{"gene":"HNRNPUL1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"E1B-AP5 (HNRNPUL1) is asymmetrically arginine-methylated in vivo within its RGG-box domain. HRMT1L2 (hPRMT1) efficiently methylates a recombinant RGG-box of E1B-AP5 in vitro but did not detectably methylate endogenous E1B-AP5. HRMT1L1 (PRMT2) was identified as an interaction partner via yeast two-hybrid screening, co-localizes with E1B-AP5 in the nuclear fraction, and its SH3 domain is essential for the interaction in vivo, suggesting HRMT1L1 is responsible for specific E1B-AP5 methylation in vivo.","method":"In vivo methylation assay, in vitro methylation assay with recombinant RGG-box, yeast two-hybrid screening, co-immunoprecipitation, in situ immunofluorescence, SH3 domain mutant analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro assay, Y2H, co-IP, immunofluorescence) in single lab; endogenous PRMT1 result is negative, PRMT2 assignment is partially indirect","pmids":["11513728"],"is_preprint":false},{"year":2003,"finding":"E1B-AP5 (HNRNPUL1) represses basic transcription driven by viral and cellular promoters, with repression activity mapped to its N-terminal domain. It activates a glucocorticoid-dependent promoter in the absence of ligand. E1B-AP5 forms a complex in vivo and in vitro with the bromodomain-containing protein BRD7; the BRD7 bromodomain is not required for this interaction. A triple complex of E1B-AP5, BRD7, and histones H2A/H2B/H3/H4 was demonstrated. Disruption of the E1B-AP5–BRD7 complex increased E1B-AP5 repression activity and converted it from an activator to a strong repressor of the hormone-dependent promoter.","method":"Reporter transcription assays, yeast two-hybrid screening, co-immunoprecipitation (in vivo), GST pull-down (in vitro), deletion/domain mutant analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro pull-down with functional reporter assays, single lab, multiple orthogonal methods","pmids":["12489984"],"is_preprint":false},{"year":2005,"finding":"E1B-AP5 (HNRNPUL1) directly interacts with both wild-type and mutant p53. The binding site on p53 maps to its C-terminal region; multiple regions of E1B-AP5 contact p53, with a major site between amino acids 395–732. E1B-AP5 inhibits p53 transcriptional activity in reporter assays and, when transfected into human tumour cells, blunts the transcriptional induction of p53-target genes in response to UV radiation despite allowing p53 protein accumulation.","method":"GST pull-down with cell lysates and in vitro translated proteins, co-immunoprecipitation, reporter transcription assays, UV treatment with gene-expression readout, deletion mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pull-down and co-IP with functional reporter and cellular assays, single lab","pmids":["15907477"],"is_preprint":false},{"year":2008,"finding":"E1B-AP5 (HNRNPUL1) is recruited to adenovirus replication centers where it co-localizes with ATRIP and RPA32. E1B-AP5 associates with ATRIP and RPA complex component RPA70 by co-immunoprecipitation in both uninfected and infected cells, and directly binds RPA70 and RPA32 in vitro (GST pull-down). E1B-AP5 is required for ATR-dependent phosphorylation of RPA32 during adenovirus infection and contributes to phosphorylation of Smc1 and H2AX.","method":"Co-immunoprecipitation, GST pull-down (in vitro direct binding), immunofluorescence co-localization, siRNA knockdown with phosphorylation readout","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vitro binding confirmed by GST pull-down, reciprocal Co-IP, functional knockdown with phosphorylation readout, and co-localization; multiple orthogonal methods in one study","pmids":["18480432"],"is_preprint":false},{"year":2013,"finding":"hnRNPUL1 associates with PARP1 and is recruited to DNA double-strand break (DSB) sites in a PARP1-mediated poly(ADP-ribosyl)ation-dependent manner. Conversely, hnRNPUL1 knockdown enhances PARP1 recruitment to DSB sites. hnRNPUL1 also transcriptionally regulates the PARP1 gene.","method":"Co-immunoprecipitation, laser micro-irradiation/recruitment assays, siRNA knockdown, transcription reporter/expression assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional recruitment and knockdown assays with defined readouts, single lab","pmids":["23577092"],"is_preprint":false},{"year":2015,"finding":"hnRNPUL1 is a substrate of PRMT1; PRMT1 methylates arginine residues within the RGG/RG motifs of hnRNPUL1 both in vitro and in vivo. Specific sites of asymmetric dimethylation (R584, R618, R620, R645, R656) and monomethylation (R661, R685, R690) were identified by mass spectrometry. An RGG/RG-to-RK hypomethylation mutant (hnRNPUL1-RK) fails to interact with PRMT1, shows impaired co-immunoprecipitation with the DNA damage protein NBS1, and is not recruited to DNA damage sites (in the presence of transcriptional inhibitors), demonstrating that arginine methylation regulates NBS1 interaction and damage-site recruitment.","method":"Mass spectrometry (site mapping in U2OS cells), in vitro methylation assay, in vivo methylation assay, co-immunoprecipitation, site-directed mutagenesis (RGG→RK), laser-induced DNA damage recruitment assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mass spectrometry site identification combined with in vitro assay, mutagenesis, Co-IP, and functional recruitment assay; multiple orthogonal methods in single rigorous study","pmids":["26020839"],"is_preprint":false},{"year":2022,"finding":"In zebrafish, loss of Hnrnpul1 causes reduced body/fin growth, missing bones, craniofacial tendon defects, and adult-onset scoliosis. RNA-sequencing of Hnrnpul1 mutants demonstrates roles in alternative splicing and transcriptional regulation, particularly of genes involved in translation, ubiquitination, and DNA damage, establishing Hnrnpul1 as required for skeletal and limb development in vivo.","method":"Zebrafish knockout/mutant analysis, RNA-sequencing (alternative splicing and transcriptomics), whole-exome sequencing in human patients","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined morphological and molecular phenotypes (RNA-seq), single lab","pmids":["35325113"],"is_preprint":false},{"year":2022,"finding":"In the MEF2D-HNRNPUL1 fusion oncoprotein, the HNRNPUL1 C-terminal moiety contributes to trans-regulatory activity, cofactor recruitment, and homodimerization of the fusion. The fusion protein acquires increased chromatin-binding mostly through MEF2D-responsive element (MRE) motifs. X-ray crystallography characterized the MEF2D–MRE complex at atomic resolution; disrupting the fusion–DNA interaction alleviated aberrant target gene expression and B-cell differentiation arrest.","method":"Knock-in mouse model, RNA-sequencing, ChIP-sequencing, X-ray crystallography, mutagenesis of DNA-binding interface, co-factor recruitment assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — crystal structure with mutagenesis and ChIP-seq in single lab; findings are specific to the fusion protein context, not WT HNRNPUL1 alone","pmids":["35544603"],"is_preprint":false},{"year":2023,"finding":"NAT10 promotes ac4C modification of HNRNPUL1 mRNA, increasing its stability and thus its protein expression. HNRNPUL1 knockdown suppresses cervical cancer cell division, invasion, and migration; ectopic HNRNPUL1 expression partially rescues the growth inhibition caused by NAT10 knockdown, placing HNRNPUL1 downstream of NAT10 in this axis.","method":"acRIP-seq (ac4C mapping), RNA-seq, siRNA knockdown, mRNA stability assay, overexpression rescue, xenograft in vivo models","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq identifies modification site, functional rescue experiment places HNRNPUL1 in pathway, single lab","pmids":["37484809"],"is_preprint":false},{"year":2026,"finding":"AlphaFold modeling and experimental validation show hnRNPUL1 contains a central folded region with tightly juxtaposed SPRY and dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions (IDRs). The dPNK domain binds both nucleotides and RNA. A single amino acid substitution in the dPNK domain can reactivate polynucleotide kinase activity. Mutations altering nucleotide binding change the ability of the full-length protein to bind RNA and shift protein interactions from homotypic to heterotypic (IDR-driven). A nucleotide-binding-preventing mutation also destabilizes the protein. Rare ALS patient coding variants in HNRNPUL1 alter nucleotide binding, RNA binding, and interaction with FUS.","method":"AlphaFold structural prediction with experimental validation, nucleotide-binding assays, RNA-binding assays, site-directed mutagenesis (reactivation of kinase activity, nucleotide-binding mutants), protein stability assays, protein–protein interaction assays, patient variant analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of domain activities, mutagenesis reactivating kinase, RNA/nucleotide binding assays, and protein interaction assays; multiple orthogonal methods in single rigorous study","pmids":["41971996"],"is_preprint":false}],"current_model":"HNRNPUL1 (E1B-AP5) is a nuclear RNA-binding protein whose central SPRY and dead polynucleotide kinase (dPNK) domains coordinate nucleotide and RNA binding as well as protein–protein interactions; its intrinsically disordered RGG/RG motifs are asymmetrically arginine-methylated by PRMT1 (and possibly PRMT2/HRMT1L1), which is required for interaction with the DNA damage sensor NBS1 and recruitment to double-strand break sites via a PARP1-dependent mechanism; it also directly binds ATR pathway components ATRIP and RPA70/RPA32 (regulating RPA32 phosphorylation), interacts with and inhibits p53 transcriptional activity, and forms a complex with BRD7 to modulate transcriptional repression and activation, while in vivo loss-of-function causes defects in alternative splicing and skeletal/limb development."},"narrative":{"mechanistic_narrative":"HNRNPUL1 (E1B-AP5) is a nuclear RNA-binding protein that couples RNA metabolism to the DNA damage response and transcriptional control [PMID:26020839, PMID:18480432]. Structurally it is built around a central folded region of tightly juxtaposed SPRY and catalytically dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions; the dPNK domain binds both nucleotides and RNA, and nucleotide binding governs full-length RNA-binding behavior, protein stability, and a switch between homotypic and heterotypic (IDR-driven) protein interactions [PMID:41971996]. Its intrinsically disordered RGG/RG motifs are asymmetrically arginine-methylated by PRMT1 at defined arginine residues, and this methylation is required for interaction with the DNA damage sensor NBS1 and for recruitment of HNRNPUL1 to damage sites [PMID:26020839]; recruitment to double-strand breaks proceeds through association with PARP1 in a poly(ADP-ribosyl)ation-dependent manner, and HNRNPUL1 in turn restrains PARP1 accumulation and regulates PARP1 gene transcription [PMID:23577092]. HNRNPUL1 directly binds the ATR-pathway components ATRIP, RPA70, and RPA32, localizing to replication centers and supporting ATR-dependent phosphorylation of RPA32, Smc1, and H2AX [PMID:18480432]. In parallel it acts as a transcriptional regulator: it represses basal transcription through its N-terminal domain, forms a complex with the bromodomain protein BRD7 and core histones that modulates repression and hormone-dependent activation [PMID:12489984], and directly binds p53 to inhibit p53-dependent transactivation [PMID:15907477]. In vivo loss of Hnrnpul1 in zebrafish disrupts alternative splicing and transcription of translation-, ubiquitination-, and DNA damage-related genes and causes skeletal and limb developmental defects [PMID:35325113]. Rare ALS-associated coding variants alter its nucleotide binding, RNA binding, and interaction with FUS [PMID:41971996].","teleology":[{"year":2001,"claim":"Established that HNRNPUL1 is post-translationally modified by arginine methylation within its RGG-box and engages arginine methyltransferase machinery, framing it as a regulated RNA-binding protein.","evidence":"In vivo and in vitro methylation assays on the recombinant RGG-box, yeast two-hybrid screening, and co-IP/immunofluorescence identifying HRMT1L1/PRMT2 as an SH3-dependent interactor","pmids":["11513728"],"confidence":"Medium","gaps":["Endogenous methyltransferase responsible in vivo was not definitively resolved (PRMT1 negative on endogenous substrate, PRMT2 assignment partly indirect)","Functional consequence of methylation not addressed at this stage"]},{"year":2003,"claim":"Defined HNRNPUL1 as a context-dependent transcriptional regulator acting through a BRD7-containing chromatin complex, answering what nuclear function it serves beyond RNA binding.","evidence":"Reporter transcription assays, yeast two-hybrid, reciprocal co-IP and GST pull-down, and demonstration of a triple complex with BRD7 and core histones, plus domain mapping","pmids":["12489984"],"confidence":"Medium","gaps":["Target promoters and physiological gene sets unknown","Mechanism converting it between activator and repressor not resolved at the molecular level"]},{"year":2005,"claim":"Showed HNRNPUL1 directly inhibits p53 transcriptional output, linking it to tumor-suppressor signaling and stress responses.","evidence":"GST pull-down and co-IP mapping the p53 C-terminal interaction, reporter assays, and UV-induced target-gene readouts in tumor cells","pmids":["15907477"],"confidence":"Medium","gaps":["Whether endogenous HNRNPUL1 levels regulate p53 targets under physiological stress unclear","Structural basis of the multi-region p53 contact not defined"]},{"year":2008,"claim":"Placed HNRNPUL1 within the ATR-RPA branch of the DNA damage/replication response through direct binding to ATRIP and RPA, addressing how it participates in damage signaling.","evidence":"Co-IP, direct in vitro GST pull-down with RPA70/RPA32, immunofluorescence co-localization at replication centers, and siRNA knockdown with phosphorylation readouts (RPA32, Smc1, H2AX) during adenovirus infection","pmids":["18480432"],"confidence":"High","gaps":["Most data obtained in the adenovirus-infection context; extent of role in cellular DSB signaling not fully established here","How HNRNPUL1 promotes RPA32 phosphorylation mechanistically unknown"]},{"year":2013,"claim":"Identified the recruitment mechanism to double-strand breaks via PARP1 and PAR, and a reciprocal regulatory loop on PARP1 itself.","evidence":"Co-IP, laser micro-irradiation recruitment assays, siRNA knockdown, and transcription/expression assays on the PARP1 gene","pmids":["23577092"],"confidence":"Medium","gaps":["Direct PAR-binding module on HNRNPUL1 not mapped","Functional outcome at the break (repair pathway choice) not resolved"]},{"year":2015,"claim":"Resolved that PRMT1-mediated asymmetric arginine methylation of the RGG/RG motifs is the molecular switch enabling NBS1 interaction and damage-site recruitment, unifying the methylation and DDR findings.","evidence":"Mass-spectrometry site mapping in U2OS cells, in vitro/in vivo methylation assays, RGG-to-RK mutagenesis, co-IP with NBS1, and laser-induced damage recruitment assays","pmids":["26020839"],"confidence":"High","gaps":["Whether methylation is dynamically regulated by damage signaling not established","Relative contributions of individual methylated arginines not dissected"]},{"year":2022,"claim":"Demonstrated the in vivo physiological requirement for Hnrnpul1 in alternative splicing/transcription and in skeletal and limb development.","evidence":"Zebrafish knockout with morphological phenotyping, RNA-sequencing of splicing and transcriptome changes, and human whole-exome sequencing","pmids":["35325113"],"confidence":"Medium","gaps":["Direct RNA targets and splicing regulatory mechanism not defined","Human disease causality from exome data not firmly established"]},{"year":2022,"claim":"Characterized how the HNRNPUL1 C-terminal moiety contributes trans-regulatory activity and dimerization within the MEF2D-HNRNPUL1 leukemic fusion, a disease-specific context.","evidence":"Knock-in mouse model, RNA-seq, ChIP-seq, X-ray crystallography of the MEF2D-MRE complex, and DNA-interface mutagenesis","pmids":["35544603"],"confidence":"Medium","gaps":["Findings pertain to the fusion oncoprotein, not wild-type HNRNPUL1 function","Role of HNRNPUL1 IDRs in cofactor recruitment not separated from MEF2D activity"]},{"year":2023,"claim":"Positioned HNRNPUL1 as a NAT10/ac4C-regulated effector promoting cervical cancer cell proliferation and invasion.","evidence":"acRIP-seq ac4C mapping, mRNA stability assays, siRNA knockdown, overexpression rescue, and xenograft models","pmids":["37484809"],"confidence":"Medium","gaps":["Downstream effectors of HNRNPUL1 in this oncogenic axis not identified","Generality beyond cervical cancer untested"]},{"year":2026,"claim":"Provided the structural-biochemical framework: a folded SPRY-dPNK core whose nucleotide binding governs RNA binding, protein stability, and a homotypic-to-heterotypic interaction switch, and linked patient ALS variants to these activities.","evidence":"AlphaFold modeling with experimental validation, nucleotide- and RNA-binding assays, kinase-reactivating and binding-disrupting mutagenesis, stability assays, protein-interaction assays (including FUS), and patient variant analysis","pmids":["41971996"],"confidence":"High","gaps":["Physiological RNA ligands of the dPNK domain unknown","Whether ALS variants cause neurodegeneration in vivo not established"]},{"year":null,"claim":"How HNRNPUL1's RNA-binding/structural activities are mechanistically coupled to its splicing, DDR, and transcriptional roles, and the identity of its physiological RNA targets, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined endogenous RNA target set linking the dPNK/RNA-binding activity to splicing or DDR outcomes","Mechanism integrating transcriptional repression (p53/BRD7) with damage signaling not unified","No structure of full-length protein in complex with NBS1, RPA, or PARP1"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,9]}],"complexes":["E1B-AP5–BRD7–histone complex"],"partners":["BRD7","TP53","ATRIP","RPA70","RPA32","PARP1","NBS1","PRMT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BUJ2","full_name":"Heterogeneous nuclear ribonucleoprotein U-like protein 1","aliases":["Adenovirus early region 1B-associated protein 5","E1B-55 kDa-associated protein 5","E1B-AP5"],"length_aa":856,"mass_kda":95.7,"function":"Acts as a basic transcriptional regulator. Represses basic transcription driven by several virus and cellular promoters. When associated with BRD7, activates transcription of glucocorticoid-responsive promoter in the absence of ligand-stimulation. Also plays a role in mRNA processing and transport. Binds avidly to poly(G) and poly(C) RNA homopolymers in vitro","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BUJ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HNRNPUL1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HNRNPUL1","total_profiled":1310},"omim":[{"mim_id":"618950","title":"SULEIMAN-EL-HATTAB SYNDROME; SULEHS","url":"https://www.omim.org/entry/618950"},{"mim_id":"618489","title":"BROMODOMAIN-CONTAINING PROTEIN 7; BRD7","url":"https://www.omim.org/entry/618489"},{"mim_id":"605800","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN U-LIKE 1; HNRNPUL1","url":"https://www.omim.org/entry/605800"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HNRNPUL1"},"hgnc":{"alias_symbol":["E1B-AP5","E1BAP5","FLJ12944"],"prev_symbol":["HNRPUL1"]},"alphafold":{"accession":"Q9BUJ2","domains":[{"cath_id":"-","chopping":"9-39","consensus_level":"high","plddt":93.2697,"start":9,"end":39},{"cath_id":"2.60.120.920","chopping":"214-411","consensus_level":"high","plddt":95.6635,"start":214,"end":411},{"cath_id":"3.40.50.300","chopping":"419-602","consensus_level":"high","plddt":88.2202,"start":419,"end":602}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUJ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUJ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUJ2-F1-predicted_aligned_error_v6.png","plddt_mean":66.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HNRNPUL1","jax_strain_url":"https://www.jax.org/strain/search?query=HNRNPUL1"},"sequence":{"accession":"Q9BUJ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BUJ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BUJ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUJ2"}},"corpus_meta":[{"pmid":"32561361","id":"PMC_32561361","title":"Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.","date":"2020","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/32561361","citation_count":70,"is_preprint":false},{"pmid":"11513728","id":"PMC_11513728","title":"Heterogeneous nuclear ribonucleoprotein E1B-AP5 is methylated in its Arg-Gly-Gly (RGG) box and interacts with human arginine methyltransferase HRMT1L1.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11513728","citation_count":67,"is_preprint":false},{"pmid":"16690874","id":"PMC_16690874","title":"Gene variants of VAMP8 and HNRPUL1 are associated with early-onset myocardial infarction.","date":"2006","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16690874","citation_count":62,"is_preprint":false},{"pmid":"18480432","id":"PMC_18480432","title":"A role for E1B-AP5 in ATR signaling pathways during adenovirus infection.","date":"2008","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/18480432","citation_count":47,"is_preprint":false},{"pmid":"12489984","id":"PMC_12489984","title":"Regulation of transcription by the heterogeneous nuclear ribonucleoprotein E1B-AP5 is mediated by complex formation with the novel bromodomain-containing protein BRD7.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12489984","citation_count":47,"is_preprint":false},{"pmid":"26020839","id":"PMC_26020839","title":"Arginine methylation of hnRNPUL1 regulates interaction with NBS1 and recruitment to sites of DNA damage.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26020839","citation_count":41,"is_preprint":false},{"pmid":"23577092","id":"PMC_23577092","title":"The role of hnRPUL1 involved in DNA damage response is related to PARP1.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23577092","citation_count":39,"is_preprint":false},{"pmid":"37484809","id":"PMC_37484809","title":"NAT10-mediated RNA acetylation enhances HNRNPUL1 mRNA stability to contribute cervical cancer progression.","date":"2023","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37484809","citation_count":33,"is_preprint":false},{"pmid":"35544603","id":"PMC_35544603","title":"Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/35544603","citation_count":21,"is_preprint":false},{"pmid":"15907477","id":"PMC_15907477","title":"The interaction of the hnRNP family member E1B-AP5 with p53.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15907477","citation_count":19,"is_preprint":false},{"pmid":"34688610","id":"PMC_34688610","title":"HNRNPUL1 inhibits cisplatin sensitivity of esophageal squamous cell carcinoma through regulating the formation of circMAN1A2.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34688610","citation_count":12,"is_preprint":false},{"pmid":"35325113","id":"PMC_35325113","title":"Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo.","date":"2022","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/35325113","citation_count":8,"is_preprint":false},{"pmid":"38711442","id":"PMC_38711442","title":"AKAP8 promotes ovarian cancer progression and antagonizes PARP inhibitor sensitivity through regulating hnRNPUL1 transcription.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38711442","citation_count":3,"is_preprint":false},{"pmid":"39254804","id":"PMC_39254804","title":"LINC00461 promotes bladder cancer cells EMT through miR-518b/HNRNPUL1 axis.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39254804","citation_count":1,"is_preprint":false},{"pmid":"41971996","id":"PMC_41971996","title":"hnRNPUL1 has a dead polynucleotide kinase domain that regulates RNA and protein interactions.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41971996","citation_count":0,"is_preprint":false},{"pmid":"40552937","id":"PMC_40552937","title":"Lnc056 Enhances Hair Follicle Stem Cells Proliferation by Binding Transcription Factor HNRNPUL1 to Up-Regulate TRIP6 Expression.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40552937","citation_count":0,"is_preprint":false},{"pmid":"41543969","id":"PMC_41543969","title":"BET bromodomain inhibition: a potential therapeutic avenue in MEF2D-HNRNPUL1-rearranged B-cell acute lymphoblastic leukaemia.","date":"2026","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/41543969","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10656,"output_tokens":3400,"usd":0.041484,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10872,"output_tokens":3937,"usd":0.076393,"stage2_stop_reason":"end_turn"},"total_usd":0.117877,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"E1B-AP5 (HNRNPUL1) is asymmetrically arginine-methylated in vivo within its RGG-box domain. HRMT1L2 (hPRMT1) efficiently methylates a recombinant RGG-box of E1B-AP5 in vitro but did not detectably methylate endogenous E1B-AP5. HRMT1L1 (PRMT2) was identified as an interaction partner via yeast two-hybrid screening, co-localizes with E1B-AP5 in the nuclear fraction, and its SH3 domain is essential for the interaction in vivo, suggesting HRMT1L1 is responsible for specific E1B-AP5 methylation in vivo.\",\n      \"method\": \"In vivo methylation assay, in vitro methylation assay with recombinant RGG-box, yeast two-hybrid screening, co-immunoprecipitation, in situ immunofluorescence, SH3 domain mutant analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro assay, Y2H, co-IP, immunofluorescence) in single lab; endogenous PRMT1 result is negative, PRMT2 assignment is partially indirect\",\n      \"pmids\": [\"11513728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"E1B-AP5 (HNRNPUL1) represses basic transcription driven by viral and cellular promoters, with repression activity mapped to its N-terminal domain. It activates a glucocorticoid-dependent promoter in the absence of ligand. E1B-AP5 forms a complex in vivo and in vitro with the bromodomain-containing protein BRD7; the BRD7 bromodomain is not required for this interaction. A triple complex of E1B-AP5, BRD7, and histones H2A/H2B/H3/H4 was demonstrated. Disruption of the E1B-AP5–BRD7 complex increased E1B-AP5 repression activity and converted it from an activator to a strong repressor of the hormone-dependent promoter.\",\n      \"method\": \"Reporter transcription assays, yeast two-hybrid screening, co-immunoprecipitation (in vivo), GST pull-down (in vitro), deletion/domain mutant analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro pull-down with functional reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12489984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"E1B-AP5 (HNRNPUL1) directly interacts with both wild-type and mutant p53. The binding site on p53 maps to its C-terminal region; multiple regions of E1B-AP5 contact p53, with a major site between amino acids 395–732. E1B-AP5 inhibits p53 transcriptional activity in reporter assays and, when transfected into human tumour cells, blunts the transcriptional induction of p53-target genes in response to UV radiation despite allowing p53 protein accumulation.\",\n      \"method\": \"GST pull-down with cell lysates and in vitro translated proteins, co-immunoprecipitation, reporter transcription assays, UV treatment with gene-expression readout, deletion mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pull-down and co-IP with functional reporter and cellular assays, single lab\",\n      \"pmids\": [\"15907477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E1B-AP5 (HNRNPUL1) is recruited to adenovirus replication centers where it co-localizes with ATRIP and RPA32. E1B-AP5 associates with ATRIP and RPA complex component RPA70 by co-immunoprecipitation in both uninfected and infected cells, and directly binds RPA70 and RPA32 in vitro (GST pull-down). E1B-AP5 is required for ATR-dependent phosphorylation of RPA32 during adenovirus infection and contributes to phosphorylation of Smc1 and H2AX.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down (in vitro direct binding), immunofluorescence co-localization, siRNA knockdown with phosphorylation readout\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vitro binding confirmed by GST pull-down, reciprocal Co-IP, functional knockdown with phosphorylation readout, and co-localization; multiple orthogonal methods in one study\",\n      \"pmids\": [\"18480432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hnRNPUL1 associates with PARP1 and is recruited to DNA double-strand break (DSB) sites in a PARP1-mediated poly(ADP-ribosyl)ation-dependent manner. Conversely, hnRNPUL1 knockdown enhances PARP1 recruitment to DSB sites. hnRNPUL1 also transcriptionally regulates the PARP1 gene.\",\n      \"method\": \"Co-immunoprecipitation, laser micro-irradiation/recruitment assays, siRNA knockdown, transcription reporter/expression assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional recruitment and knockdown assays with defined readouts, single lab\",\n      \"pmids\": [\"23577092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"hnRNPUL1 is a substrate of PRMT1; PRMT1 methylates arginine residues within the RGG/RG motifs of hnRNPUL1 both in vitro and in vivo. Specific sites of asymmetric dimethylation (R584, R618, R620, R645, R656) and monomethylation (R661, R685, R690) were identified by mass spectrometry. An RGG/RG-to-RK hypomethylation mutant (hnRNPUL1-RK) fails to interact with PRMT1, shows impaired co-immunoprecipitation with the DNA damage protein NBS1, and is not recruited to DNA damage sites (in the presence of transcriptional inhibitors), demonstrating that arginine methylation regulates NBS1 interaction and damage-site recruitment.\",\n      \"method\": \"Mass spectrometry (site mapping in U2OS cells), in vitro methylation assay, in vivo methylation assay, co-immunoprecipitation, site-directed mutagenesis (RGG→RK), laser-induced DNA damage recruitment assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mass spectrometry site identification combined with in vitro assay, mutagenesis, Co-IP, and functional recruitment assay; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"26020839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish, loss of Hnrnpul1 causes reduced body/fin growth, missing bones, craniofacial tendon defects, and adult-onset scoliosis. RNA-sequencing of Hnrnpul1 mutants demonstrates roles in alternative splicing and transcriptional regulation, particularly of genes involved in translation, ubiquitination, and DNA damage, establishing Hnrnpul1 as required for skeletal and limb development in vivo.\",\n      \"method\": \"Zebrafish knockout/mutant analysis, RNA-sequencing (alternative splicing and transcriptomics), whole-exome sequencing in human patients\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined morphological and molecular phenotypes (RNA-seq), single lab\",\n      \"pmids\": [\"35325113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the MEF2D-HNRNPUL1 fusion oncoprotein, the HNRNPUL1 C-terminal moiety contributes to trans-regulatory activity, cofactor recruitment, and homodimerization of the fusion. The fusion protein acquires increased chromatin-binding mostly through MEF2D-responsive element (MRE) motifs. X-ray crystallography characterized the MEF2D–MRE complex at atomic resolution; disrupting the fusion–DNA interaction alleviated aberrant target gene expression and B-cell differentiation arrest.\",\n      \"method\": \"Knock-in mouse model, RNA-sequencing, ChIP-sequencing, X-ray crystallography, mutagenesis of DNA-binding interface, co-factor recruitment assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — crystal structure with mutagenesis and ChIP-seq in single lab; findings are specific to the fusion protein context, not WT HNRNPUL1 alone\",\n      \"pmids\": [\"35544603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAT10 promotes ac4C modification of HNRNPUL1 mRNA, increasing its stability and thus its protein expression. HNRNPUL1 knockdown suppresses cervical cancer cell division, invasion, and migration; ectopic HNRNPUL1 expression partially rescues the growth inhibition caused by NAT10 knockdown, placing HNRNPUL1 downstream of NAT10 in this axis.\",\n      \"method\": \"acRIP-seq (ac4C mapping), RNA-seq, siRNA knockdown, mRNA stability assay, overexpression rescue, xenograft in vivo models\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq identifies modification site, functional rescue experiment places HNRNPUL1 in pathway, single lab\",\n      \"pmids\": [\"37484809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AlphaFold modeling and experimental validation show hnRNPUL1 contains a central folded region with tightly juxtaposed SPRY and dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions (IDRs). The dPNK domain binds both nucleotides and RNA. A single amino acid substitution in the dPNK domain can reactivate polynucleotide kinase activity. Mutations altering nucleotide binding change the ability of the full-length protein to bind RNA and shift protein interactions from homotypic to heterotypic (IDR-driven). A nucleotide-binding-preventing mutation also destabilizes the protein. Rare ALS patient coding variants in HNRNPUL1 alter nucleotide binding, RNA binding, and interaction with FUS.\",\n      \"method\": \"AlphaFold structural prediction with experimental validation, nucleotide-binding assays, RNA-binding assays, site-directed mutagenesis (reactivation of kinase activity, nucleotide-binding mutants), protein stability assays, protein–protein interaction assays, patient variant analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of domain activities, mutagenesis reactivating kinase, RNA/nucleotide binding assays, and protein interaction assays; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41971996\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HNRNPUL1 (E1B-AP5) is a nuclear RNA-binding protein whose central SPRY and dead polynucleotide kinase (dPNK) domains coordinate nucleotide and RNA binding as well as protein–protein interactions; its intrinsically disordered RGG/RG motifs are asymmetrically arginine-methylated by PRMT1 (and possibly PRMT2/HRMT1L1), which is required for interaction with the DNA damage sensor NBS1 and recruitment to double-strand break sites via a PARP1-dependent mechanism; it also directly binds ATR pathway components ATRIP and RPA70/RPA32 (regulating RPA32 phosphorylation), interacts with and inhibits p53 transcriptional activity, and forms a complex with BRD7 to modulate transcriptional repression and activation, while in vivo loss-of-function causes defects in alternative splicing and skeletal/limb development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HNRNPUL1 (E1B-AP5) is a nuclear RNA-binding protein that couples RNA metabolism to the DNA damage response and transcriptional control [#5, #3]. Structurally it is built around a central folded region of tightly juxtaposed SPRY and catalytically dead polynucleotide kinase (dPNK) domains flanked by intrinsically disordered regions; the dPNK domain binds both nucleotides and RNA, and nucleotide binding governs full-length RNA-binding behavior, protein stability, and a switch between homotypic and heterotypic (IDR-driven) protein interactions [#9]. Its intrinsically disordered RGG/RG motifs are asymmetrically arginine-methylated by PRMT1 at defined arginine residues, and this methylation is required for interaction with the DNA damage sensor NBS1 and for recruitment of HNRNPUL1 to damage sites [#5]; recruitment to double-strand breaks proceeds through association with PARP1 in a poly(ADP-ribosyl)ation-dependent manner, and HNRNPUL1 in turn restrains PARP1 accumulation and regulates PARP1 gene transcription [#4]. HNRNPUL1 directly binds the ATR-pathway components ATRIP, RPA70, and RPA32, localizing to replication centers and supporting ATR-dependent phosphorylation of RPA32, Smc1, and H2AX [#3]. In parallel it acts as a transcriptional regulator: it represses basal transcription through its N-terminal domain, forms a complex with the bromodomain protein BRD7 and core histones that modulates repression and hormone-dependent activation [#1], and directly binds p53 to inhibit p53-dependent transactivation [#2]. In vivo loss of Hnrnpul1 in zebrafish disrupts alternative splicing and transcription of translation-, ubiquitination-, and DNA damage-related genes and causes skeletal and limb developmental defects [#6]. Rare ALS-associated coding variants alter its nucleotide binding, RNA binding, and interaction with FUS [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that HNRNPUL1 is post-translationally modified by arginine methylation within its RGG-box and engages arginine methyltransferase machinery, framing it as a regulated RNA-binding protein.\",\n      \"evidence\": \"In vivo and in vitro methylation assays on the recombinant RGG-box, yeast two-hybrid screening, and co-IP/immunofluorescence identifying HRMT1L1/PRMT2 as an SH3-dependent interactor\",\n      \"pmids\": [\"11513728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous methyltransferase responsible in vivo was not definitively resolved (PRMT1 negative on endogenous substrate, PRMT2 assignment partly indirect)\", \"Functional consequence of methylation not addressed at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined HNRNPUL1 as a context-dependent transcriptional regulator acting through a BRD7-containing chromatin complex, answering what nuclear function it serves beyond RNA binding.\",\n      \"evidence\": \"Reporter transcription assays, yeast two-hybrid, reciprocal co-IP and GST pull-down, and demonstration of a triple complex with BRD7 and core histones, plus domain mapping\",\n      \"pmids\": [\"12489984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target promoters and physiological gene sets unknown\", \"Mechanism converting it between activator and repressor not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed HNRNPUL1 directly inhibits p53 transcriptional output, linking it to tumor-suppressor signaling and stress responses.\",\n      \"evidence\": \"GST pull-down and co-IP mapping the p53 C-terminal interaction, reporter assays, and UV-induced target-gene readouts in tumor cells\",\n      \"pmids\": [\"15907477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endogenous HNRNPUL1 levels regulate p53 targets under physiological stress unclear\", \"Structural basis of the multi-region p53 contact not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed HNRNPUL1 within the ATR-RPA branch of the DNA damage/replication response through direct binding to ATRIP and RPA, addressing how it participates in damage signaling.\",\n      \"evidence\": \"Co-IP, direct in vitro GST pull-down with RPA70/RPA32, immunofluorescence co-localization at replication centers, and siRNA knockdown with phosphorylation readouts (RPA32, Smc1, H2AX) during adenovirus infection\",\n      \"pmids\": [\"18480432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most data obtained in the adenovirus-infection context; extent of role in cellular DSB signaling not fully established here\", \"How HNRNPUL1 promotes RPA32 phosphorylation mechanistically unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the recruitment mechanism to double-strand breaks via PARP1 and PAR, and a reciprocal regulatory loop on PARP1 itself.\",\n      \"evidence\": \"Co-IP, laser micro-irradiation recruitment assays, siRNA knockdown, and transcription/expression assays on the PARP1 gene\",\n      \"pmids\": [\"23577092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PAR-binding module on HNRNPUL1 not mapped\", \"Functional outcome at the break (repair pathway choice) not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved that PRMT1-mediated asymmetric arginine methylation of the RGG/RG motifs is the molecular switch enabling NBS1 interaction and damage-site recruitment, unifying the methylation and DDR findings.\",\n      \"evidence\": \"Mass-spectrometry site mapping in U2OS cells, in vitro/in vivo methylation assays, RGG-to-RK mutagenesis, co-IP with NBS1, and laser-induced damage recruitment assays\",\n      \"pmids\": [\"26020839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether methylation is dynamically regulated by damage signaling not established\", \"Relative contributions of individual methylated arginines not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated the in vivo physiological requirement for Hnrnpul1 in alternative splicing/transcription and in skeletal and limb development.\",\n      \"evidence\": \"Zebrafish knockout with morphological phenotyping, RNA-sequencing of splicing and transcriptome changes, and human whole-exome sequencing\",\n      \"pmids\": [\"35325113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA targets and splicing regulatory mechanism not defined\", \"Human disease causality from exome data not firmly established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Characterized how the HNRNPUL1 C-terminal moiety contributes trans-regulatory activity and dimerization within the MEF2D-HNRNPUL1 leukemic fusion, a disease-specific context.\",\n      \"evidence\": \"Knock-in mouse model, RNA-seq, ChIP-seq, X-ray crystallography of the MEF2D-MRE complex, and DNA-interface mutagenesis\",\n      \"pmids\": [\"35544603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Findings pertain to the fusion oncoprotein, not wild-type HNRNPUL1 function\", \"Role of HNRNPUL1 IDRs in cofactor recruitment not separated from MEF2D activity\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned HNRNPUL1 as a NAT10/ac4C-regulated effector promoting cervical cancer cell proliferation and invasion.\",\n      \"evidence\": \"acRIP-seq ac4C mapping, mRNA stability assays, siRNA knockdown, overexpression rescue, and xenograft models\",\n      \"pmids\": [\"37484809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of HNRNPUL1 in this oncogenic axis not identified\", \"Generality beyond cervical cancer untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the structural-biochemical framework: a folded SPRY-dPNK core whose nucleotide binding governs RNA binding, protein stability, and a homotypic-to-heterotypic interaction switch, and linked patient ALS variants to these activities.\",\n      \"evidence\": \"AlphaFold modeling with experimental validation, nucleotide- and RNA-binding assays, kinase-reactivating and binding-disrupting mutagenesis, stability assays, protein-interaction assays (including FUS), and patient variant analysis\",\n      \"pmids\": [\"41971996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological RNA ligands of the dPNK domain unknown\", \"Whether ALS variants cause neurodegeneration in vivo not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HNRNPUL1's RNA-binding/structural activities are mechanistically coupled to its splicing, DDR, and transcriptional roles, and the identity of its physiological RNA targets, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined endogenous RNA target set linking the dPNK/RNA-binding activity to splicing or DDR outcomes\", \"Mechanism integrating transcriptional repression (p53/BRD7) with damage signaling not unified\", \"No structure of full-length protein in complex with NBS1, RPA, or PARP1\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [\"E1B-AP5\\u2013BRD7\\u2013histone complex\"],\n    \"partners\": [\"BRD7\", \"TP53\", \"ATRIP\", \"RPA70\", \"RPA32\", \"PARP1\", \"NBS1\", \"PRMT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}