to paused Pol II and cooperating with DSIF to repress elongation until P-TEFb-mediated CTD phosphorylation releases the block; additionally, NELFE directly binds the nuclear cap-binding complex (CBC) in a manner mutually exclusive with ARS2–PHAX to link cap recognition to early transcriptional control, is recruited to DNA double-strand break sites via PARP1 to enforce transcriptional silencing and support repair, and functions as an oncogenic RNA-binding protein that destabilizes select mRNAs (e.g., NDRG2) and amplifies MYC signaling in certain cancers."},"narrative":{"teleology":[{"year":1998,"claim":"Before any functional data, NELFE was mapped to the HLA class III region arranged head-to-head with SKIV2L, establishing it as a ubiquitously expressed gene with a potential housekeeping role but no known mechanism.","evidence":"Genomic sequencing and expression analysis of the HLA class III locus","pmids":["9799600"],"confidence":"Low","gaps":["No functional or biochemical characterization performed","No evidence of protein-level activity"]},{"year":1999,"claim":"The discovery that NELFE is a subunit of the NELF complex that cooperates with DSIF to repress Pol II elongation — reversible by P-TEFb — established the core mechanism of promoter-proximal pausing and defined NELFE as a putative RNA-binding component of this machinery.","evidence":"Biochemical purification from HeLa nuclear extract and reconstituted in vitro transcription elongation assay","pmids":["10199401"],"confidence":"High","gaps":["RNA-binding activity of NELFE not directly demonstrated","No structural information on NELFE","In vivo relevance of pausing not tested"]},{"year":2006,"claim":"Solving the NMR structure of the NELFE RRM and demonstrating its binding to single-stranded HIV-1 TAR RNA established that NELFE possesses a canonical RNA-recognition motif with low-micromolar affinity, confirming its RNA-binding function and defining the structural basis.","evidence":"NMR solution structure of recombinant NELF-E RRM; fluorescence equilibrium binding titrations","pmids":["16898873"],"confidence":"High","gaps":["Endogenous RNA targets in the cell unknown","Role of RNA binding in pausing not directly tested","Whether NELFE recognizes a specific sequence motif remained unclear"]},{"year":2014,"claim":"Identification of a specific consensus RNA motif (NBE) recognized by the NELFE RRM, and demonstration that NBE sequences are enriched at promoter-proximal pause sites genome-wide, provided the missing link between NELFE RNA binding and its role in establishing pausing at specific genes.","evidence":"In vitro SELEX, quantitative RNA-binding biochemistry, genome-wide bioinformatic analysis of NBE distribution near TSSs","pmids":["24453987"],"confidence":"High","gaps":["Causal relationship between NBE presence and pausing not demonstrated by mutagenesis in vivo","Whether all paused genes require NBE-mediated NELF-E tethering is unclear"]},{"year":2017,"claim":"Three independent studies expanded NELFE's functional repertoire: (1) crystal structure of the CBC–NELF-E peptide complex showed that NELFE directly binds CBC at a site mutually exclusive with ARS2–PHAX, linking cap recognition to pausing; (2) NELFE is recruited to DNA double-strand breaks in a PARP1- and Pol II-dependent manner to silence transcription and support repair; (3) NELFE copy-number amplification drives MYC signaling and hepatocellular carcinoma progression.","evidence":"Crystal structure and binding assays (CBC interaction); I-SceI/CRISPR DSB induction with live-cell recruitment and repair assays (DSB role); SCNA analysis of 1,225 HCC samples with functional KD/OE and transcriptomics (oncogenic role)","pmids":["29101316","28336775","28697339"],"confidence":"High","gaps":["How CBC binding and RNA binding are coordinated on NELF-E during co-transcriptional pausing is not resolved","Mechanism of PARP1-dependent NELF-E recruitment to DSBs is not molecularly defined","Whether MYC amplification by NELFE depends on its elongation-control or RNA-destabilization activity is unknown"]},{"year":2019,"claim":"Demonstration that NELFE destabilizes NDRG2 mRNA to activate Wnt/β-catenin signaling in pancreatic cancer established a direct mRNA-destabilizing activity distinct from its canonical elongation-repressive function.","evidence":"RNA immunoprecipitation, mRNA decay assays, and shRNA knockdown in pancreatic cancer cell lines","pmids":["31638184"],"confidence":"Medium","gaps":["Mechanism of mRNA destabilization (e.g., recruited deadenylase/decapping) not identified","Whether NDRG2 mRNA is a direct RRM-mediated target or requires co-factors is unclear","Single-lab finding not independently replicated"]},{"year":null,"claim":"Key unresolved questions include how NELFE's RNA-binding (RRM–NBE) and cap-binding (CBC interaction) activities are structurally integrated on the paused elongation complex, the molecular mechanism by which NELFE destabilizes specific mRNAs independently of NELF-complex-mediated pausing, and whether its roles in DNA damage silencing and oncogenesis are mechanistically linked to its elongation-control function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the full NELF complex on a paused Pol II elongation complex with nascent RNA","Mechanism of mRNA destabilization by NELFE not defined","Relationship between elongation-control and oncogenic functions not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]}],"complexes":["NELF complex"],"partners":["NELFA","DSIF","CBP20","CBP80","PARP1"],"other_free_text":[]},"mechanistic_narrative":"NELFE (NELF-E/RD) is the RNA-binding subunit of the four-subunit Negative Elongation Factor (NELF) complex, which cooperates with DSIF to repress RNA polymerase II transcriptional elongation at promoter-proximal pause sites until P-TEFb-mediated CTD phosphorylation releases the block [PMID:10199401]. Its conserved RRM domain adopts a βαββαβ fold that binds single-stranded nascent RNA at a specific consensus motif (NBE, CUGAGGA(U)) enriched +20–30 nt downstream of transcription start sites in paused genes, thereby tethering NELF to the elongation complex [PMID:16898873, PMID:24453987]. NELFE also directly engages the nuclear cap-binding complex (CBC) through its C-terminal peptide in a manner mutually exclusive with ARS2–PHAX, linking cap recognition to early transcriptional control, and is recruited to DNA double-strand breaks in a PARP1- and Pol II-dependent fashion to enforce transcriptional silencing and support DNA repair [PMID:29101316, PMID:28336775]. Beyond its canonical elongation-control role, NELFE functions as an RNA-binding protein that destabilizes select mRNAs such as NDRG2 and amplifies MYC signaling, contributing to oncogenesis in hepatocellular and pancreatic cancers [PMID:28697339, PMID:31638184]."},"prefetch_data":{"uniprot":{"accession":"P18615","full_name":"Negative elongation factor E","aliases":["RNA-binding protein RD"],"length_aa":380,"mass_kda":43.2,"function":"Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:10199401, PubMed:27256882). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:11940650, PubMed:12612062, PubMed:27256882). Provides the strongest RNA binding activity of the NELF complex and may initially recruit the NELF complex to RNA (PubMed:18303858, PubMed:27256882, PubMed:27282391) (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/P18615/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NELFE","classification":"Common Essential","n_dependent_lines":562,"n_total_lines":1208,"dependency_fraction":0.4652317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR2B","stoichiometry":4.0},{"gene":"SUPT5H","stoichiometry":4.0},{"gene":"INTS5","stoichiometry":0.2},{"gene":"POLR2E","stoichiometry":0.2},{"gene":"POLR2F","stoichiometry":0.2},{"gene":"POLR2K","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NELFE","total_profiled":1310},"omim":[{"mim_id":"621228","title":"LONG INTERGENIC NONCODING RNA 1013; LINC01013","url":"https://www.omim.org/entry/621228"},{"mim_id":"611180","title":"NEGATIVE ELONGATION FACTOR COMPLEX, MEMBER B; NELFB","url":"https://www.omim.org/entry/611180"},{"mim_id":"606026","title":"NEGATIVE ELONGATION FACTOR COMPLEX, MEMBER A; NELFA","url":"https://www.omim.org/entry/606026"},{"mim_id":"605297","title":"NEGATIVE ELONGATION FACTOR COMPLEX, MEMBER C/D; NELFCD","url":"https://www.omim.org/entry/605297"},{"mim_id":"173870","title":"POLY(ADP-RIBOSE) POLYMERASE 1; PARP1","url":"https://www.omim.org/entry/173870"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear bodies","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NELFE"},"hgnc":{"alias_symbol":["RD","D6S45","NELF-E","RDP"],"prev_symbol":["RDBP"]},"alphafold":{"accession":"P18615","domains":[{"cath_id":"3.30.70.330","chopping":"262-331","consensus_level":"high","plddt":88.4074,"start":262,"end":331},{"cath_id":"1.20.5","chopping":"206-235","consensus_level":"medium","plddt":59.3487,"start":206,"end":235}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18615","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18615-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18615-F1-predicted_aligned_error_v6.png","plddt_mean":63.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NELFE","jax_strain_url":"https://www.jax.org/strain/search?query=NELFE"},"sequence":{"accession":"P18615","fasta_url":"https://rest.uniprot.org/uniprotkb/P18615.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18615/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18615"}},"corpus_meta":[{"pmid":"7542800","id":"PMC_7542800","title":"Whole-genome random sequencing and assembly of Haemophilus influenzae Rd.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7542800","citation_count":4048,"is_preprint":false},{"pmid":"12520046","id":"PMC_12520046","title":"The Ribosomal Database Project (RDP-II): previewing a new autoaligner that allows regular updates and the new prokaryotic taxonomy.","date":"2003","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12520046","citation_count":951,"is_preprint":false},{"pmid":"15608200","id":"PMC_15608200","title":"The Ribosomal Database Project (RDP-II): sequences and tools for high-throughput rRNA analysis.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15608200","citation_count":946,"is_preprint":false},{"pmid":"10199401","id":"PMC_10199401","title":"NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10199401","citation_count":679,"is_preprint":false},{"pmid":"9847171","id":"PMC_9847171","title":"A new version of the RDP (Ribosomal Database Project).","date":"1999","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9847171","citation_count":645,"is_preprint":false},{"pmid":"8398150","id":"PMC_8398150","title":"Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice.","date":"1993","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8398150","citation_count":559,"is_preprint":false},{"pmid":"659071","id":"PMC_659071","title":"Differential effect of the rd mutation on rods and cones in the mouse retina.","date":"1978","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/659071","citation_count":461,"is_preprint":false},{"pmid":"8594608","id":"PMC_8594608","title":"The Ribosomal Database Project (RDP).","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8594608","citation_count":391,"is_preprint":false},{"pmid":"1941717","id":"PMC_1941717","title":"Circadian photoreception in the retinally degenerate mouse (rd/rd).","date":"1991","source":"Journal of comparative physiology. A, Sensory, neural, and behavioral physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1941717","citation_count":356,"is_preprint":false},{"pmid":"8640555","id":"PMC_8640555","title":"Photoreceptor cell rescue in retinal degeneration (rd) mice by in vivo gene therapy.","date":"1996","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/8640555","citation_count":278,"is_preprint":false},{"pmid":"16043876","id":"PMC_16043876","title":"Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice.","date":"2005","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/16043876","citation_count":184,"is_preprint":false},{"pmid":"17163879","id":"PMC_17163879","title":"The Rc and Rd genes are involved in proanthocyanidin synthesis in rice pericarp.","date":"2006","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17163879","citation_count":181,"is_preprint":false},{"pmid":"17282997","id":"PMC_17282997","title":"The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene.","date":"2007","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17282997","citation_count":180,"is_preprint":false},{"pmid":"16424920","id":"PMC_16424920","title":"Plant and animal pathogen recognition receptors signal through non-RD kinases.","date":"2006","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/16424920","citation_count":168,"is_preprint":false},{"pmid":"7542802","id":"PMC_7542802","title":"Frequency and distribution of DNA uptake signal sequences in the Haemophilus influenzae Rd genome.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7542802","citation_count":160,"is_preprint":false},{"pmid":"21165980","id":"PMC_21165980","title":"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.","date":"2011","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21165980","citation_count":132,"is_preprint":false},{"pmid":"28697339","id":"PMC_28697339","title":"Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma.","date":"2017","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/28697339","citation_count":126,"is_preprint":false},{"pmid":"21185898","id":"PMC_21185898","title":"Ginsenoside Rd attenuates early oxidative damage and sequential inflammatory response after transient focal ischemia in rats.","date":"2010","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/21185898","citation_count":111,"is_preprint":false},{"pmid":"168408","id":"PMC_168408","title":"Structure, subunit composition, and molecular weight of RD-114 RNA.","date":"1975","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/168408","citation_count":93,"is_preprint":false},{"pmid":"21219973","id":"PMC_21219973","title":"Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia.","date":"2011","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21219973","citation_count":92,"is_preprint":false},{"pmid":"9930315","id":"PMC_9930315","title":"Adenovirus-mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor cell death in the rd/rd mouse.","date":"1998","source":"Gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/9930315","citation_count":92,"is_preprint":false},{"pmid":"4113865","id":"PMC_4113865","title":"Purification and immunological characterization of the major internal protein of the RD-114 virus.","date":"1972","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/4113865","citation_count":85,"is_preprint":false},{"pmid":"28970547","id":"PMC_28970547","title":"Ginsenosides Rb3 and Rd reduce polyps formation while reinstate the dysbiotic gut microbiota and the intestinal microenvironment in ApcMin/+ mice.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28970547","citation_count":80,"is_preprint":false},{"pmid":"28431340","id":"PMC_28431340","title":"First macrocyclic 3rd-generation ALK inhibitor for treatment of ALK/ROS1 cancer: Clinical and designing strategy update of lorlatinib.","date":"2017","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28431340","citation_count":80,"is_preprint":false},{"pmid":"16950547","id":"PMC_16950547","title":"Ginsenoside Rd elicits Th1 and Th2 immune responses to ovalbumin in mice.","date":"2006","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/16950547","citation_count":78,"is_preprint":false},{"pmid":"26869821","id":"PMC_26869821","title":"Ginsenoside Rd and ischemic stroke; a short review of literatures.","date":"2015","source":"Journal of ginseng research","url":"https://pubmed.ncbi.nlm.nih.gov/26869821","citation_count":73,"is_preprint":false},{"pmid":"28336775","id":"PMC_28336775","title":"NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28336775","citation_count":71,"is_preprint":false},{"pmid":"2785984","id":"PMC_2785984","title":"Organization of the Haemophilus influenzae Rd genome.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2785984","citation_count":70,"is_preprint":false},{"pmid":"18640874","id":"PMC_18640874","title":"Role of M. tuberculosis RD-1 region encoded secretory proteins in protective response and virulence.","date":"2008","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/18640874","citation_count":68,"is_preprint":false},{"pmid":"14656296","id":"PMC_14656296","title":"Light-induced c-fos in melanopsin retinal ganglion cells of young and aged rodless/coneless (rd/rd cl) mice.","date":"2003","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/14656296","citation_count":60,"is_preprint":false},{"pmid":"27641158","id":"PMC_27641158","title":"Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27641158","citation_count":57,"is_preprint":false},{"pmid":"24453987","id":"PMC_24453987","title":"Defining NELF-E RNA binding in HIV-1 and promoter-proximal pause regions.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24453987","citation_count":56,"is_preprint":false},{"pmid":"4358169","id":"PMC_4358169","title":"RD 114 virus-specific sequences in feline cellular RNA: detection and characterization.","date":"1973","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/4358169","citation_count":53,"is_preprint":false},{"pmid":"1326828","id":"PMC_1326828","title":"Mapping of the RD phenotype of the Nancy strain of coxsackievirus B3.","date":"1992","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/1326828","citation_count":50,"is_preprint":false},{"pmid":"23717145","id":"PMC_23717145","title":"Enzymatic Biotransformation of Ginsenoside Rb1 and Gypenoside XVII into Ginsenosides Rd and F2 by Recombinant β-glucosidase from Flavobacterium johnsoniae.","date":"2012","source":"Journal of ginseng research","url":"https://pubmed.ncbi.nlm.nih.gov/23717145","citation_count":49,"is_preprint":false},{"pmid":"9183740","id":"PMC_9183740","title":"Aberrant expression of c-Fos accompanies photoreceptor cell death in the rd mouse.","date":"1997","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/9183740","citation_count":46,"is_preprint":false},{"pmid":"12606554","id":"PMC_12606554","title":"Purification and characterization of a chimeric enzyme from Haemophilus influenzae Rd that exhibits glutathione-dependent peroxidase activity.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12606554","citation_count":45,"is_preprint":false},{"pmid":"16163270","id":"PMC_16163270","title":"Early markers of retinal degeneration in rd/rd mice.","date":"2005","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16163270","citation_count":44,"is_preprint":false},{"pmid":"22231470","id":"PMC_22231470","title":"Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia.","date":"2012","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/22231470","citation_count":43,"is_preprint":false},{"pmid":"3158613","id":"PMC_3158613","title":"N-ras gene activation in the RD human rhabdomyosarcoma cell line.","date":"1985","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/3158613","citation_count":43,"is_preprint":false},{"pmid":"29101316","id":"PMC_29101316","title":"Structural basis for mutually exclusive co-transcriptional nuclear cap-binding complexes with either NELF-E or ARS2.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29101316","citation_count":42,"is_preprint":false},{"pmid":"170535","id":"PMC_170535","title":"Segregation of RD-114 AND FeL-V-related sequences in crosses between domestic cat and leopard cat.","date":"1975","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/170535","citation_count":42,"is_preprint":false},{"pmid":"30551351","id":"PMC_30551351","title":"Ginsenoside Rd contributes the attenuation of cardiac hypertrophy in vivo and in vitro.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30551351","citation_count":42,"is_preprint":false},{"pmid":"32682919","id":"PMC_32682919","title":"Ginsenoside Rd reverses cognitive deficits by modulating BDNF-dependent CREB pathway in chronic restraint stress mice.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32682919","citation_count":41,"is_preprint":false},{"pmid":"23260260","id":"PMC_23260260","title":"Associations of the C2-CFB-RDBP-SKIV2L locus with age-related macular degeneration and polypoidal choroidal vasculopathy.","date":"2012","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/23260260","citation_count":38,"is_preprint":false},{"pmid":"28351925","id":"PMC_28351925","title":"Serum IgG2 and tissue IgG2 plasma cell elevation in orbital IgG4-related disease (IgG4-RD): Potential use in IgG4-RD assessment.","date":"2017","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/28351925","citation_count":38,"is_preprint":false},{"pmid":"16862069","id":"PMC_16862069","title":"Efficiency of lentiviral transduction during development in normal and rd mice.","date":"2006","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16862069","citation_count":37,"is_preprint":false},{"pmid":"32792947","id":"PMC_32792947","title":"Imatinib and Dasatinib Provoke Mitochondrial Dysfunction Leading to Oxidative Stress in C2C12 Myotubes and Human RD Cells.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32792947","citation_count":36,"is_preprint":false},{"pmid":"9804131","id":"PMC_9804131","title":"Retinal degeneration in the rd mouse in the absence of c-fos.","date":"1998","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9804131","citation_count":35,"is_preprint":false},{"pmid":"197261","id":"PMC_197261","title":"Endogenous RD-114 virus genome expression in malignant tissues of domestic cats.","date":"1977","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/197261","citation_count":34,"is_preprint":false},{"pmid":"21463541","id":"PMC_21463541","title":"Inner and outer retinal mechanisms engaged by epiretinal stimulation in normal and rd mice.","date":"2011","source":"Visual neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21463541","citation_count":34,"is_preprint":false},{"pmid":"26358038","id":"PMC_26358038","title":"Ginsenoside Rd Improves Learning and Memory Ability in APP Transgenic Mice.","date":"2015","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/26358038","citation_count":33,"is_preprint":false},{"pmid":"26840295","id":"PMC_26840295","title":"Ginsenoside-Rd Promotes Neurite Outgrowth of PC12 Cells through MAPK/ERK- and PI3K/AKT-Dependent Pathways.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26840295","citation_count":32,"is_preprint":false},{"pmid":"25713930","id":"PMC_25713930","title":"Tyrosinase-catalyzed metabolism of rhododendrol (RD) in B16 melanoma cells: production of RD-pheomelanin and covalent binding with thiol proteins.","date":"2015","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/25713930","citation_count":32,"is_preprint":false},{"pmid":"8641465","id":"PMC_8641465","title":"Expression of GCAP1 and GCAP2 in the retinal degeneration (rd) mutant chicken retina.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8641465","citation_count":31,"is_preprint":false},{"pmid":"16898873","id":"PMC_16898873","title":"Structural studies on the RNA-recognition motif of NELF E, a cellular negative transcription elongation factor involved in the regulation of HIV transcription.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16898873","citation_count":31,"is_preprint":false},{"pmid":"30576064","id":"PMC_30576064","title":"Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis.","date":"2018","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/30576064","citation_count":31,"is_preprint":false},{"pmid":"12393480","id":"PMC_12393480","title":"Scianna antigens including Rd are expressed by ERMAP.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12393480","citation_count":31,"is_preprint":false},{"pmid":"18638517","id":"PMC_18638517","title":"Ginsenoside Rd prevents and rescues rat intestinal epithelial cells from irradiation-induced apoptosis.","date":"2008","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/18638517","citation_count":31,"is_preprint":false},{"pmid":"32415270","id":"PMC_32415270","title":"Protopanaxadiol ginsenoside Rd protects against NMDA receptor-mediated excitotoxicity by attenuating calcineurin-regulated DAPK1 activity.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32415270","citation_count":30,"is_preprint":false},{"pmid":"2161864","id":"PMC_2161864","title":"Presumptive identification of enteroviruses with RD, HEp-2, and RMK cell lines.","date":"1990","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/2161864","citation_count":30,"is_preprint":false},{"pmid":"32295691","id":"PMC_32295691","title":"Antitumor activity of ginsenoside Rd in gastric cancer via up-regulation of Caspase-3 and Caspase-9.","date":"2020","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/32295691","citation_count":30,"is_preprint":false},{"pmid":"23073826","id":"PMC_23073826","title":"Ginsenoside Rd maintains adult neural stem cell proliferation during lead-impaired neurogenesis.","date":"2012","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/23073826","citation_count":30,"is_preprint":false},{"pmid":"7949306","id":"PMC_7949306","title":"Differences in circadian photosensitivity between retinally degenerate CBA/J mice (rd/rd) and normal CBA/N mice (+/+).","date":"1994","source":"Journal of biological rhythms","url":"https://pubmed.ncbi.nlm.nih.gov/7949306","citation_count":29,"is_preprint":false},{"pmid":"9799600","id":"PMC_9799600","title":"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.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9799600","citation_count":28,"is_preprint":false},{"pmid":"2176558","id":"PMC_2176558","title":"A clonal prostaglandin-responsive cell line (RDP 4-1) derived from rat dental pulp.","date":"1990","source":"Bone and mineral","url":"https://pubmed.ncbi.nlm.nih.gov/2176558","citation_count":28,"is_preprint":false},{"pmid":"27073742","id":"PMC_27073742","title":"Ginsenoside Rd and ginsenoside Re offer neuroprotection in a novel model of Parkinson's disease.","date":"2016","source":"American journal of neurodegenerative disease","url":"https://pubmed.ncbi.nlm.nih.gov/27073742","citation_count":28,"is_preprint":false},{"pmid":"3106649","id":"PMC_3106649","title":"Expression of interferon-inducible genes in RD-114 cells.","date":"1987","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/3106649","citation_count":28,"is_preprint":false},{"pmid":"11162545","id":"PMC_11162545","title":"Analysis of the Desulfovibrio gigas transcriptional unit containing rubredoxin (rd) and rubredoxin-oxygen oxidoreductase (roo) genes and upstream ORFs.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11162545","citation_count":26,"is_preprint":false},{"pmid":"26833867","id":"PMC_26833867","title":"Neuroprotective Effect of Ginsenoside Rd in Spinal Cord Injury Rats.","date":"2016","source":"Basic & clinical pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/26833867","citation_count":25,"is_preprint":false},{"pmid":"30342194","id":"PMC_30342194","title":"Ribes diacanthum Pall (RDP) ameliorates UUO-induced renal fibrosis via both canonical and non-canonical TGF-β signaling pathways in mice.","date":"2018","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30342194","citation_count":25,"is_preprint":false},{"pmid":"32920289","id":"PMC_32920289","title":"Effects of a dammarane-type saponin, ginsenoside Rd, in nicotine-induced vascular endothelial injury.","date":"2020","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32920289","citation_count":25,"is_preprint":false},{"pmid":"21872268","id":"PMC_21872268","title":"Immunosuppressive effects of ginsenoside-Rd on skin allograft rejection in rats.","date":"2011","source":"The Journal of surgical research","url":"https://pubmed.ncbi.nlm.nih.gov/21872268","citation_count":25,"is_preprint":false},{"pmid":"19556007","id":"PMC_19556007","title":"Role of RDBP and SKIV2L variants in the major histocompatibility complex class III region in polypoidal choroidal vasculopathy etiology.","date":"2009","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/19556007","citation_count":23,"is_preprint":false},{"pmid":"27012233","id":"PMC_27012233","title":"Whole-Cell Biocatalysis for Producing Ginsenoside Rd from Rb1 Using Lactobacillus rhamnosus GG.","date":"2016","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27012233","citation_count":23,"is_preprint":false},{"pmid":"34531323","id":"PMC_34531323","title":"Activation loop phosphorylation of a non-RD receptor kinase initiates plant innate immune signaling.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34531323","citation_count":22,"is_preprint":false},{"pmid":"32999164","id":"PMC_32999164","title":"Ginsenoside Rd Inhibits Glioblastoma Cell Proliferation by Up-Regulating the Expression of miR-144-5p.","date":"2020","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/32999164","citation_count":22,"is_preprint":false},{"pmid":"20099200","id":"PMC_20099200","title":"Increased ubiquitination of multidrug resistance 1 by ginsenoside Rd.","date":"2010","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20099200","citation_count":22,"is_preprint":false},{"pmid":"2532744","id":"PMC_2532744","title":"Immunocytochemical localization of opsin in degenerating photoreceptors of RCS rats and rd and rds mice.","date":"1989","source":"Progress in clinical and biological research","url":"https://pubmed.ncbi.nlm.nih.gov/2532744","citation_count":21,"is_preprint":false},{"pmid":"29090586","id":"PMC_29090586","title":"Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia.","date":"2017","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/29090586","citation_count":20,"is_preprint":false},{"pmid":"3557867","id":"PMC_3557867","title":"Rhodopsin, vitamin A, and interstitial retinol-binding protein in the rd chicken.","date":"1987","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/3557867","citation_count":20,"is_preprint":false},{"pmid":"28729651","id":"PMC_28729651","title":"Combination of ginsenoside Rb1 and Rd protects the retina against bright light-induced degeneration.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28729651","citation_count":20,"is_preprint":false},{"pmid":"22131312","id":"PMC_22131312","title":"Canine ASCT1 and ASCT2 are functional receptors for RD-114 virus in dogs.","date":"2011","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/22131312","citation_count":20,"is_preprint":false},{"pmid":"31638184","id":"PMC_31638184","title":"NELFE promoted pancreatic cancer metastasis and the epithelial‑to‑mesenchymal transition by decreasing the stabilization of NDRG2 mRNA.","date":"2019","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31638184","citation_count":19,"is_preprint":false},{"pmid":"33526068","id":"PMC_33526068","title":"Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33526068","citation_count":19,"is_preprint":false},{"pmid":"37033737","id":"PMC_37033737","title":"Ginsenoside Rd attenuated hyperglycemia via Akt pathway and modulated gut microbiota in streptozotocin-induced diabetic rats.","date":"2023","source":"Current research in food science","url":"https://pubmed.ncbi.nlm.nih.gov/37033737","citation_count":19,"is_preprint":false},{"pmid":"9310300","id":"PMC_9310300","title":"Fos expression in the retina of rd/rd mice during the light/dark cycle.","date":"1997","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/9310300","citation_count":19,"is_preprint":false},{"pmid":"2045537","id":"PMC_2045537","title":"Expression of glial fibrillary acidic protein by Müller cells in rd chick retina.","date":"1991","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/2045537","citation_count":19,"is_preprint":false},{"pmid":"12897013","id":"PMC_12897013","title":"Haemophilus influenzae Rd lacks a stringently conserved fatty acid biosynthetic enzyme and thermal control of membrane lipid composition.","date":"2003","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/12897013","citation_count":19,"is_preprint":false},{"pmid":"30260020","id":"PMC_30260020","title":"The inhibitory effects of ginsenoside Rd on the human glioma U251 cells and its underlying mechanisms.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30260020","citation_count":19,"is_preprint":false},{"pmid":"23874798","id":"PMC_23874798","title":"Electrical stimulation of inner retinal neurons in wild-type and retinally degenerate (rd/rd) mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23874798","citation_count":18,"is_preprint":false},{"pmid":"7538211","id":"PMC_7538211","title":"Changes in expression of glutamate receptor subunits following photoreceptor degeneration in the rd mouse retina.","date":"1995","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/7538211","citation_count":18,"is_preprint":false},{"pmid":"1381682","id":"PMC_1381682","title":"Photoreceptor-specific mRNAs in mice carrying different allelic combinations at the rd and rds loci.","date":"1992","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/1381682","citation_count":18,"is_preprint":false},{"pmid":"38922307","id":"PMC_38922307","title":"OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.","date":"2024","source":"Future oncology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38922307","citation_count":17,"is_preprint":false},{"pmid":"34364858","id":"PMC_34364858","title":"iEnhancer-RD: Identification of enhancers and their strength using RKPK features and deep neural networks.","date":"2021","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34364858","citation_count":17,"is_preprint":false},{"pmid":"12676864","id":"PMC_12676864","title":"Haemophilus influenzae Rd KW20 has virulence properties.","date":"2003","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12676864","citation_count":17,"is_preprint":false},{"pmid":"10098732","id":"PMC_10098732","title":"Restoration of p16INK4A protein induces myogenic differentiation in RD rhabdomyosarcoma cells.","date":"1999","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10098732","citation_count":17,"is_preprint":false},{"pmid":"23580426","id":"PMC_23580426","title":"Characterization of feline ASCT1 and ASCT2 as RD-114 virus receptor.","date":"2013","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/23580426","citation_count":16,"is_preprint":false},{"pmid":"12974945","id":"PMC_12974945","title":"Systematic analysis of the TGF-beta/Smad signalling pathway in the rhabdomyosarcoma cell line RD.","date":"2003","source":"International journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12974945","citation_count":16,"is_preprint":false},{"pmid":"37249244","id":"PMC_37249244","title":"Ginsenoside Rd, a natural production for attenuating fibrogenesis and inflammation in hepatic fibrosis by regulating the ERRα-mediated P2X7r pathway.","date":"2023","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/37249244","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48412,"output_tokens":2041,"usd":0.087926},"stage2":{"model":"claude-opus-4-6","input_tokens":5368,"output_tokens":2137,"usd":0.120398},"total_usd":0.208324,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"NELF (Negative Elongation Factor) is a multisubunit complex that cooperates with DSIF to repress RNA polymerase II elongation; this repression is reversed by P-TEFb-dependent phosphorylation of the Pol II CTD. NELFE (then called RD) was identified as the smallest subunit of NELF, a putative RNA-binding protein.\",\n      \"method\": \"Biochemical purification from HeLa nuclear extract, in vitro transcription elongation assay with DRB, functional reconstitution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original purification and reconstituted in vitro transcription assay; foundational paper with 679 citations\",\n      \"pmids\": [\"10199401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The RRM (RNA-recognition motif) of NELF-E adopts a βαββαβ fold and binds to HIV-1 TAR RNA; the RRM binds single-stranded TAR RNA with Kd values in the low-micromolar range, and the interaction is with the single-stranded portions rather than the stem.\",\n      \"method\": \"NMR solution structure determination of recombinant NELF-E RRM; fluorescence equilibrium titrations with fluorescently labeled RNA oligonucleotides\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus quantitative binding assays\",\n      \"pmids\": [\"16898873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NELF-E contains a conserved RRM that recognizes a specific consensus RNA sequence (NBE: CUGAGGA(U) for Drosophila); an NBE-like element is present in the TAR loop of HIV-1 RNA and is required for high-affinity binding. NBE motifs are enriched +20 to +30 nt downstream of transcription start sites in paused genes genome-wide, supporting a direct role for NELF-E RNA binding in promoter-proximal pausing.\",\n      \"method\": \"In vitro SELEX, quantitative RNA-binding biochemistry, genome-wide bioinformatic analysis of NBE distribution, nuclear run-on SELEX\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro selection plus quantitative biochemistry plus genome-wide functional correlation; multiple orthogonal methods\",\n      \"pmids\": [\"24453987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal peptide of NELF-E binds directly to the nuclear cap-binding complex (CBC) at the same site as the homologous C-terminal peptide of ARS2; CBC–NELF-E and CBC–ARS2–PHAX are mutually exclusive co-transcriptional complexes, and cap-analogue binding to CBC enhances affinity for both peptides. NELF-E binding to CBC is incompatible with PHAX binding.\",\n      \"method\": \"Crystal structure of CBC–NELF-E peptide complex; biochemical binding assays; direct interaction mapping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus biochemical validation of mutually exclusive complex formation\",\n      \"pmids\": [\"29101316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NELFE-E and NELF-A are rapidly recruited to DNA double-strand break (DSB) sites in a PARP1-dependent manner; NELF-E recruitment and its repressive activity are required for transcriptional silencing at DSBs, and NELF-E is preferentially recruited to DSBs upstream of transcriptionally active genes. RNA Pol II presence is a prerequisite for NELF-E recruitment. NELF-E is required for intact DSB repair.\",\n      \"method\": \"I-SceI endonuclease and CRISPR-Cas9 DSB induction; live-cell recruitment assays; PARP1 inhibition; Pol II ChIP; transcription repression assays at break sites; repair efficiency measurement\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (two DSB systems, inhibitor studies, Pol II dependence) in a single study\",\n      \"pmids\": [\"28336775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oncogenic copy-number amplification of NELFE enhances MYC signaling and promotes hepatocellular carcinoma (HCC) progression; NELFE selectively regulates MYC-associated gene transcription and induces a unique tumor transcriptome.\",\n      \"method\": \"Somatic copy-number alteration analysis of 1,225 clinical HCC samples; loss-of-function and gain-of-function experiments; transcriptome profiling\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional KD/OE with transcriptomic readout but pathway placement relies partly on correlative analysis\",\n      \"pmids\": [\"28697339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NELFE destabilizes NDRG2 mRNA in pancreatic cancer cells, thereby activating Wnt/β-catenin signaling; NELFE knockdown inhibits EMT by suppressing β-catenin expression and nuclear accumulation.\",\n      \"method\": \"RNA immunoprecipitation; mRNA decay assays; luciferase reporter assays; shRNA knockdown with invasion/migration phenotypic readout\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP and mRNA decay assays support direct mRNA binding/destabilization mechanism; single lab\",\n      \"pmids\": [\"31638184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NELFE (RD) is located in the HLA class III region, 205 bp downstream of complement factor B (Bf), and its gene is arranged head-to-head with SKIV2L in a pair sharing a common CpG-containing 5′ regulatory region; NELFE is ubiquitously expressed, consistent with a housekeeping function.\",\n      \"method\": \"Genomic sequencing, exon-intron mapping, expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genomic/expression characterization only, no direct functional mechanism tested\",\n      \"pmids\": [\"9799600\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NELFE (NELF-E/RD) is the RNA-binding subunit of the four-subunit Negative Elongation Factor (NELF) complex; its conserved RRM binds nascent RNA at a specific consensus sequence (NBE) enriched at promoter-proximal pause sites, tethering NELF to paused Pol II and cooperating with DSIF to repress elongation until P-TEFb-mediated CTD phosphorylation releases the block; additionally, NELFE directly binds the nuclear cap-binding complex (CBC) in a manner mutually exclusive with ARS2–PHAX to link cap recognition to early transcriptional control, is recruited to DNA double-strand break sites via PARP1 to enforce transcriptional silencing and support repair, and functions as an oncogenic RNA-binding protein that destabilizes select mRNAs (e.g., NDRG2) and amplifies MYC signaling in certain cancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NELFE (NELF-E/RD) is the RNA-binding subunit of the four-subunit Negative Elongation Factor (NELF) complex, which cooperates with DSIF to repress RNA polymerase II transcriptional elongation at promoter-proximal pause sites until P-TEFb-mediated CTD phosphorylation releases the block [PMID:10199401]. Its conserved RRM domain adopts a βαββαβ fold that binds single-stranded nascent RNA at a specific consensus motif (NBE, CUGAGGA(U)) enriched +20–30 nt downstream of transcription start sites in paused genes, thereby tethering NELF to the elongation complex [PMID:16898873, PMID:24453987]. NELFE also directly engages the nuclear cap-binding complex (CBC) through its C-terminal peptide in a manner mutually exclusive with ARS2–PHAX, linking cap recognition to early transcriptional control, and is recruited to DNA double-strand breaks in a PARP1- and Pol II-dependent fashion to enforce transcriptional silencing and support DNA repair [PMID:29101316, PMID:28336775]. Beyond its canonical elongation-control role, NELFE functions as an RNA-binding protein that destabilizes select mRNAs such as NDRG2 and amplifies MYC signaling, contributing to oncogenesis in hepatocellular and pancreatic cancers [PMID:28697339, PMID:31638184].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before any functional data, NELFE was mapped to the HLA class III region arranged head-to-head with SKIV2L, establishing it as a ubiquitously expressed gene with a potential housekeeping role but no known mechanism.\",\n      \"evidence\": \"Genomic sequencing and expression analysis of the HLA class III locus\",\n      \"pmids\": [\"9799600\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional or biochemical characterization performed\",\n        \"No evidence of protein-level activity\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The discovery that NELFE is a subunit of the NELF complex that cooperates with DSIF to repress Pol II elongation — reversible by P-TEFb — established the core mechanism of promoter-proximal pausing and defined NELFE as a putative RNA-binding component of this machinery.\",\n      \"evidence\": \"Biochemical purification from HeLa nuclear extract and reconstituted in vitro transcription elongation assay\",\n      \"pmids\": [\"10199401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"RNA-binding activity of NELFE not directly demonstrated\",\n        \"No structural information on NELFE\",\n        \"In vivo relevance of pausing not tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solving the NMR structure of the NELFE RRM and demonstrating its binding to single-stranded HIV-1 TAR RNA established that NELFE possesses a canonical RNA-recognition motif with low-micromolar affinity, confirming its RNA-binding function and defining the structural basis.\",\n      \"evidence\": \"NMR solution structure of recombinant NELF-E RRM; fluorescence equilibrium binding titrations\",\n      \"pmids\": [\"16898873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous RNA targets in the cell unknown\",\n        \"Role of RNA binding in pausing not directly tested\",\n        \"Whether NELFE recognizes a specific sequence motif remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of a specific consensus RNA motif (NBE) recognized by the NELFE RRM, and demonstration that NBE sequences are enriched at promoter-proximal pause sites genome-wide, provided the missing link between NELFE RNA binding and its role in establishing pausing at specific genes.\",\n      \"evidence\": \"In vitro SELEX, quantitative RNA-binding biochemistry, genome-wide bioinformatic analysis of NBE distribution near TSSs\",\n      \"pmids\": [\"24453987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Causal relationship between NBE presence and pausing not demonstrated by mutagenesis in vivo\",\n        \"Whether all paused genes require NBE-mediated NELF-E tethering is unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three independent studies expanded NELFE's functional repertoire: (1) crystal structure of the CBC–NELF-E peptide complex showed that NELFE directly binds CBC at a site mutually exclusive with ARS2–PHAX, linking cap recognition to pausing; (2) NELFE is recruited to DNA double-strand breaks in a PARP1- and Pol II-dependent manner to silence transcription and support repair; (3) NELFE copy-number amplification drives MYC signaling and hepatocellular carcinoma progression.\",\n      \"evidence\": \"Crystal structure and binding assays (CBC interaction); I-SceI/CRISPR DSB induction with live-cell recruitment and repair assays (DSB role); SCNA analysis of 1,225 HCC samples with functional KD/OE and transcriptomics (oncogenic role)\",\n      \"pmids\": [\"29101316\", \"28336775\", \"28697339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CBC binding and RNA binding are coordinated on NELF-E during co-transcriptional pausing is not resolved\",\n        \"Mechanism of PARP1-dependent NELF-E recruitment to DSBs is not molecularly defined\",\n        \"Whether MYC amplification by NELFE depends on its elongation-control or RNA-destabilization activity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that NELFE destabilizes NDRG2 mRNA to activate Wnt/β-catenin signaling in pancreatic cancer established a direct mRNA-destabilizing activity distinct from its canonical elongation-repressive function.\",\n      \"evidence\": \"RNA immunoprecipitation, mRNA decay assays, and shRNA knockdown in pancreatic cancer cell lines\",\n      \"pmids\": [\"31638184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of mRNA destabilization (e.g., recruited deadenylase/decapping) not identified\",\n        \"Whether NDRG2 mRNA is a direct RRM-mediated target or requires co-factors is unclear\",\n        \"Single-lab finding not independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how NELFE's RNA-binding (RRM–NBE) and cap-binding (CBC interaction) activities are structurally integrated on the paused elongation complex, the molecular mechanism by which NELFE destabilizes specific mRNAs independently of NELF-complex-mediated pausing, and whether its roles in DNA damage silencing and oncogenesis are mechanistically linked to its elongation-control function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of the full NELF complex on a paused Pol II elongation complex with nascent RNA\",\n        \"Mechanism of mRNA destabilization by NELFE not defined\",\n        \"Relationship between elongation-control and oncogenic functions not dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"NELF complex\"\n    ],\n    \"partners\": [\n      \"NELFA\",\n      \"DSIF\",\n      \"CBP20\",\n      \"CBP80\",\n      \"PARP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}