{"gene":"UBAP2L","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2020,"finding":"UBAP2L forms distinct granule cores inside stress granules that are spatially separate from G3BP1-containing cores, as shown by super-resolution and expansion microscopy. Reverse genetic experiments established that UBAP2L nucleates stress granules independently of G3BP1/2, acting upstream of G3BP1 core formation and SG assembly and growth.","method":"Super-resolution microscopy, expansion microscopy, reverse genetics (knockdown), cell biology assays under multiple stress conditions","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal imaging and genetic methods, independently corroborated by other labs","pmids":["31956030"],"is_preprint":false},{"year":2019,"finding":"UBAP2L is required for both stress granule assembly and disassembly. Its RGG motif mediates recruitment of SG components (mRNPs, RBPs, ribosomal subunits), and its DUF domain mediates interaction with G3BP1/2. Deletion of the DUF domain causes cytoplasmic-nuclear translocation of UBAP2L and G3BP1/2, compromising SG formation. Overexpression of UBAP2L alone nucleates SGs in the absence of stress.","method":"Overexpression, domain deletion mutants, co-immunoprecipitation, fluorescence microscopy, cell fractionation","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple domain mutants and orthogonal methods in single lab, corroborated by independent studies","pmids":["31114027"],"is_preprint":false},{"year":2019,"finding":"PRMT1 asymmetrically dimethylates UBAP2L at its RGG motif. Increased arginine methylation of the RGG motif blocks UBAP2L interactions with SG components and ablates SG assembly, whereas decreased methylation enhances these interactions and promotes SG assembly.","method":"In vitro methylation assay, mutant constructs, co-immunoprecipitation, fluorescence microscopy","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical methylation assay with mutagenesis of the modification site and functional SG assembly readout","pmids":["31114027"],"is_preprint":false},{"year":2022,"finding":"UBAP2L (and its paralogue UBAP2) are the human orthologues of yeast Def1 and are required for UV-induced ubiquitylation and degradation of RNA polymerase II (RPB1 subunit) through recruitment of Elongin-Cul5 ubiquitin ligase, representing the 'last resort' pathway for stalled RNAPII.","method":"UV irradiation, knockdown/knockout, ubiquitylation assays, co-immunoprecipitation with Elongin-Cul5, RNAPII degradation assays","journal":"DNA Repair","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional epistasis with yeast orthologue, biochemical recruitment assay, and degradation readout with multiple methods","pmids":["35633597"],"is_preprint":false},{"year":2014,"finding":"UBAP2L physically interacts with BMI1 (Polycomb group protein) and is part of a BMI1-containing PcG subcomplex. BMI1 overexpression rescues the deleterious effects of UBAP2L depletion on long-term hematopoietic stem cell (LT-HSC) activity, placing UBAP2L in a BMI1-dependent pathway that is distinct from the Ink4a/Arf-suppressing function of BMI1.","method":"Affinity purification/MS of BMI1 complexes, co-immunoprecipitation, shRNA knockdown, in vivo transplantation rescue experiments","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical interaction plus epistasis rescue experiment in vivo","pmids":["25185265"],"is_preprint":false},{"year":2023,"finding":"UBAP2L is a spindle-associated protein required for proper PLK1 localization and protein stability during mitosis. UBAP2L depletion leads to increased PLK1 protein levels and aberrant PLK1 accumulation at kinetochores, centrosomes, and mitotic spindle. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its stress-response role. Mitotic defects of UBAP2L-depleted cells are largely rescued by chemical inhibition of PLK1, suggesting UBAP2L controls ubiquitin-mediated PLK1 turnover.","method":"siRNA depletion, immunofluorescence, mitotic structure analysis, domain deletion mutants, PLK1 inhibitor rescue, Western blot for protein levels","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain mapping, epistasis rescue with PLK1 inhibitor, and localization studies with functional readout","pmids":["37039032"],"is_preprint":false},{"year":2024,"finding":"UBAP2L localizes to nuclear pores and facilitates assembly and stability of Nuclear Pore Complexes (NPCs) at the intact nuclear envelope. It promotes formation of the Y-complex (NPC scaffold), Y-complex localization to the NE, and Y-complex interactions with POM121 and Nup153. UBAP2L also enables timely localization of FXR1 (a Nup transport factor) to the NE and its interaction with the Y-complex.","method":"siRNA depletion, super-resolution microscopy, co-immunoprecipitation, fractionation, nuclear transport assays","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, biochemical interaction, functional transport assay) in single study","pmids":["38652117"],"is_preprint":false},{"year":2024,"finding":"UBAP2L localizes to processing bodies (PBs) under certain conditions (in addition to stress granules), contributes to PB biogenesis, mediates SG-PB interactions, and can nucleate hybrid granules containing both SG and PB components. UBAP2L binds both G3BP (SG protein) and DDX6 (PB protein).","method":"siRNA depletion, live imaging, fluorescence microscopy, co-immunoprecipitation, granule quantification assays","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, localization with direct functional consequence for both PB and SG biogenesis","pmids":["39007803"],"is_preprint":false},{"year":2023,"finding":"UBAP2L associates with G3BP1 through a snoRNA-bridged mechanism. In vitro binding analysis demonstrated that snoRNAs are required for UBAP2L association with G3BP1. Decreased snoRNA expression reduces the UBAP2L-G3BP1 interaction and suppresses SG formation.","method":"Proteomics, RNA sequencing, in vitro binding assay, snoRNA knockdown, co-immunoprecipitation","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding reconstitution showing RNA requirement, but single lab","pmids":["37059803"],"is_preprint":false},{"year":2024,"finding":"SARS-CoV-2 NSP3 binds FMR1/FXR1/FXR2 (FMRPs) and directly competes with UBAP2L for binding to the two central KH domains of FMRPs, preventing FMRP incorporation into stress granules. A peptide motif in UBAP2L and in NSP3 share the same binding interface on FMRPs.","method":"Co-immunoprecipitation, direct peptide competition binding assay, NSP3 mutant viruses, in vitro infection, structural/biochemical binding experiments","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct competition binding assay, mutant viruses, and functional SG incorporation assay with multiple methods","pmids":["38177924"],"is_preprint":false},{"year":2021,"finding":"UBAP2L (NICE-4) specifically interacts with mTOR and Raptor but not Rictor, indicating NICE-4 is a component of mTORC1 but not mTORC2. NICE-4 depletion markedly suppresses basal mTORC1 activity.","method":"SILAC-based mTOR interactome screen, immunoprecipitation confirmation, mTORC1 activity assays (phospho-S6K), siRNA knockdown","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — confirmed by co-IP, but single lab with limited mechanistic depth","pmids":["34171383"],"is_preprint":false},{"year":2025,"finding":"O-GlcNAcylation of UBAP2L promotes its protein stability by inhibiting TRIM37-mediated ubiquitination. O-GlcNAcylated UBAP2L regulates stress granule formation and, through SGs, enhances mRNA stability of MELK and activates PI3K signaling.","method":"Immunoprecipitation, mass spectrometry, modification-based proteomics, RNA-seq, RIP-seq, ubiquitination assay, in vitro and in vivo functional experiments","journal":"Journal of Experimental and Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods identifying the modification and its writer/eraser, but single lab","pmids":["41029457"],"is_preprint":false},{"year":2023,"finding":"PCK1 inactivates UBAP2L phosphorylation at serine 454, and this inactivation is associated with enhanced autophagy and inhibition of colorectal cancer cell growth.","method":"Overexpression and knockdown of PCK1, phosphorylation site mapping (Ser454), autophagy assays, in vitro and in vivo proliferation assays","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — specific phosphorylation site identified but mechanistic link between PCK1 and UBAP2L phosphorylation not biochemically reconstituted; single lab","pmids":["37062825"],"is_preprint":false},{"year":2017,"finding":"UBAP2L knockdown inhibited SNAIL1 expression and its binding to the E-cadherin promoter via SMAD2 signaling, resulting in increased E-cadherin expression and reduced EMT in hepatocellular carcinoma cells.","method":"siRNA knockdown, Western blot, qRT-PCR, wound healing/transwell invasion assays, chromatin immunoprecipitation for SNAIL1 binding to E-cadherin promoter","journal":"Cellular Physiology and Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP and functional assays establish pathway placement, but single lab with limited mechanistic depth","pmids":["28334716"],"is_preprint":false},{"year":2022,"finding":"UBAP2L promotes gastric cancer metastasis through the PI3K/AKT pathway, stimulating p65 nuclear aggregation (NF-κB activation) and SP1 expression. Mass spectrometry and rescue experiments placed UBAP2L upstream of PI3K/AKT/SP1/NF-κB.","method":"Mass spectrometry, pathway annotation, siRNA knockdown and overexpression, rescue experiments, in vivo metastasis assay","journal":"Cell Death Discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement by MS and rescue experiments, single lab","pmids":["35304439"],"is_preprint":false},{"year":2025,"finding":"UBAP2L-nucleated stress granules recruit RACK1 (a promoter of apoptosis) into SGs, inhibiting apoptosis and contributing to oxaliplatin resistance. Transcriptional upregulation of UBAP2L is driven by oxaliplatin-induced AKT-mediated phosphorylation and activation of HSF1.","method":"SG formation assays, RACK1 co-localization in SGs, HSF1 phosphorylation analysis, AKT inhibition, in vivo xenograft experiments","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional co-localization and pathway inhibition experiments, single lab","pmids":["40804300"],"is_preprint":false},{"year":2021,"finding":"ANXA2P2 enhances the physical interaction between UBAP2L mRNA and LIN28B (an mRNA stability factor), increasing UBAP2L mRNA stability and levels. NCTD treatment inhibits STAT3 phosphorylation, reducing ANXA2P2 transcription and consequently reducing UBAP2L mRNA stability.","method":"RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal biochemical methods (RIP, pulldown, ChIP) but single lab and limited mechanistic follow-up on UBAP2L itself","pmids":["34043991"],"is_preprint":false},{"year":2025,"finding":"UBAP2L regulates CRC cell radiotherapy resistance in a GPX4-dependent manner; UBAP2L knockdown inhibits CRC proliferation and radio-resistance by downregulating GPX4 (a ferroptosis regulator), and ferrostatin-1 (ferroptosis inhibitor) reverses the inhibitory effect of UBAP2L knockdown.","method":"Gain/loss-of-function experiments, ferroptosis inhibitor/activator rescue (ferrostatin-1, RSL3), Western blot for GPX4","journal":"Journal of Cancer Research and Clinical Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological rescue only, mechanism linking UBAP2L to GPX4 not biochemically defined","pmids":["40665007"],"is_preprint":false}],"current_model":"UBAP2L is a multifunctional ubiquitin- and RNA-binding protein that acts as a master nucleator of stress granules (acting upstream of G3BP1, independently of G3BP1/2, via its RGG motif for mRNP recruitment and DUF domain for G3BP1/2 interaction), is asymmetrically dimethylated by PRMT1 on its RGG motif to regulate SG dynamics, also localizes to and regulates processing body biogenesis and SG-PB interactions via DDX6 binding, facilitates nuclear pore complex assembly at the intact nuclear envelope by scaffolding the Y-complex with POM121 and Nup153, controls PLK1 protein stability and localization during mitosis through ubiquitin-mediated turnover, participates in UV-induced RNAPII ubiquitylation and degradation as the human orthologue of yeast Def1 by recruiting Elongin-Cul5 ligase, interacts with BMI1 in a Polycomb subcomplex to regulate hematopoietic stem cell activity, and specifically interacts with mTORC1 (Raptor-containing complex) to sustain its basal activity."},"narrative":{"mechanistic_narrative":"UBAP2L is a multifunctional ubiquitin- and RNA-binding protein that serves as a master nucleator of cytoplasmic stress granules (SGs), acting upstream of and independently from G3BP1/2 [PMID:31956030]. It assembles distinct granule cores spatially separate from G3BP1 cores and drives both SG assembly and disassembly, recruiting mRNPs, RNA-binding proteins, and ribosomal subunits through its RGG motif while engaging G3BP1/2 through its DUF domain; overexpression of UBAP2L alone nucleates SGs without stress [PMID:31956030, PMID:31114027]. The RGG-dependent SG-component interactions are governed by PRMT1-catalyzed asymmetric dimethylation, which dampens recruitment and SG assembly when increased [PMID:31114027], and the UBAP2L–G3BP1 association is further bridged by snoRNAs [PMID:37059803]. Beyond SGs, UBAP2L localizes to processing bodies (PBs), contributes to PB biogenesis, and mediates SG–PB interactions and hybrid granule formation through binding both G3BP and DDX6 [PMID:39007803]. Outside of RNA granules, UBAP2L scaffolds nuclear pore complex assembly at the intact nuclear envelope by promoting Y-complex formation and its interactions with POM121 and Nup153 [PMID:38652117], controls PLK1 protein stability and mitotic localization via its C-terminal domain through ubiquitin-mediated turnover [PMID:37039032], and functions as the human orthologue of yeast Def1 to drive UV-induced ubiquitylation and degradation of RNA polymerase II by recruiting the Elongin-Cul5 ligase [PMID:35633597]. UBAP2L also physically interacts with BMI1 within a Polycomb subcomplex to sustain hematopoietic stem cell activity [PMID:25185265] and associates with mTOR/Raptor to maintain basal mTORC1 activity [PMID:34171383]. In cancer contexts, UBAP2L stability and activity are tuned by O-GlcNAcylation antagonizing TRIM37-mediated ubiquitination [PMID:41029457] and by PCK1-modulated Ser454 phosphorylation [PMID:37062825].","teleology":[{"year":2014,"claim":"Established the first physical and functional partner of UBAP2L by showing it joins a BMI1-containing Polycomb subcomplex required for stem cell maintenance, defining a chromatin/regulatory role distinct from BMI1's canonical Ink4a/Arf axis.","evidence":"Affinity purification/MS of BMI1 complexes, co-IP, shRNA knockdown, and in vivo transplantation rescue in hematopoietic stem cells","pmids":["25185265"],"confidence":"High","gaps":["Molecular role of UBAP2L within the PcG subcomplex undefined","No structural basis for the BMI1 interaction","Does not connect this Polycomb role to UBAP2L's cytoplasmic functions"]},{"year":2017,"claim":"Linked UBAP2L to EMT regulation, showing it supports SNAIL1-driven E-cadherin repression via SMAD2 signaling in hepatocellular carcinoma.","evidence":"siRNA knockdown, ChIP for SNAIL1 at the E-cadherin promoter, and invasion assays","pmids":["28334716"],"confidence":"Medium","gaps":["Direct molecular link between UBAP2L and SMAD2/SNAIL1 not biochemically defined","Single cell-line context","Connection to UBAP2L's RNA-granule or scaffolding functions unclear"]},{"year":2019,"claim":"Defined UBAP2L's domain logic in stress granule biology, showing the RGG motif recruits SG components and the DUF domain engages G3BP1/2, and that PRMT1-mediated arginine methylation of the RGG motif tunes assembly.","evidence":"Domain deletion mutants, co-IP, fluorescence microscopy, in vitro methylation assay with site mutants and SG assembly readout","pmids":["31114027"],"confidence":"High","gaps":["Demethylase / methylation-reversal mechanism unidentified","How DUF deletion drives nuclear translocation mechanistically unresolved","Stress-signal that triggers methylation changes unknown"]},{"year":2020,"claim":"Resolved the hierarchy of SG nucleation by demonstrating UBAP2L forms cores spatially and functionally distinct from G3BP1 and acts upstream of G3BP1 core assembly, repositioning UBAP2L as a master SG nucleator rather than a G3BP1 accessory.","evidence":"Super-resolution and expansion microscopy with reverse-genetic knockdown across multiple stress conditions","pmids":["31956030"],"confidence":"High","gaps":["Biophysical driver of UBAP2L core condensation undefined","Relationship between UBAP2L cores and G3BP1 cores during maturation incompletely mapped"]},{"year":2021,"claim":"Placed UBAP2L (NICE-4) in mTOR signaling by identifying it as a specific mTORC1 (Raptor) interactor required for basal mTORC1 activity, extending its functional repertoire beyond RNA granules.","evidence":"SILAC mTOR interactome screen, co-IP confirmation, and phospho-S6K mTORC1 activity assays with siRNA knockdown","pmids":["34171383"],"confidence":"Medium","gaps":["Mechanism by which UBAP2L sustains mTORC1 activity unknown","Direct vs indirect Raptor binding not resolved","Single-lab finding without reciprocal in-pathway validation"]},{"year":2022,"claim":"Identified UBAP2L as the human Def1 orthologue mediating the 'last resort' pathway for stalled RNA polymerase II, recruiting Elongin-Cul5 to ubiquitylate and degrade RPB1 after UV damage.","evidence":"UV irradiation, knockdown/knockout, ubiquitylation and RNAPII degradation assays, co-IP with Elongin-Cul5","pmids":["35633597"],"confidence":"High","gaps":["Domain of UBAP2L responsible for Elongin-Cul5 recruitment not mapped","Interplay with redundant RNAPII degradation pathways unresolved"]},{"year":2023,"claim":"Extended the G3BP1-interaction mechanism by showing snoRNAs bridge UBAP2L to G3BP1, making the interaction RNA-dependent.","evidence":"Proteomics, RNA-seq, in vitro binding reconstitution, snoRNA knockdown, and co-IP","pmids":["37059803"],"confidence":"Medium","gaps":["Which specific snoRNAs and binding sites mediate bridging undefined","Single-lab finding","Relationship to RGG/DUF-mediated interactions not integrated"]},{"year":2023,"claim":"Uncovered a mitotic function distinct from stress response, showing UBAP2L's C-terminal domain controls PLK1 protein stability and localization via ubiquitin-mediated turnover.","evidence":"siRNA depletion, immunofluorescence, domain mutants, PLK1 inhibitor rescue, and Western blot for PLK1 levels","pmids":["37039032"],"confidence":"High","gaps":["Direct E3 ligase coupling UBAP2L to PLK1 turnover not identified","Whether UBAP2L acts as adaptor or substrate-receptor unresolved"]},{"year":2024,"claim":"Defined a nuclear-envelope function, showing UBAP2L scaffolds nuclear pore complex assembly by promoting Y-complex formation and its contacts with POM121 and Nup153.","evidence":"siRNA depletion, super-resolution microscopy, co-IP, fractionation, and nuclear transport assays","pmids":["38652117"],"confidence":"High","gaps":["Structural basis of Y-complex scaffolding by UBAP2L unknown","Whether NPC role shares determinants with its SG/granule activities unclear"]},{"year":2024,"claim":"Broadened UBAP2L's granule role to processing bodies, showing it binds DDX6, promotes PB biogenesis, and nucleates hybrid SG-PB granules.","evidence":"siRNA depletion, live imaging, fluorescence microscopy, co-IP, and granule quantification","pmids":["39007803"],"confidence":"High","gaps":["Determinants that partition UBAP2L between SGs and PBs undefined","Functional consequence of hybrid granules unclear"]},{"year":2024,"claim":"Mapped a defined UBAP2L peptide-FMRP binding interface that SARS-CoV-2 NSP3 hijacks, blocking FMRP incorporation into stress granules and revealing a viral antagonism mechanism.","evidence":"Co-IP, direct peptide competition binding assay, NSP3 mutant viruses, and SG incorporation assays","pmids":["38177924"],"confidence":"High","gaps":["Functional role of FMRP recruitment within UBAP2L-nucleated SGs incompletely defined","Generality of the shared interface across other RGG proteins untested"]},{"year":2025,"claim":"Identified post-translational and pathway controls on UBAP2L in cancer: O-GlcNAcylation stabilizes UBAP2L against TRIM37 ubiquitination to drive SG-dependent mRNA stabilization and PI3K signaling, and UBAP2L-nucleated SGs sequester RACK1 to confer chemoresistance.","evidence":"Modification proteomics, RIP-seq, ubiquitination assays, SG/RACK1 colocalization, AKT-HSF1 phosphorylation analysis, and xenograft experiments","pmids":["41029457","40804300"],"confidence":"Medium","gaps":["TRIM37 vs O-GlcNAc balance regulation in vivo unresolved","Direct causality between SG sequestration and apoptosis suppression incompletely defined","Single-lab findings"]},{"year":null,"claim":"How UBAP2L's many roles—SG/PB nucleation, NPC assembly, PLK1 and RNAPII turnover, mTORC1 and Polycomb function—are coordinated or share structural determinants remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking the RGG/DUF/C-terminal domains to distinct functions","Regulatory hierarchy among modifications (methylation, O-GlcNAcylation, phosphorylation) undefined","Tissue-specific deployment of each function uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,7]}],"complexes":["stress granule","processing body","nuclear pore Y-complex","BMI1 Polycomb subcomplex"],"partners":["G3BP1","DDX6","BMI1","POM121","NUP153","RPTOR","FXR1","TRIM37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14157","full_name":"Ubiquitin-associated protein 2-like","aliases":["Protein NICE-4","RNA polymerase II degradation factor UBAP2L"],"length_aa":1087,"mass_kda":114.5,"function":"Recruits the ubiquitination machinery to RNA polymerase II for polyubiquitination, removal and degradation, when the transcription-coupled nucleotide excision repair (TC-NER) machinery fails to resolve DNA damage (PubMed:35633597). Plays an important role in the activity of long-term repopulating hematopoietic stem cells (LT-HSCs) (By similarity). Is a regulator of stress granule assembly, required for their efficient formation (PubMed:29395067, PubMed:35977029). Required for proper brain development and neocortex lamination (By similarity)","subcellular_location":"Nucleus; Chromosome; Cytoplasm; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q14157/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBAP2L","classification":"Not Classified","n_dependent_lines":223,"n_total_lines":1208,"dependency_fraction":0.18460264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"ERG28","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBAP2L","total_profiled":1310},"omim":[{"mim_id":"620494","title":"NEURODEVELOPMENTAL DISORDER WITH IMPAIRED LANGUAGE, BEHAVIORAL ABNORMALITIES, AND DYSMORPHIC FACIES; NEDLBF","url":"https://www.omim.org/entry/620494"},{"mim_id":"616472","title":"UBIQUITIN-ASSOCIATED PROTEIN 2-LIKE; UBAP2L","url":"https://www.omim.org/entry/616472"},{"mim_id":"164831","title":"BMI1 PROTOONCOGENE, POLYCOMB RING FINGER; BMI1","url":"https://www.omim.org/entry/164831"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBAP2L"},"hgnc":{"alias_symbol":["NICE-4","KIAA0144"],"prev_symbol":[]},"alphafold":{"accession":"Q14157","domains":[{"cath_id":"-","chopping":"57-89","consensus_level":"medium","plddt":92.5585,"start":57,"end":89}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14157","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14157-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14157-F1-predicted_aligned_error_v6.png","plddt_mean":42.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBAP2L","jax_strain_url":"https://www.jax.org/strain/search?query=UBAP2L"},"sequence":{"accession":"Q14157","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14157.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14157/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14157"}},"corpus_meta":[{"pmid":"31956030","id":"PMC_31956030","title":"UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1.","date":"2020","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/31956030","citation_count":94,"is_preprint":false},{"pmid":"31114027","id":"PMC_31114027","title":"UBAP2L arginine methylation by PRMT1 modulates stress granule assembly.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/31114027","citation_count":77,"is_preprint":false},{"pmid":"11156724","id":"PMC_11156724","title":"Low-molecular-weight heparin therapy in percutaneous coronary intervention: the NICE 1 and NICE 4 trials. National Investigators Collaborating on Enoxaparin Investigators.","date":"2000","source":"The Journal of invasive cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/11156724","citation_count":33,"is_preprint":false},{"pmid":"29196913","id":"PMC_29196913","title":"UBAP2L silencing inhibits cell proliferation and G2/M phase transition in breast cancer.","date":"2017","source":"Breast cancer (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/29196913","citation_count":32,"is_preprint":false},{"pmid":"25185265","id":"PMC_25185265","title":"UBAP2L is a novel BMI1-interacting protein essential for hematopoietic stem cell activity.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/25185265","citation_count":32,"is_preprint":false},{"pmid":"28334716","id":"PMC_28334716","title":"Downregulation of UBAP2L Inhibits the Epithelial-Mesenchymal Transition via SNAIL1 Regulation in Hepatocellular Carcinoma Cells.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28334716","citation_count":23,"is_preprint":false},{"pmid":"28981479","id":"PMC_28981479","title":"Ubiquitin Associated Protein 2-Like (UBAP2L) Overexpression in Patients with Hepatocellular Carcinoma and its Clinical Significance.","date":"2017","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/28981479","citation_count":21,"is_preprint":false},{"pmid":"35304439","id":"PMC_35304439","title":"UBAP2L promotes gastric cancer metastasis by activating NF-κB through PI3K/AKT pathway.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35304439","citation_count":19,"is_preprint":false},{"pmid":"35633597","id":"PMC_35633597","title":"UBAP2/UBAP2L regulate UV-induced ubiquitylation of RNA polymerase II and are the human orthologues of yeast 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Reverse genetic experiments established that UBAP2L nucleates stress granules independently of G3BP1/2, acting upstream of G3BP1 core formation and SG assembly and growth.\",\n      \"method\": \"Super-resolution microscopy, expansion microscopy, reverse genetics (knockdown), cell biology assays under multiple stress conditions\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal imaging and genetic methods, independently corroborated by other labs\",\n      \"pmids\": [\"31956030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBAP2L is required for both stress granule assembly and disassembly. Its RGG motif mediates recruitment of SG components (mRNPs, RBPs, ribosomal subunits), and its DUF domain mediates interaction with G3BP1/2. Deletion of the DUF domain causes cytoplasmic-nuclear translocation of UBAP2L and G3BP1/2, compromising SG formation. Overexpression of UBAP2L alone nucleates SGs in the absence of stress.\",\n      \"method\": \"Overexpression, domain deletion mutants, co-immunoprecipitation, fluorescence microscopy, cell fractionation\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple domain mutants and orthogonal methods in single lab, corroborated by independent studies\",\n      \"pmids\": [\"31114027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PRMT1 asymmetrically dimethylates UBAP2L at its RGG motif. Increased arginine methylation of the RGG motif blocks UBAP2L interactions with SG components and ablates SG assembly, whereas decreased methylation enhances these interactions and promotes SG assembly.\",\n      \"method\": \"In vitro methylation assay, mutant constructs, co-immunoprecipitation, fluorescence microscopy\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical methylation assay with mutagenesis of the modification site and functional SG assembly readout\",\n      \"pmids\": [\"31114027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBAP2L (and its paralogue UBAP2) are the human orthologues of yeast Def1 and are required for UV-induced ubiquitylation and degradation of RNA polymerase II (RPB1 subunit) through recruitment of Elongin-Cul5 ubiquitin ligase, representing the 'last resort' pathway for stalled RNAPII.\",\n      \"method\": \"UV irradiation, knockdown/knockout, ubiquitylation assays, co-immunoprecipitation with Elongin-Cul5, RNAPII degradation assays\",\n      \"journal\": \"DNA Repair\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis with yeast orthologue, biochemical recruitment assay, and degradation readout with multiple methods\",\n      \"pmids\": [\"35633597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"UBAP2L physically interacts with BMI1 (Polycomb group protein) and is part of a BMI1-containing PcG subcomplex. BMI1 overexpression rescues the deleterious effects of UBAP2L depletion on long-term hematopoietic stem cell (LT-HSC) activity, placing UBAP2L in a BMI1-dependent pathway that is distinct from the Ink4a/Arf-suppressing function of BMI1.\",\n      \"method\": \"Affinity purification/MS of BMI1 complexes, co-immunoprecipitation, shRNA knockdown, in vivo transplantation rescue experiments\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical interaction plus epistasis rescue experiment in vivo\",\n      \"pmids\": [\"25185265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBAP2L is a spindle-associated protein required for proper PLK1 localization and protein stability during mitosis. UBAP2L depletion leads to increased PLK1 protein levels and aberrant PLK1 accumulation at kinetochores, centrosomes, and mitotic spindle. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its stress-response role. Mitotic defects of UBAP2L-depleted cells are largely rescued by chemical inhibition of PLK1, suggesting UBAP2L controls ubiquitin-mediated PLK1 turnover.\",\n      \"method\": \"siRNA depletion, immunofluorescence, mitotic structure analysis, domain deletion mutants, PLK1 inhibitor rescue, Western blot for protein levels\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, epistasis rescue with PLK1 inhibitor, and localization studies with functional readout\",\n      \"pmids\": [\"37039032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBAP2L localizes to nuclear pores and facilitates assembly and stability of Nuclear Pore Complexes (NPCs) at the intact nuclear envelope. It promotes formation of the Y-complex (NPC scaffold), Y-complex localization to the NE, and Y-complex interactions with POM121 and Nup153. UBAP2L also enables timely localization of FXR1 (a Nup transport factor) to the NE and its interaction with the Y-complex.\",\n      \"method\": \"siRNA depletion, super-resolution microscopy, co-immunoprecipitation, fractionation, nuclear transport assays\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, biochemical interaction, functional transport assay) in single study\",\n      \"pmids\": [\"38652117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBAP2L localizes to processing bodies (PBs) under certain conditions (in addition to stress granules), contributes to PB biogenesis, mediates SG-PB interactions, and can nucleate hybrid granules containing both SG and PB components. UBAP2L binds both G3BP (SG protein) and DDX6 (PB protein).\",\n      \"method\": \"siRNA depletion, live imaging, fluorescence microscopy, co-immunoprecipitation, granule quantification assays\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, localization with direct functional consequence for both PB and SG biogenesis\",\n      \"pmids\": [\"39007803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBAP2L associates with G3BP1 through a snoRNA-bridged mechanism. In vitro binding analysis demonstrated that snoRNAs are required for UBAP2L association with G3BP1. Decreased snoRNA expression reduces the UBAP2L-G3BP1 interaction and suppresses SG formation.\",\n      \"method\": \"Proteomics, RNA sequencing, in vitro binding assay, snoRNA knockdown, co-immunoprecipitation\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding reconstitution showing RNA requirement, but single lab\",\n      \"pmids\": [\"37059803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SARS-CoV-2 NSP3 binds FMR1/FXR1/FXR2 (FMRPs) and directly competes with UBAP2L for binding to the two central KH domains of FMRPs, preventing FMRP incorporation into stress granules. A peptide motif in UBAP2L and in NSP3 share the same binding interface on FMRPs.\",\n      \"method\": \"Co-immunoprecipitation, direct peptide competition binding assay, NSP3 mutant viruses, in vitro infection, structural/biochemical binding experiments\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct competition binding assay, mutant viruses, and functional SG incorporation assay with multiple methods\",\n      \"pmids\": [\"38177924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBAP2L (NICE-4) specifically interacts with mTOR and Raptor but not Rictor, indicating NICE-4 is a component of mTORC1 but not mTORC2. NICE-4 depletion markedly suppresses basal mTORC1 activity.\",\n      \"method\": \"SILAC-based mTOR interactome screen, immunoprecipitation confirmation, mTORC1 activity assays (phospho-S6K), siRNA knockdown\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — confirmed by co-IP, but single lab with limited mechanistic depth\",\n      \"pmids\": [\"34171383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"O-GlcNAcylation of UBAP2L promotes its protein stability by inhibiting TRIM37-mediated ubiquitination. O-GlcNAcylated UBAP2L regulates stress granule formation and, through SGs, enhances mRNA stability of MELK and activates PI3K signaling.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, modification-based proteomics, RNA-seq, RIP-seq, ubiquitination assay, in vitro and in vivo functional experiments\",\n      \"journal\": \"Journal of Experimental and Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods identifying the modification and its writer/eraser, but single lab\",\n      \"pmids\": [\"41029457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCK1 inactivates UBAP2L phosphorylation at serine 454, and this inactivation is associated with enhanced autophagy and inhibition of colorectal cancer cell growth.\",\n      \"method\": \"Overexpression and knockdown of PCK1, phosphorylation site mapping (Ser454), autophagy assays, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — specific phosphorylation site identified but mechanistic link between PCK1 and UBAP2L phosphorylation not biochemically reconstituted; single lab\",\n      \"pmids\": [\"37062825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"UBAP2L knockdown inhibited SNAIL1 expression and its binding to the E-cadherin promoter via SMAD2 signaling, resulting in increased E-cadherin expression and reduced EMT in hepatocellular carcinoma cells.\",\n      \"method\": \"siRNA knockdown, Western blot, qRT-PCR, wound healing/transwell invasion assays, chromatin immunoprecipitation for SNAIL1 binding to E-cadherin promoter\",\n      \"journal\": \"Cellular Physiology and Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP and functional assays establish pathway placement, but single lab with limited mechanistic depth\",\n      \"pmids\": [\"28334716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBAP2L promotes gastric cancer metastasis through the PI3K/AKT pathway, stimulating p65 nuclear aggregation (NF-κB activation) and SP1 expression. Mass spectrometry and rescue experiments placed UBAP2L upstream of PI3K/AKT/SP1/NF-κB.\",\n      \"method\": \"Mass spectrometry, pathway annotation, siRNA knockdown and overexpression, rescue experiments, in vivo metastasis assay\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement by MS and rescue experiments, single lab\",\n      \"pmids\": [\"35304439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBAP2L-nucleated stress granules recruit RACK1 (a promoter of apoptosis) into SGs, inhibiting apoptosis and contributing to oxaliplatin resistance. Transcriptional upregulation of UBAP2L is driven by oxaliplatin-induced AKT-mediated phosphorylation and activation of HSF1.\",\n      \"method\": \"SG formation assays, RACK1 co-localization in SGs, HSF1 phosphorylation analysis, AKT inhibition, in vivo xenograft experiments\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional co-localization and pathway inhibition experiments, single lab\",\n      \"pmids\": [\"40804300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANXA2P2 enhances the physical interaction between UBAP2L mRNA and LIN28B (an mRNA stability factor), increasing UBAP2L mRNA stability and levels. NCTD treatment inhibits STAT3 phosphorylation, reducing ANXA2P2 transcription and consequently reducing UBAP2L mRNA stability.\",\n      \"method\": \"RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal biochemical methods (RIP, pulldown, ChIP) but single lab and limited mechanistic follow-up on UBAP2L itself\",\n      \"pmids\": [\"34043991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBAP2L regulates CRC cell radiotherapy resistance in a GPX4-dependent manner; UBAP2L knockdown inhibits CRC proliferation and radio-resistance by downregulating GPX4 (a ferroptosis regulator), and ferrostatin-1 (ferroptosis inhibitor) reverses the inhibitory effect of UBAP2L knockdown.\",\n      \"method\": \"Gain/loss-of-function experiments, ferroptosis inhibitor/activator rescue (ferrostatin-1, RSL3), Western blot for GPX4\",\n      \"journal\": \"Journal of Cancer Research and Clinical Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological rescue only, mechanism linking UBAP2L to GPX4 not biochemically defined\",\n      \"pmids\": [\"40665007\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBAP2L is a multifunctional ubiquitin- and RNA-binding protein that acts as a master nucleator of stress granules (acting upstream of G3BP1, independently of G3BP1/2, via its RGG motif for mRNP recruitment and DUF domain for G3BP1/2 interaction), is asymmetrically dimethylated by PRMT1 on its RGG motif to regulate SG dynamics, also localizes to and regulates processing body biogenesis and SG-PB interactions via DDX6 binding, facilitates nuclear pore complex assembly at the intact nuclear envelope by scaffolding the Y-complex with POM121 and Nup153, controls PLK1 protein stability and localization during mitosis through ubiquitin-mediated turnover, participates in UV-induced RNAPII ubiquitylation and degradation as the human orthologue of yeast Def1 by recruiting Elongin-Cul5 ligase, interacts with BMI1 in a Polycomb subcomplex to regulate hematopoietic stem cell activity, and specifically interacts with mTORC1 (Raptor-containing complex) to sustain its basal activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBAP2L is a multifunctional ubiquitin- and RNA-binding protein that serves as a master nucleator of cytoplasmic stress granules (SGs), acting upstream of and independently from G3BP1/2 [#0]. It assembles distinct granule cores spatially separate from G3BP1 cores and drives both SG assembly and disassembly, recruiting mRNPs, RNA-binding proteins, and ribosomal subunits through its RGG motif while engaging G3BP1/2 through its DUF domain; overexpression of UBAP2L alone nucleates SGs without stress [#0, #1]. The RGG-dependent SG-component interactions are governed by PRMT1-catalyzed asymmetric dimethylation, which dampens recruitment and SG assembly when increased [#2], and the UBAP2L–G3BP1 association is further bridged by snoRNAs [#8]. Beyond SGs, UBAP2L localizes to processing bodies (PBs), contributes to PB biogenesis, and mediates SG–PB interactions and hybrid granule formation through binding both G3BP and DDX6 [#7]. Outside of RNA granules, UBAP2L scaffolds nuclear pore complex assembly at the intact nuclear envelope by promoting Y-complex formation and its interactions with POM121 and Nup153 [#6], controls PLK1 protein stability and mitotic localization via its C-terminal domain through ubiquitin-mediated turnover [#5], and functions as the human orthologue of yeast Def1 to drive UV-induced ubiquitylation and degradation of RNA polymerase II by recruiting the Elongin-Cul5 ligase [#3]. UBAP2L also physically interacts with BMI1 within a Polycomb subcomplex to sustain hematopoietic stem cell activity [#4] and associates with mTOR/Raptor to maintain basal mTORC1 activity [#10]. In cancer contexts, UBAP2L stability and activity are tuned by O-GlcNAcylation antagonizing TRIM37-mediated ubiquitination [#11] and by PCK1-modulated Ser454 phosphorylation [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the first physical and functional partner of UBAP2L by showing it joins a BMI1-containing Polycomb subcomplex required for stem cell maintenance, defining a chromatin/regulatory role distinct from BMI1's canonical Ink4a/Arf axis.\",\n      \"evidence\": \"Affinity purification/MS of BMI1 complexes, co-IP, shRNA knockdown, and in vivo transplantation rescue in hematopoietic stem cells\",\n      \"pmids\": [\"25185265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role of UBAP2L within the PcG subcomplex undefined\", \"No structural basis for the BMI1 interaction\", \"Does not connect this Polycomb role to UBAP2L's cytoplasmic functions\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked UBAP2L to EMT regulation, showing it supports SNAIL1-driven E-cadherin repression via SMAD2 signaling in hepatocellular carcinoma.\",\n      \"evidence\": \"siRNA knockdown, ChIP for SNAIL1 at the E-cadherin promoter, and invasion assays\",\n      \"pmids\": [\"28334716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between UBAP2L and SMAD2/SNAIL1 not biochemically defined\", \"Single cell-line context\", \"Connection to UBAP2L's RNA-granule or scaffolding functions unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined UBAP2L's domain logic in stress granule biology, showing the RGG motif recruits SG components and the DUF domain engages G3BP1/2, and that PRMT1-mediated arginine methylation of the RGG motif tunes assembly.\",\n      \"evidence\": \"Domain deletion mutants, co-IP, fluorescence microscopy, in vitro methylation assay with site mutants and SG assembly readout\",\n      \"pmids\": [\"31114027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demethylase / methylation-reversal mechanism unidentified\", \"How DUF deletion drives nuclear translocation mechanistically unresolved\", \"Stress-signal that triggers methylation changes unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the hierarchy of SG nucleation by demonstrating UBAP2L forms cores spatially and functionally distinct from G3BP1 and acts upstream of G3BP1 core assembly, repositioning UBAP2L as a master SG nucleator rather than a G3BP1 accessory.\",\n      \"evidence\": \"Super-resolution and expansion microscopy with reverse-genetic knockdown across multiple stress conditions\",\n      \"pmids\": [\"31956030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical driver of UBAP2L core condensation undefined\", \"Relationship between UBAP2L cores and G3BP1 cores during maturation incompletely mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed UBAP2L (NICE-4) in mTOR signaling by identifying it as a specific mTORC1 (Raptor) interactor required for basal mTORC1 activity, extending its functional repertoire beyond RNA granules.\",\n      \"evidence\": \"SILAC mTOR interactome screen, co-IP confirmation, and phospho-S6K mTORC1 activity assays with siRNA knockdown\",\n      \"pmids\": [\"34171383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which UBAP2L sustains mTORC1 activity unknown\", \"Direct vs indirect Raptor binding not resolved\", \"Single-lab finding without reciprocal in-pathway validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified UBAP2L as the human Def1 orthologue mediating the 'last resort' pathway for stalled RNA polymerase II, recruiting Elongin-Cul5 to ubiquitylate and degrade RPB1 after UV damage.\",\n      \"evidence\": \"UV irradiation, knockdown/knockout, ubiquitylation and RNAPII degradation assays, co-IP with Elongin-Cul5\",\n      \"pmids\": [\"35633597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain of UBAP2L responsible for Elongin-Cul5 recruitment not mapped\", \"Interplay with redundant RNAPII degradation pathways unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the G3BP1-interaction mechanism by showing snoRNAs bridge UBAP2L to G3BP1, making the interaction RNA-dependent.\",\n      \"evidence\": \"Proteomics, RNA-seq, in vitro binding reconstitution, snoRNA knockdown, and co-IP\",\n      \"pmids\": [\"37059803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which specific snoRNAs and binding sites mediate bridging undefined\", \"Single-lab finding\", \"Relationship to RGG/DUF-mediated interactions not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a mitotic function distinct from stress response, showing UBAP2L's C-terminal domain controls PLK1 protein stability and localization via ubiquitin-mediated turnover.\",\n      \"evidence\": \"siRNA depletion, immunofluorescence, domain mutants, PLK1 inhibitor rescue, and Western blot for PLK1 levels\",\n      \"pmids\": [\"37039032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct E3 ligase coupling UBAP2L to PLK1 turnover not identified\", \"Whether UBAP2L acts as adaptor or substrate-receptor unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a nuclear-envelope function, showing UBAP2L scaffolds nuclear pore complex assembly by promoting Y-complex formation and its contacts with POM121 and Nup153.\",\n      \"evidence\": \"siRNA depletion, super-resolution microscopy, co-IP, fractionation, and nuclear transport assays\",\n      \"pmids\": [\"38652117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Y-complex scaffolding by UBAP2L unknown\", \"Whether NPC role shares determinants with its SG/granule activities unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened UBAP2L's granule role to processing bodies, showing it binds DDX6, promotes PB biogenesis, and nucleates hybrid SG-PB granules.\",\n      \"evidence\": \"siRNA depletion, live imaging, fluorescence microscopy, co-IP, and granule quantification\",\n      \"pmids\": [\"39007803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants that partition UBAP2L between SGs and PBs undefined\", \"Functional consequence of hybrid granules unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a defined UBAP2L peptide-FMRP binding interface that SARS-CoV-2 NSP3 hijacks, blocking FMRP incorporation into stress granules and revealing a viral antagonism mechanism.\",\n      \"evidence\": \"Co-IP, direct peptide competition binding assay, NSP3 mutant viruses, and SG incorporation assays\",\n      \"pmids\": [\"38177924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of FMRP recruitment within UBAP2L-nucleated SGs incompletely defined\", \"Generality of the shared interface across other RGG proteins untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified post-translational and pathway controls on UBAP2L in cancer: O-GlcNAcylation stabilizes UBAP2L against TRIM37 ubiquitination to drive SG-dependent mRNA stabilization and PI3K signaling, and UBAP2L-nucleated SGs sequester RACK1 to confer chemoresistance.\",\n      \"evidence\": \"Modification proteomics, RIP-seq, ubiquitination assays, SG/RACK1 colocalization, AKT-HSF1 phosphorylation analysis, and xenograft experiments\",\n      \"pmids\": [\"41029457\", \"40804300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIM37 vs O-GlcNAc balance regulation in vivo unresolved\", \"Direct causality between SG sequestration and apoptosis suppression incompletely defined\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBAP2L's many roles—SG/PB nucleation, NPC assembly, PLK1 and RNAPII turnover, mTORC1 and Polycomb function—are coordinated or share structural determinants remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking the RGG/DUF/C-terminal domains to distinct functions\", \"Regulatory hierarchy among modifications (methylation, O-GlcNAcylation, phosphorylation) undefined\", \"Tissue-specific deployment of each function uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"complexes\": [\n      \"stress granule\",\n      \"processing body\",\n      \"nuclear pore Y-complex\",\n      \"BMI1 Polycomb subcomplex\"\n    ],\n    \"partners\": [\n      \"G3BP1\",\n      \"DDX6\",\n      \"BMI1\",\n      \"POM121\",\n      \"Nup153\",\n      \"RPTOR\",\n      \"FXR1\",\n      \"TRIM37\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}