{"gene":"RPL26","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":2005,"finding":"RPL26 binds to the 5' UTR of p53 mRNA, and its overexpression enhances association of p53 mRNA with heavier polysomes, increases the rate of p53 translation, induces G1 cell-cycle arrest, and augments irradiation-induced apoptosis. After DNA damage, RPL26 preferentially binds the 5'UTR of p53 mRNA to promote p53 protein induction.","method":"RNA binding assays, polysome profiling, overexpression and RNAi knockdown with p53 translation readout, irradiation-induced apoptosis assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA pulldown, polysome profiling, gain- and loss-of-function), replicated in subsequent studies","pmids":["16213212"],"is_preprint":false},{"year":2008,"finding":"Mdm2 binds RPL26, drives its polyubiquitylation and proteasomal degradation, and attenuates the association of RPL26 with p53 mRNA, thereby repressing L26-mediated augmentation of p53 protein synthesis. Under genotoxic stress, this inhibitory effect of Mdm2 on RPL26 is attenuated, enabling rapid increase in p53 synthesis.","method":"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor experiments, polysome profiling, overexpression/knockdown with p53 translation readout","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, proteasome pathway confirmation, multiple orthogonal methods in one study","pmids":["18951086"],"is_preprint":false},{"year":2010,"finding":"RPL26 interacts with HDM2 to form a ternary complex (RPL26-HDM2-p53) that inhibits the ubiquitin ligase activity of HDM2, thereby stabilizing p53. Ribosomal stress (low-dose actinomycin D) enhances RPL26-HDM2 interaction and activates p53. Overexpression of RPL26 inhibits cell proliferation and induces p53-dependent G1 cell cycle arrest.","method":"Yeast two-hybrid, in vivo and in vitro co-immunoprecipitation, ubiquitin ligase activity assay, overexpression with cell proliferation/cell cycle readout","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus in vivo and in vitro validation, enzymatic activity assay, multiple orthogonal methods","pmids":["20542919"],"is_preprint":false},{"year":2012,"finding":"Nucleolin (NCL) and RPL26 interact with each other. NCL binds to the same 5'-3'-UTR interaction region of p53 mRNA that is critical for RPL26 recruitment after DNA damage. NCL oligomerizes via its RNA-binding domain, which also mediates NCL-RPL26 interaction. Excessive RPL26 disrupts NCL dimerization. Point mutations in the NCL-interacting region of RPL26 reduce NCL-RPL26 interactions and attenuate both RPL26 binding to p53 mRNA and p53 induction by RPL26.","method":"Co-immunoprecipitation, RNA binding assays, site-directed mutagenesis, dimerization assays, p53 translation assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, mutagenesis, multiple functional readouts in one study, consistent with prior work","pmids":["22433872"],"is_preprint":false},{"year":2012,"finding":"A de novo two-nucleotide deletion in RPL26 in a Diamond-Blackfan anemia proband causes a ribosome biogenesis defect affecting maturation of both small and large subunits (specific pre-rRNA processing defect), establishing RPL26 as a DBA gene and a regulator of p53 activity.","method":"Gene sequencing, pre-rRNA processing analysis (Northern blot or equivalent), patient cell analysis","journal":"Human Mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct rRNA processing assay in patient cells, but single patient and single lab","pmids":["22431104"],"is_preprint":false},{"year":2015,"finding":"The Six1 oncoprotein downregulates RPL26 expression, contributing to decreased p53 levels via a mechanism independent of MDM2. Mutation analysis confirms that RPL26 inhibits miR-27a binding to p53 mRNA and prevents microRNA-mediated downregulation of p53, demonstrating that RPL26 acts as a competitive regulator protecting p53 mRNA from miR-27a.","method":"Overexpression/knockdown of Six1 and RPL26, luciferase reporter assays with p53 3'UTR, mutation analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and mutation analysis, two orthogonal methods, single lab","pmids":["26687066"],"is_preprint":false},{"year":2016,"finding":"RPL26 regulates p73 expression via two distinct mechanisms: (1) mRNA translation — RPL26 directly binds the 3'UTR of p73 mRNA, is necessary for efficient polysome assembly on p73 mRNA, and enhances association of cap-binding protein eIF4E with p73 mRNA; and (2) protein stability — RPL26 regulates p73 stability partially through MDM2. Knockdown of RPL26 promotes, whereas ectopic expression inhibits, cell growth in a TAp73-dependent manner.","method":"RNA pulldown (RPL26 binding to p73 3'UTR), polysome profiling, Co-IP (RPL26-eIF4E), eGFP reporter assays, CRISPR-Cas9 MDM2 knockout, cell growth assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pulldown, polysome, Co-IP, reporter), single lab","pmids":["27825141"],"is_preprint":false},{"year":2019,"finding":"RPL26 (uL24) is the principal target of UFMylation. UFMylated RPL26 is highly enriched on ER membrane-bound ribosomes and polysomes. UFMylation and de-UFMylation of RPL26 is catalyzed by enzyme complexes tethered to the cytoplasmic surface of the ER. Structural modeling and biochemical analysis place UFMylated RPL26 and the UFMylation machinery in close proximity to the SEC61 translocon, suggesting a direct role in cotranslational protein translocation into the ER.","method":"Mass spectrometry, biochemical fractionation, ribosome profiling (Ribo-seq), structural modeling, Co-IP","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS, fractionation, Ribo-seq, structural modeling), independently replicated by Wang et al. 2019","pmids":["30626644"],"is_preprint":false},{"year":2019,"finding":"RPL26 UFMylation occurs on two conserved lysine residues near the COOH-terminus of RPL26 at the ER upon ribosome stalling during protein translocation. RPL26 UFMylation enables degradation of stalled nascent chains via lysosomal (not proteasomal) targeting. RPL26 UFMylation is upregulated during erythroid differentiation; compromising UFMylation impairs protein secretion and hemoglobin production, causing anemia in mice.","method":"Mass spectrometry (identification of UFMylation sites on K132/K134), site-directed mutagenesis, ribosome stalling assays, lysosomal inhibitor experiments, mouse knockout model, erythroid differentiation assays","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site identification by MS plus mutagenesis, in vivo mouse model, multiple orthogonal methods, independently consistent with Walczak et al. 2019","pmids":["31595041"],"is_preprint":false},{"year":2023,"finding":"UFMylation of RPL26/uL24 at the ribosome-translocon junction (RTJ) is strictly required for UPS- and RQC-dependent degradation of arrest peptides (APs) generated when ribosomes stall during co-translational translocation into the ER. UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-arrested peptides.","method":"Cell-based stalling reporter assays, genetic complementation with UFMylation-site mutants of RPL26, proteasome inhibitor experiments, RQC pathway analysis","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional mutagenesis of UFMylation sites, multiple pathway epistasis experiments, peer-reviewed, consistent with prior work","pmids":["37036982"],"is_preprint":false},{"year":2023,"finding":"UFMylation of RPL26/uL24 at the ribosome-translocon junction is required for RQC-dependent degradation of ER arrest peptides (preprint version confirming peer-reviewed findings).","method":"Cell-based stalling reporters, UFMylation-site mutants of RPL26, proteasome/RQC pathway epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint; methods consistent with and essentially identical to peer-reviewed PNAS paper (PMID 37036982)","pmids":["36945571"],"is_preprint":true},{"year":2023,"finding":"UBE2S (an E2 ubiquitin-conjugating enzyme) targets RPL26 for ubiquitination and proteasomal degradation, thereby upregulating c-Myc to enhance NSCLC progression. Inhibiting UBE2S suppresses RPL26-c-Myc-mediated tumor growth in vivo.","method":"Immunoprecipitation combined with mass spectrometry (substrate identification), overexpression/knockdown of UBE2S, xenograft mouse model","journal":"American Journal of Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS for substrate identification, in vivo validation, single lab","pmids":["37693154"],"is_preprint":false},{"year":2022,"finding":"CDK5RAP3 interacts with RPL26 to regulate the mTOR pathway. CDK5RAP3 and RPL26 deficiency inhibited mTOR/p-mTOR and induced autophagy, resulting in increased apoptosis and slowed cell growth.","method":"Co-immunoprecipitation (CDK5RAP3-RPL26 interaction), knockdown of CDK5RAP3 and RPL26, mTOR pathway analysis, apoptosis/autophagy assays","journal":"Cell Proliferation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up on RPL26 specifically","pmids":["35509151"],"is_preprint":false},{"year":1998,"finding":"Yeast ribosomal protein L26 (ortholog of human RPL26/uL24) is located at the ribosomal subunit interface, as determined by chemical cross-linking showing two protein pairs involving L26 and 40S subunit proteins in intact 80S ribosomes.","method":"Chemical cross-linking with DSP/SPDP, 2D diagonal SDS-PAGE, fluorescent labeling with IAF","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical reconstitution with cross-linking, single lab, yeast ortholog","pmids":["9672752"],"is_preprint":false},{"year":2012,"finding":"Yeast L26 (ortholog of human RPL26/uL24) assembles into pre-60S ribosomal particles in the nucleus/nucleolus and is mainly required to optimize 27S pre-rRNA maturation; its absence partially impairs release of pre-60S particles from the nucleolus. Ribosomes lacking L26 show differential reactivity to DMS in domain I of 25S/5.8S rRNAs but can support translation in vivo with wild-type accuracy.","method":"Yeast genetics (null mutant construction), polysome analysis, pre-rRNA processing analysis, DMS chemical probing, in vivo translation fidelity assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (polysome analysis, pre-rRNA processing, chemical probing, translation fidelity), yeast ortholog, single lab","pmids":["22688513"],"is_preprint":false},{"year":2019,"finding":"Bacterial homologs of RPL26/uL24 (E. coli uL4 and uL24) individually and cooperatively stabilize a 79-nucleotide fragment of 23S rRNA essential for 50S ribosome assembly, acting as molecular clamps. Binding of both proteins simultaneously enhances mechanical stabilization and they show cooperative binding to the rRNA fragment.","method":"Single-molecule force spectroscopy (optical tweezers), in vitro rRNA-protein binding assays","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro single-molecule reconstitution, but bacterial (E. coli) homolog, single lab","pmids":["30705137"],"is_preprint":false},{"year":2021,"finding":"Polysome profiling using primary B-cells from a DBA patient with a novel RPL26 (uL24) missense variant showed reduced 60S and 80S fractions compared to an unaffected parent, consistent with a large ribosomal subunit assembly defect caused by RPL26 haploinsufficiency.","method":"B-cell polysome profiling, comparison of patient vs. unaffected parent","journal":"Journal of Pediatric Hematology/Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient, single method, no molecular mechanistic follow-up beyond subunit quantification","pmids":["33122585"],"is_preprint":false},{"year":2026,"finding":"RPL26 UFMylation deficiency (K132/K134R knock-in mice) in intestinal epithelial cells suppresses ER-phagy by promoting ubiquitin-mediated degradation of ATG16L1, triggering ER stress-dependent apoptosis in Paneth cells and causing loss of goblet and Paneth cells, shortened intestine, and elevated inflammation.","method":"Knock-in mouse model (RPL26 UFMylation site mutant), intestinal histology, ATG16L1 ubiquitination assays, ER stress markers, flow cytometry","journal":"Cellular Signalling","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in mouse model with UFMylation-site specific mutation, multiple orthogonal cellular assays, clear mechanistic pathway defined","pmids":["41962728"],"is_preprint":false}],"current_model":"RPL26 (uL24) is a 60S ribosomal subunit protein that functions both as a structural ribosomal component located at the ribosomal subunit interface and as an extraribosomal regulator: it binds the 5'UTR of p53 mRNA after DNA damage to enhance p53 translation, is counteracted by nucleolin (which binds the same UTR region) and by Mdm2/HDM2 (which polyubiquitylates and degrades RPL26 and also disrupts its mRNA association), and directly inhibits Mdm2/HDM2 ubiquitin ligase activity to stabilize p53; additionally, RPL26 is the principal substrate of UFMylation at the ER, where UFM1 conjugation to its C-terminal lysines (K132/K134) by ER-tethered enzyme complexes near the SEC61 translocon enables ribosome-associated quality control of stalled secretory nascent chains by modulating the ribosome-translocon junction to allow proteasome access, and RPL26 UFMylation is also required for ER-phagy-dependent intestinal homeostasis."},"narrative":{"mechanistic_narrative":"RPL26 (uL24) is a 60S ribosomal subunit protein that doubles as a structural component of the large subunit and an extraribosomal regulator of the p53 tumor-suppressor pathway and ER-associated quality control [PMID:16213212, PMID:30626644]. As a ribosomal protein it is positioned at the ribosomal subunit interface and is incorporated into pre-60S particles in the nucleolus, where it optimizes 27S/large-subunit pre-rRNA maturation and subunit assembly [PMID:9672752, PMID:22688513]. In its regulatory capacity, RPL26 binds the 5'UTR of p53 mRNA following DNA damage to drive its association with heavier polysomes and enhance p53 translation, producing G1 arrest and augmenting apoptosis [PMID:16213212]; it additionally protects p53 mRNA from miR-27a-mediated repression and forms a ternary RPL26–HDM2–p53 complex that inhibits HDM2 ubiquitin ligase activity to stabilize p53 [PMID:20542919, PMID:26687066]. This activity is constrained by counter-regulators: Mdm2/HDM2 binds RPL26, drives its polyubiquitylation and proteasomal degradation, and displaces it from p53 mRNA, while nucleolin competes for the same UTR region and modulates RPL26 function through a direct interaction [PMID:18951086, PMID:22433872]. RPL26 exerts parallel translational and stability control over the p53 family member p73 [PMID:27825141]. Independently, RPL26 is the principal substrate of UFMylation, which occurs on C-terminal lysines K132/K134 by ER-tethered enzyme complexes near the SEC61 translocon; this modification of translocon-bound 60S subunits remodels the ribosome-translocon junction to enable RQC- and proteasome-dependent clearance of stalled secretory nascent chains and supports ER-phagy-dependent intestinal homeostasis [PMID:30626644, PMID:31595041, PMID:37036982, PMID:41962728]. A de novo RPL26 deletion causes Diamond-Blackfan anemia through a ribosome biogenesis defect [PMID:22431104].","teleology":[{"year":1998,"claim":"Established the structural placement of RPL26 within the ribosome, defining it as a subunit-interface protein rather than a peripheral component.","evidence":"Chemical cross-linking and 2D diagonal SDS-PAGE of intact 80S ribosomes in yeast","pmids":["9672752"],"confidence":"Medium","gaps":["Based on yeast ortholog","No human structural confirmation","Cross-linking infers proximity, not precise contacts"]},{"year":2005,"claim":"Revealed an extraribosomal function: RPL26 binds the p53 mRNA 5'UTR after DNA damage to enhance p53 translation, linking a ribosomal protein to the DNA-damage response.","evidence":"RNA binding assays, polysome profiling, gain/loss-of-function with p53 translation and apoptosis readouts","pmids":["16213212"],"confidence":"High","gaps":["Did not define the counter-regulatory machinery","Structural basis of UTR recognition unresolved"]},{"year":2008,"claim":"Identified Mdm2 as the negative regulator that polyubiquitylates RPL26 and strips it from p53 mRNA, establishing how the p53-translation arm is switched off and re-activated under stress.","evidence":"Reciprocal Co-IP, ubiquitylation and proteasome-inhibitor assays, polysome profiling","pmids":["18951086"],"confidence":"High","gaps":["Ubiquitin ligase responsible not fully resolved in this study","Stress-induced attenuation mechanism not detailed"]},{"year":2010,"claim":"Showed RPL26 also stabilizes p53 by forming an RPL26-HDM2-p53 ternary complex that inhibits HDM2 ligase activity, adding a non-translational arm responsive to ribosomal stress.","evidence":"Yeast two-hybrid, in vivo/in vitro Co-IP, ubiquitin ligase activity assay, cell cycle readouts","pmids":["20542919"],"confidence":"High","gaps":["Structural basis of HDM2 inhibition unknown","Relationship between ligase inhibition and mRNA binding arms not integrated"]},{"year":2012,"claim":"Defined nucleolin as a competitor binding the same p53 UTR region and a direct RPL26 partner, refining how p53-mRNA recruitment is balanced.","evidence":"Co-IP, RNA binding, site-directed mutagenesis, dimerization and p53 translation assays","pmids":["22433872"],"confidence":"High","gaps":["Quantitative competition kinetics undefined","In vivo relevance of NCL-RPL26 stoichiometry unclear"]},{"year":2012,"claim":"Linked RPL26 loss to human disease by showing a de novo deletion causes Diamond-Blackfan anemia via defective pre-rRNA processing.","evidence":"Gene sequencing and pre-rRNA processing analysis in patient cells","pmids":["22431104"],"confidence":"Medium","gaps":["Single patient, single lab","Relative contribution of p53 hyperactivation vs biogenesis defect not dissected"]},{"year":2012,"claim":"Clarified the conserved biogenesis role: RPL26 optimizes 27S pre-rRNA maturation and pre-60S nuclear export, dissociating its assembly role from translational fidelity.","evidence":"Yeast null mutant, polysome analysis, pre-rRNA processing, DMS probing, translation fidelity assays","pmids":["22688513"],"confidence":"High","gaps":["Yeast ortholog","Human pre-rRNA processing dependence not directly shown here"]},{"year":2015,"claim":"Expanded RPL26's p53-protective function to microRNA defense, showing it blocks miR-27a binding to p53 mRNA and is repressed by the Six1 oncoprotein independently of MDM2.","evidence":"Six1/RPL26 perturbation, luciferase reporters with p53 3'UTR, mutation analysis","pmids":["26687066"],"confidence":"Medium","gaps":["Single lab","Direct RPL26-miR-27a competition not structurally resolved"]},{"year":2016,"claim":"Generalized RPL26's regulatory reach to p73, acting on both translation (3'UTR binding, eIF4E recruitment) and protein stability via MDM2.","evidence":"RNA pulldown, polysome profiling, Co-IP with eIF4E, reporters, MDM2 CRISPR knockout, growth assays","pmids":["27825141"],"confidence":"Medium","gaps":["Single lab","Mechanistic overlap with p53 regulation not delineated"]},{"year":2019,"claim":"Identified RPL26 as the principal UFMylation substrate enriched on ER-bound ribosomes near SEC61, establishing a new post-translational modification axis tied to cotranslational translocation.","evidence":"Mass spectrometry, biochemical fractionation, Ribo-seq, structural modeling, Co-IP","pmids":["30626644"],"confidence":"High","gaps":["Functional consequence of UFMylation initially inferred from proximity","Precise enzyme recruitment mechanism not fully resolved"]},{"year":2019,"claim":"Pinpointed the UFMylation sites (K132/K134) and showed UFMylation directs lysosomal degradation of stalled nascent chains, with physiological relevance to erythroid secretion in vivo.","evidence":"MS site identification, site-directed mutagenesis, ribosome stalling and lysosomal inhibitor assays, mouse knockout, erythroid differentiation","pmids":["31595041"],"confidence":"High","gaps":["Lysosomal vs proteasomal routing partially context-dependent","Mechanism of RTJ sensing of stalls not fully defined"]},{"year":2023,"claim":"Defined the mechanism by which RPL26 UFMylation acts: it remodels the ribosome-translocon junction to grant RQC and proteasome access to ER arrest peptides.","evidence":"Cell-based stalling reporters, UFMylation-site mutant complementation, proteasome inhibition, RQC pathway epistasis (peer-reviewed plus preprint)","pmids":["37036982","36945571"],"confidence":"High","gaps":["Structural detail of RTJ remodeling not directly visualized","Reconciliation with lysosomal routing reported earlier unresolved"]},{"year":2023,"claim":"Connected RPL26 to oncogenic signaling, showing UBE2S-mediated ubiquitination and degradation of RPL26 upregulates c-Myc to drive NSCLC.","evidence":"IP-MS substrate identification, UBE2S perturbation, xenograft model","pmids":["37693154"],"confidence":"Medium","gaps":["Single lab","Mechanistic link between RPL26 degradation and c-Myc not fully defined"]},{"year":2026,"claim":"Demonstrated in vivo that RPL26 UFMylation sustains intestinal homeostasis by promoting ER-phagy through ATG16L1 stabilization, preventing Paneth/goblet cell loss.","evidence":"K132/K134R knock-in mice, intestinal histology, ATG16L1 ubiquitination, ER stress markers, flow cytometry","pmids":["41962728"],"confidence":"High","gaps":["Mechanism linking RTJ UFMylation to ATG16L1 stability not fully mapped","Tissue specificity of the phenotype not generalized"]},{"year":null,"claim":"How RPL26's distinct functional modes — ribosomal structure, p53/p73 mRNA regulation, and ER UFMylation-dependent quality control — are coordinated within a single cell, and whether they are mutually exclusive ribosome populations, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating the cytosolic p53-regulatory and ER UFMylation roles","Whether UFMylated and p53-mRNA-bound RPL26 are physically distinct pools is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[13,14]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[13,14]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[14]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17]}],"complexes":["60S ribosomal subunit","RPL26-HDM2-p53 ternary complex"],"partners":["MDM2","NCL","EIF4E","UBE2S","CDK5RAP3","UFM1","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61254","full_name":"Large ribosomal subunit protein uL24","aliases":["60S ribosomal protein L26"],"length_aa":145,"mass_kda":17.3,"function":"Component of the large ribosomal subunit (PubMed:23636399, PubMed:26100019, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:26100019, PubMed:32669547)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P61254/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL26","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RPL26","total_profiled":1310},"omim":[{"mim_id":"616177","title":"DDRGK DOMAIN-CONTAINING PROTEIN 1; DDRGK1","url":"https://www.omim.org/entry/616177"},{"mim_id":"614900","title":"DIAMOND-BLACKFAN ANEMIA 11; DBA11","url":"https://www.omim.org/entry/614900"},{"mim_id":"613372","title":"UFM1-SPECIFIC LIGASE 1; UFL1","url":"https://www.omim.org/entry/613372"},{"mim_id":"610554","title":"UBIQUITIN-FOLD MODIFIER-CONJUGATING ENZYME 1; UFC1","url":"https://www.omim.org/entry/610554"},{"mim_id":"610553","title":"UBIQUITIN-FOLD MODIFIER 1; UFM1","url":"https://www.omim.org/entry/610553"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL26"},"hgnc":{"alias_symbol":["L26","uL24"],"prev_symbol":[]},"alphafold":{"accession":"P61254","domains":[{"cath_id":"2.30.30.30","chopping":"18-132","consensus_level":"high","plddt":94.8809,"start":18,"end":132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61254","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61254-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61254-F1-predicted_aligned_error_v6.png","plddt_mean":92.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL26","jax_strain_url":"https://www.jax.org/strain/search?query=RPL26"},"sequence":{"accession":"P61254","fasta_url":"https://rest.uniprot.org/uniprotkb/P61254.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61254/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61254"}},"corpus_meta":[{"pmid":"16213212","id":"PMC_16213212","title":"Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16213212","citation_count":544,"is_preprint":false},{"pmid":"18951086","id":"PMC_18951086","title":"Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18951086","citation_count":201,"is_preprint":false},{"pmid":"3263805","id":"PMC_3263805","title":"Hodgkin's disease, lymphocyte predominance type, nodular--further evidence for a B cell derivation. 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Methods & clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/37519407","citation_count":5,"is_preprint":false},{"pmid":"30232907","id":"PMC_30232907","title":"Systemic immune response of gnotobiotic mice infected with porcine circovirus type 2 after administration of Lactobacillus reuteri L26 Biocenol™.","date":"2018","source":"Beneficial microbes","url":"https://pubmed.ncbi.nlm.nih.gov/30232907","citation_count":5,"is_preprint":false},{"pmid":"39765022","id":"PMC_39765022","title":"UL24 herpesvirus determinants of pathogenesis: Roles in virus-host interactions.","date":"2024","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/39765022","citation_count":4,"is_preprint":false},{"pmid":"36179070","id":"PMC_36179070","title":"Human Cytomegalovirus UL24 and UL43 Cooperate to Modulate the Expression of Immunoregulatory UL16 Binding Protein 1.","date":"2022","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36179070","citation_count":4,"is_preprint":false},{"pmid":"36447815","id":"PMC_36447815","title":"Human cytomegalovirus UL24 and UL43 products participate in SAMHD1 subcellular localization.","date":"2022","source":"Virusdisease","url":"https://pubmed.ncbi.nlm.nih.gov/36447815","citation_count":4,"is_preprint":false},{"pmid":"37766377","id":"PMC_37766377","title":"The Disruption of a Nuclear Export Signal in the C-Terminus of the Herpes Simplex Virus 1 Determinant of Pathogenicity UL24 Protein Leads to a Syncytial Plaque Phenotype.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37766377","citation_count":4,"is_preprint":false},{"pmid":"24434141","id":"PMC_24434141","title":"The ribosomal protein rpl26 promoter is required for its 3' sense terminus ncRNA transcription in Schizosaccharomyces pombe, implicating a new transcriptional mechanism for ncRNAs.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24434141","citation_count":4,"is_preprint":false},{"pmid":"12580380","id":"PMC_12580380","title":"Comparison of six Australian isolates of Bovine herpes virus 2 based on UL24 gene after a passage in MDBK cells.","date":"2002","source":"Acta virologica","url":"https://pubmed.ncbi.nlm.nih.gov/12580380","citation_count":3,"is_preprint":false},{"pmid":"39457049","id":"PMC_39457049","title":"Comparative Review of the Conserved UL24 Protein Family in Herpesviruses.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39457049","citation_count":2,"is_preprint":false},{"pmid":"39268718","id":"PMC_39268718","title":"RPL26 variants: A rare cause of Diamond-Blackfan anemia syndrome with multiple congenital anomalies at the forefront.","date":"2024","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39268718","citation_count":2,"is_preprint":false},{"pmid":"39710607","id":"PMC_39710607","title":"Familial RPL26 Variant Causing Congenital Anomalies Without Hematological Features of Diamond Blackfan Anemia.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39710607","citation_count":2,"is_preprint":false},{"pmid":"25937123","id":"PMC_25937123","title":"Similar regulation of two distinct UL24 promoters by regulatory proteins of equine herpesvirus type 1 (EHV-1).","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25937123","citation_count":2,"is_preprint":false},{"pmid":"40974994","id":"PMC_40974994","title":"The UL24 gene affects duck plague virus replication, and its deletion attenuates virulence, enabling use as a vaccine.","date":"2025","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/40974994","citation_count":1,"is_preprint":false},{"pmid":"36945571","id":"PMC_36945571","title":"RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36945571","citation_count":1,"is_preprint":false},{"pmid":"41610489","id":"PMC_41610489","title":"UL24 deletion attenuates Marek's disease virus replication and pathogenicity.","date":"2026","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41610489","citation_count":1,"is_preprint":false},{"pmid":"16116622","id":"PMC_16116622","title":"Recovery of cDNAs encoding ribosomal proteins S9 and L26 from Aedes albopictus mosquito cells and identification of their homologs in the malaria vector, Anopheles gambiae.","date":"2005","source":"Archives of insect biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16116622","citation_count":1,"is_preprint":false},{"pmid":"41609088","id":"PMC_41609088","title":"Long Non-Coding RNA RAB11B-AS1 Suppresses Cervical Cancer Progression by Upregulating RPL26 Expression.","date":"2026","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/41609088","citation_count":0,"is_preprint":false},{"pmid":"40340823","id":"PMC_40340823","title":"Integrated multi-omics analysis and functional validation uncovers RPL26 roles in regulating growth traits of Asian water buffaloes (Bubalus bubalis).","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40340823","citation_count":0,"is_preprint":false},{"pmid":"41962728","id":"PMC_41962728","title":"RPL26 UFMylation deficiency triggers Paneth cell apoptosis associated with ER stress by impairing ATG16L1-dependent ER-phagy.","date":"2026","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41962728","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45937,"output_tokens":4697,"usd":0.104133,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12789,"output_tokens":4468,"usd":0.087822,"stage2_stop_reason":"end_turn"},"total_usd":0.191955,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"RPL26 binds to the 5' UTR of p53 mRNA, and its overexpression enhances association of p53 mRNA with heavier polysomes, increases the rate of p53 translation, induces G1 cell-cycle arrest, and augments irradiation-induced apoptosis. After DNA damage, RPL26 preferentially binds the 5'UTR of p53 mRNA to promote p53 protein induction.\",\n      \"method\": \"RNA binding assays, polysome profiling, overexpression and RNAi knockdown with p53 translation readout, irradiation-induced apoptosis assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA pulldown, polysome profiling, gain- and loss-of-function), replicated in subsequent studies\",\n      \"pmids\": [\"16213212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mdm2 binds RPL26, drives its polyubiquitylation and proteasomal degradation, and attenuates the association of RPL26 with p53 mRNA, thereby repressing L26-mediated augmentation of p53 protein synthesis. Under genotoxic stress, this inhibitory effect of Mdm2 on RPL26 is attenuated, enabling rapid increase in p53 synthesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibitor experiments, polysome profiling, overexpression/knockdown with p53 translation readout\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, proteasome pathway confirmation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18951086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RPL26 interacts with HDM2 to form a ternary complex (RPL26-HDM2-p53) that inhibits the ubiquitin ligase activity of HDM2, thereby stabilizing p53. Ribosomal stress (low-dose actinomycin D) enhances RPL26-HDM2 interaction and activates p53. Overexpression of RPL26 inhibits cell proliferation and induces p53-dependent G1 cell cycle arrest.\",\n      \"method\": \"Yeast two-hybrid, in vivo and in vitro co-immunoprecipitation, ubiquitin ligase activity assay, overexpression with cell proliferation/cell cycle readout\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus in vivo and in vitro validation, enzymatic activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"20542919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nucleolin (NCL) and RPL26 interact with each other. NCL binds to the same 5'-3'-UTR interaction region of p53 mRNA that is critical for RPL26 recruitment after DNA damage. NCL oligomerizes via its RNA-binding domain, which also mediates NCL-RPL26 interaction. Excessive RPL26 disrupts NCL dimerization. Point mutations in the NCL-interacting region of RPL26 reduce NCL-RPL26 interactions and attenuate both RPL26 binding to p53 mRNA and p53 induction by RPL26.\",\n      \"method\": \"Co-immunoprecipitation, RNA binding assays, site-directed mutagenesis, dimerization assays, p53 translation assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, mutagenesis, multiple functional readouts in one study, consistent with prior work\",\n      \"pmids\": [\"22433872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A de novo two-nucleotide deletion in RPL26 in a Diamond-Blackfan anemia proband causes a ribosome biogenesis defect affecting maturation of both small and large subunits (specific pre-rRNA processing defect), establishing RPL26 as a DBA gene and a regulator of p53 activity.\",\n      \"method\": \"Gene sequencing, pre-rRNA processing analysis (Northern blot or equivalent), patient cell analysis\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct rRNA processing assay in patient cells, but single patient and single lab\",\n      \"pmids\": [\"22431104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Six1 oncoprotein downregulates RPL26 expression, contributing to decreased p53 levels via a mechanism independent of MDM2. Mutation analysis confirms that RPL26 inhibits miR-27a binding to p53 mRNA and prevents microRNA-mediated downregulation of p53, demonstrating that RPL26 acts as a competitive regulator protecting p53 mRNA from miR-27a.\",\n      \"method\": \"Overexpression/knockdown of Six1 and RPL26, luciferase reporter assays with p53 3'UTR, mutation analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and mutation analysis, two orthogonal methods, single lab\",\n      \"pmids\": [\"26687066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RPL26 regulates p73 expression via two distinct mechanisms: (1) mRNA translation — RPL26 directly binds the 3'UTR of p73 mRNA, is necessary for efficient polysome assembly on p73 mRNA, and enhances association of cap-binding protein eIF4E with p73 mRNA; and (2) protein stability — RPL26 regulates p73 stability partially through MDM2. Knockdown of RPL26 promotes, whereas ectopic expression inhibits, cell growth in a TAp73-dependent manner.\",\n      \"method\": \"RNA pulldown (RPL26 binding to p73 3'UTR), polysome profiling, Co-IP (RPL26-eIF4E), eGFP reporter assays, CRISPR-Cas9 MDM2 knockout, cell growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pulldown, polysome, Co-IP, reporter), single lab\",\n      \"pmids\": [\"27825141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPL26 (uL24) is the principal target of UFMylation. UFMylated RPL26 is highly enriched on ER membrane-bound ribosomes and polysomes. UFMylation and de-UFMylation of RPL26 is catalyzed by enzyme complexes tethered to the cytoplasmic surface of the ER. Structural modeling and biochemical analysis place UFMylated RPL26 and the UFMylation machinery in close proximity to the SEC61 translocon, suggesting a direct role in cotranslational protein translocation into the ER.\",\n      \"method\": \"Mass spectrometry, biochemical fractionation, ribosome profiling (Ribo-seq), structural modeling, Co-IP\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS, fractionation, Ribo-seq, structural modeling), independently replicated by Wang et al. 2019\",\n      \"pmids\": [\"30626644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPL26 UFMylation occurs on two conserved lysine residues near the COOH-terminus of RPL26 at the ER upon ribosome stalling during protein translocation. RPL26 UFMylation enables degradation of stalled nascent chains via lysosomal (not proteasomal) targeting. RPL26 UFMylation is upregulated during erythroid differentiation; compromising UFMylation impairs protein secretion and hemoglobin production, causing anemia in mice.\",\n      \"method\": \"Mass spectrometry (identification of UFMylation sites on K132/K134), site-directed mutagenesis, ribosome stalling assays, lysosomal inhibitor experiments, mouse knockout model, erythroid differentiation assays\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site identification by MS plus mutagenesis, in vivo mouse model, multiple orthogonal methods, independently consistent with Walczak et al. 2019\",\n      \"pmids\": [\"31595041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UFMylation of RPL26/uL24 at the ribosome-translocon junction (RTJ) is strictly required for UPS- and RQC-dependent degradation of arrest peptides (APs) generated when ribosomes stall during co-translational translocation into the ER. UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-arrested peptides.\",\n      \"method\": \"Cell-based stalling reporter assays, genetic complementation with UFMylation-site mutants of RPL26, proteasome inhibitor experiments, RQC pathway analysis\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional mutagenesis of UFMylation sites, multiple pathway epistasis experiments, peer-reviewed, consistent with prior work\",\n      \"pmids\": [\"37036982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UFMylation of RPL26/uL24 at the ribosome-translocon junction is required for RQC-dependent degradation of ER arrest peptides (preprint version confirming peer-reviewed findings).\",\n      \"method\": \"Cell-based stalling reporters, UFMylation-site mutants of RPL26, proteasome/RQC pathway epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint; methods consistent with and essentially identical to peer-reviewed PNAS paper (PMID 37036982)\",\n      \"pmids\": [\"36945571\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2S (an E2 ubiquitin-conjugating enzyme) targets RPL26 for ubiquitination and proteasomal degradation, thereby upregulating c-Myc to enhance NSCLC progression. Inhibiting UBE2S suppresses RPL26-c-Myc-mediated tumor growth in vivo.\",\n      \"method\": \"Immunoprecipitation combined with mass spectrometry (substrate identification), overexpression/knockdown of UBE2S, xenograft mouse model\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS for substrate identification, in vivo validation, single lab\",\n      \"pmids\": [\"37693154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDK5RAP3 interacts with RPL26 to regulate the mTOR pathway. CDK5RAP3 and RPL26 deficiency inhibited mTOR/p-mTOR and induced autophagy, resulting in increased apoptosis and slowed cell growth.\",\n      \"method\": \"Co-immunoprecipitation (CDK5RAP3-RPL26 interaction), knockdown of CDK5RAP3 and RPL26, mTOR pathway analysis, apoptosis/autophagy assays\",\n      \"journal\": \"Cell Proliferation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up on RPL26 specifically\",\n      \"pmids\": [\"35509151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast ribosomal protein L26 (ortholog of human RPL26/uL24) is located at the ribosomal subunit interface, as determined by chemical cross-linking showing two protein pairs involving L26 and 40S subunit proteins in intact 80S ribosomes.\",\n      \"method\": \"Chemical cross-linking with DSP/SPDP, 2D diagonal SDS-PAGE, fluorescent labeling with IAF\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical reconstitution with cross-linking, single lab, yeast ortholog\",\n      \"pmids\": [\"9672752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Yeast L26 (ortholog of human RPL26/uL24) assembles into pre-60S ribosomal particles in the nucleus/nucleolus and is mainly required to optimize 27S pre-rRNA maturation; its absence partially impairs release of pre-60S particles from the nucleolus. Ribosomes lacking L26 show differential reactivity to DMS in domain I of 25S/5.8S rRNAs but can support translation in vivo with wild-type accuracy.\",\n      \"method\": \"Yeast genetics (null mutant construction), polysome analysis, pre-rRNA processing analysis, DMS chemical probing, in vivo translation fidelity assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (polysome analysis, pre-rRNA processing, chemical probing, translation fidelity), yeast ortholog, single lab\",\n      \"pmids\": [\"22688513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bacterial homologs of RPL26/uL24 (E. coli uL4 and uL24) individually and cooperatively stabilize a 79-nucleotide fragment of 23S rRNA essential for 50S ribosome assembly, acting as molecular clamps. Binding of both proteins simultaneously enhances mechanical stabilization and they show cooperative binding to the rRNA fragment.\",\n      \"method\": \"Single-molecule force spectroscopy (optical tweezers), in vitro rRNA-protein binding assays\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro single-molecule reconstitution, but bacterial (E. coli) homolog, single lab\",\n      \"pmids\": [\"30705137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Polysome profiling using primary B-cells from a DBA patient with a novel RPL26 (uL24) missense variant showed reduced 60S and 80S fractions compared to an unaffected parent, consistent with a large ribosomal subunit assembly defect caused by RPL26 haploinsufficiency.\",\n      \"method\": \"B-cell polysome profiling, comparison of patient vs. unaffected parent\",\n      \"journal\": \"Journal of Pediatric Hematology/Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single patient, single method, no molecular mechanistic follow-up beyond subunit quantification\",\n      \"pmids\": [\"33122585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RPL26 UFMylation deficiency (K132/K134R knock-in mice) in intestinal epithelial cells suppresses ER-phagy by promoting ubiquitin-mediated degradation of ATG16L1, triggering ER stress-dependent apoptosis in Paneth cells and causing loss of goblet and Paneth cells, shortened intestine, and elevated inflammation.\",\n      \"method\": \"Knock-in mouse model (RPL26 UFMylation site mutant), intestinal histology, ATG16L1 ubiquitination assays, ER stress markers, flow cytometry\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in mouse model with UFMylation-site specific mutation, multiple orthogonal cellular assays, clear mechanistic pathway defined\",\n      \"pmids\": [\"41962728\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RPL26 (uL24) is a 60S ribosomal subunit protein that functions both as a structural ribosomal component located at the ribosomal subunit interface and as an extraribosomal regulator: it binds the 5'UTR of p53 mRNA after DNA damage to enhance p53 translation, is counteracted by nucleolin (which binds the same UTR region) and by Mdm2/HDM2 (which polyubiquitylates and degrades RPL26 and also disrupts its mRNA association), and directly inhibits Mdm2/HDM2 ubiquitin ligase activity to stabilize p53; additionally, RPL26 is the principal substrate of UFMylation at the ER, where UFM1 conjugation to its C-terminal lysines (K132/K134) by ER-tethered enzyme complexes near the SEC61 translocon enables ribosome-associated quality control of stalled secretory nascent chains by modulating the ribosome-translocon junction to allow proteasome access, and RPL26 UFMylation is also required for ER-phagy-dependent intestinal homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL26 (uL24) is a 60S ribosomal subunit protein that doubles as a structural component of the large subunit and an extraribosomal regulator of the p53 tumor-suppressor pathway and ER-associated quality control [#0, #7]. As a ribosomal protein it is positioned at the ribosomal subunit interface and is incorporated into pre-60S particles in the nucleolus, where it optimizes 27S/large-subunit pre-rRNA maturation and subunit assembly [#13, #14]. In its regulatory capacity, RPL26 binds the 5'UTR of p53 mRNA following DNA damage to drive its association with heavier polysomes and enhance p53 translation, producing G1 arrest and augmenting apoptosis [#0]; it additionally protects p53 mRNA from miR-27a-mediated repression and forms a ternary RPL26–HDM2–p53 complex that inhibits HDM2 ubiquitin ligase activity to stabilize p53 [#2, #5]. This activity is constrained by counter-regulators: Mdm2/HDM2 binds RPL26, drives its polyubiquitylation and proteasomal degradation, and displaces it from p53 mRNA, while nucleolin competes for the same UTR region and modulates RPL26 function through a direct interaction [#1, #3]. RPL26 exerts parallel translational and stability control over the p53 family member p73 [#6]. Independently, RPL26 is the principal substrate of UFMylation, which occurs on C-terminal lysines K132/K134 by ER-tethered enzyme complexes near the SEC61 translocon; this modification of translocon-bound 60S subunits remodels the ribosome-translocon junction to enable RQC- and proteasome-dependent clearance of stalled secretory nascent chains and supports ER-phagy-dependent intestinal homeostasis [#7, #8, #9, #17]. A de novo RPL26 deletion causes Diamond-Blackfan anemia through a ribosome biogenesis defect [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the structural placement of RPL26 within the ribosome, defining it as a subunit-interface protein rather than a peripheral component.\",\n      \"evidence\": \"Chemical cross-linking and 2D diagonal SDS-PAGE of intact 80S ribosomes in yeast\",\n      \"pmids\": [\"9672752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on yeast ortholog\", \"No human structural confirmation\", \"Cross-linking infers proximity, not precise contacts\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed an extraribosomal function: RPL26 binds the p53 mRNA 5'UTR after DNA damage to enhance p53 translation, linking a ribosomal protein to the DNA-damage response.\",\n      \"evidence\": \"RNA binding assays, polysome profiling, gain/loss-of-function with p53 translation and apoptosis readouts\",\n      \"pmids\": [\"16213212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the counter-regulatory machinery\", \"Structural basis of UTR recognition unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified Mdm2 as the negative regulator that polyubiquitylates RPL26 and strips it from p53 mRNA, establishing how the p53-translation arm is switched off and re-activated under stress.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitylation and proteasome-inhibitor assays, polysome profiling\",\n      \"pmids\": [\"18951086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible not fully resolved in this study\", \"Stress-induced attenuation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed RPL26 also stabilizes p53 by forming an RPL26-HDM2-p53 ternary complex that inhibits HDM2 ligase activity, adding a non-translational arm responsive to ribosomal stress.\",\n      \"evidence\": \"Yeast two-hybrid, in vivo/in vitro Co-IP, ubiquitin ligase activity assay, cell cycle readouts\",\n      \"pmids\": [\"20542919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HDM2 inhibition unknown\", \"Relationship between ligase inhibition and mRNA binding arms not integrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined nucleolin as a competitor binding the same p53 UTR region and a direct RPL26 partner, refining how p53-mRNA recruitment is balanced.\",\n      \"evidence\": \"Co-IP, RNA binding, site-directed mutagenesis, dimerization and p53 translation assays\",\n      \"pmids\": [\"22433872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative competition kinetics undefined\", \"In vivo relevance of NCL-RPL26 stoichiometry unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked RPL26 loss to human disease by showing a de novo deletion causes Diamond-Blackfan anemia via defective pre-rRNA processing.\",\n      \"evidence\": \"Gene sequencing and pre-rRNA processing analysis in patient cells\",\n      \"pmids\": [\"22431104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient, single lab\", \"Relative contribution of p53 hyperactivation vs biogenesis defect not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Clarified the conserved biogenesis role: RPL26 optimizes 27S pre-rRNA maturation and pre-60S nuclear export, dissociating its assembly role from translational fidelity.\",\n      \"evidence\": \"Yeast null mutant, polysome analysis, pre-rRNA processing, DMS probing, translation fidelity assays\",\n      \"pmids\": [\"22688513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast ortholog\", \"Human pre-rRNA processing dependence not directly shown here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded RPL26's p53-protective function to microRNA defense, showing it blocks miR-27a binding to p53 mRNA and is repressed by the Six1 oncoprotein independently of MDM2.\",\n      \"evidence\": \"Six1/RPL26 perturbation, luciferase reporters with p53 3'UTR, mutation analysis\",\n      \"pmids\": [\"26687066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct RPL26-miR-27a competition not structurally resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generalized RPL26's regulatory reach to p73, acting on both translation (3'UTR binding, eIF4E recruitment) and protein stability via MDM2.\",\n      \"evidence\": \"RNA pulldown, polysome profiling, Co-IP with eIF4E, reporters, MDM2 CRISPR knockout, growth assays\",\n      \"pmids\": [\"27825141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic overlap with p53 regulation not delineated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified RPL26 as the principal UFMylation substrate enriched on ER-bound ribosomes near SEC61, establishing a new post-translational modification axis tied to cotranslational translocation.\",\n      \"evidence\": \"Mass spectrometry, biochemical fractionation, Ribo-seq, structural modeling, Co-IP\",\n      \"pmids\": [\"30626644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of UFMylation initially inferred from proximity\", \"Precise enzyme recruitment mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pinpointed the UFMylation sites (K132/K134) and showed UFMylation directs lysosomal degradation of stalled nascent chains, with physiological relevance to erythroid secretion in vivo.\",\n      \"evidence\": \"MS site identification, site-directed mutagenesis, ribosome stalling and lysosomal inhibitor assays, mouse knockout, erythroid differentiation\",\n      \"pmids\": [\"31595041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lysosomal vs proteasomal routing partially context-dependent\", \"Mechanism of RTJ sensing of stalls not fully defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the mechanism by which RPL26 UFMylation acts: it remodels the ribosome-translocon junction to grant RQC and proteasome access to ER arrest peptides.\",\n      \"evidence\": \"Cell-based stalling reporters, UFMylation-site mutant complementation, proteasome inhibition, RQC pathway epistasis (peer-reviewed plus preprint)\",\n      \"pmids\": [\"37036982\", \"36945571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of RTJ remodeling not directly visualized\", \"Reconciliation with lysosomal routing reported earlier unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected RPL26 to oncogenic signaling, showing UBE2S-mediated ubiquitination and degradation of RPL26 upregulates c-Myc to drive NSCLC.\",\n      \"evidence\": \"IP-MS substrate identification, UBE2S perturbation, xenograft model\",\n      \"pmids\": [\"37693154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic link between RPL26 degradation and c-Myc not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated in vivo that RPL26 UFMylation sustains intestinal homeostasis by promoting ER-phagy through ATG16L1 stabilization, preventing Paneth/goblet cell loss.\",\n      \"evidence\": \"K132/K134R knock-in mice, intestinal histology, ATG16L1 ubiquitination, ER stress markers, flow cytometry\",\n      \"pmids\": [\"41962728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking RTJ UFMylation to ATG16L1 stability not fully mapped\", \"Tissue specificity of the phenotype not generalized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPL26's distinct functional modes — ribosomal structure, p53/p73 mRNA regulation, and ER UFMylation-dependent quality control — are coordinated within a single cell, and whether they are mutually exclusive ribosome populations, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating the cytosolic p53-regulatory and ER UFMylation roles\", \"Whether UFMylated and p53-mRNA-bound RPL26 are physically distinct pools is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"60S ribosomal subunit\",\n      \"RPL26-HDM2-p53 ternary complex\"\n    ],\n    \"partners\": [\n      \"MDM2\",\n      \"NCL\",\n      \"eIF4E\",\n      \"UBE2S\",\n      \"CDK5RAP3\",\n      \"UFM1\",\n      \"TP53\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}