{"gene":"RPL23A","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":1993,"finding":"Rat RPL23A (L23a) was identified as a 156 amino acid component of the 60S ribosomal large subunit, with sequence conservation across mammals, yeast (S. cerevisiae L25), archaebacteria (M. vannielii L23), and E. coli L23, establishing it as a member of the conserved L23 ribosomal protein family.","method":"cDNA sequencing, Northern blot, genomic Southern blot, sequence homology analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary sequence determination and hybridization analysis in a single study, multiple orthogonal methods","pmids":["8428950"],"is_preprint":false},{"year":1997,"finding":"Reduction of RPL23A mRNA by antisense expression in HeLa cells directly reduced colony formation, demonstrating a direct antiproliferative consequence of inhibiting RPL23A expression; RPL23A mRNA was specifically downregulated by IFN-beta treatment independently of general growth arrest.","method":"Subtraction hybridization, Northern blot, antisense transfection with colony formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (antisense) with defined cellular phenotype, single lab, two methods","pmids":["9053844"],"is_preprint":false},{"year":1999,"finding":"Drosophila RPL23A (PBP-3) was identified as a binding partner of Poly(ADP-ribose) polymerase (PARP) via its auto-modification domain, and Drosophila L23a contains a unique N-terminal Ala/Lys/Pro-rich extension resembling histone H1, suggesting dual DNA-binding and ribosomal functions.","method":"Far-Western screening of Drosophila cDNA library, sequence analysis","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Far-Western pulldown, single lab, Drosophila ortholog","pmids":["9931508"],"is_preprint":false},{"year":2000,"finding":"Human RPL23A was identified as a binding partner of vaccinia virus E3L protein in a yeast two-hybrid screen using a HeLa cDNA library.","method":"Yeast two-hybrid screen","journal":"Virus genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid, not confirmed by orthogonal method","pmids":["11129635"],"is_preprint":false},{"year":2007,"finding":"Drosophila L23a can functionally substitute for yeast L25 (the S. cerevisiae ortholog) in ribosome biogenesis: a yeast strain with chromosomal L25 disruption and fly L23a as the sole copy was viable, though with a reduced growth rate and delay in 27S→25S rRNA processing, demonstrating functional conservation of the ribosomal assembly role.","method":"Yeast chromosomal gene disruption/complementation, pulse-chase rRNA processing assay, genetic epistasis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic complementation with in vivo functional readout (rRNA processing) and growth rescue, multiple orthogonal methods in one study","pmids":["17584789"],"is_preprint":false},{"year":2017,"finding":"Bacterial SRP contacts the intra-tunnel loop of ribosomal protein uL23 (RPL23A ortholog) via the C-terminal helix of SRP's signal-sequence-binding domain, allowing SRP to scan translating ribosomes for substrate selection before signal sequence emerges from the tunnel.","method":"In vivo crosslinking, mutational analysis, ribosome biochemistry","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct crosslinking and mutagenesis establishing specific contact between SRP C-terminal helix and uL23 tunnel loop, mechanistically rigorous single study","pmids":["28134917"],"is_preprint":false},{"year":2021,"finding":"Ionizing radiation reduces RPL23A expression in mouse spermatogonia, weakening the RPL23A–RPL11 interaction; loss of this interaction releases RPL11 to inhibit MDM2, leading to p53 accumulation and apoptosis via the RPL23A–RPL11–MDM2–p53 pathway.","method":"RPL23A knockdown, immunoprecipitation, immunofluorescence, immunoblotting, flow cytometry (apoptosis/cell cycle), TUNEL in vivo","journal":"Biomedical and environmental sciences : BES","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function plus co-IP establishing protein interaction and pathway placement, single lab, multiple methods","pmids":["34782045"],"is_preprint":false},{"year":2021,"finding":"A native peptide derived from RPL23A (PDRL23A) interacts with ribosomal protein L26 (RPL26), blocking RPL26-governed p53 translation and reducing p53 protein levels, thereby decreasing p53-mediated apoptosis under hypoxic conditions and protecting cardiomyocytes from ischemia-reperfusion injury.","method":"Intracellular peptidomics, co-immunoprecipitation (PDRL23A–RPL26 interaction), in vitro cardiomyocyte injury assay, in vivo I/R model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue in vitro and in vivo, single lab, multiple orthogonal methods","pmids":["34808368"],"is_preprint":false},{"year":2022,"finding":"E3 ubiquitin ligase HERC3 directly interacts with RPL23A (identified by Co-IP and GST-pulldown) and targets it for K48-linked polyubiquitination and proteasomal degradation via HERC3's HECT domain; RPL23A in turn regulates the c-Myc/p21 axis and cell cycle progression in colorectal cancer cells.","method":"Co-immunoprecipitation, mass spectrometry, GST-pulldown, in vivo ubiquitylation assay, cycloheximide chase, loss- and gain-of-function experiments, rescue experiments","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted ubiquitination, reciprocal Co-IP, GST-pulldown, cycloheximide chase, and functional rescue with multiple orthogonal methods in one study","pmids":["35637966"],"is_preprint":false},{"year":2025,"finding":"Using high-speed atomic force microscopy, bacterial ribosomal protein uL23 (RPL23A ortholog) was directly visualized making stable and transient contacts with chaperone Trigger Factor (TF) on translating 70S ribosomes (ribosome-nascent chain complexes), with TF exhibiting dynamic extended-to-compact conformational transitions; TF binding was not observed on non-translating ribosomes.","method":"High-speed atomic force microscopy, molecular dynamics simulations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct structural visualization by HS-AFM with MD support, single study not yet peer-reviewed (preprint)","pmids":["bio_10.1101_2025.05.16.654432"],"is_preprint":true}],"current_model":"RPL23A encodes a conserved 60S ribosomal large subunit protein (uL23) that is an essential structural component of the ribosomal tunnel exit where it serves as a docking site for ribosome-associated factors (SRP, chaperones such as Trigger Factor) to facilitate cotranslational targeting and folding; outside the ribosome, RPL23A interacts with RPL11 to suppress the RPL11–MDM2–p53 apoptotic pathway, is directly ubiquitinated and degraded by E3 ligase HERC3 (K48-linked, via the HECT domain) to regulate the c-Myc/p21 axis and cell cycle, and a native peptide derived from it (PDRL23A) competes with RPL26 to suppress p53 translation under hypoxic stress."},"narrative":{"mechanistic_narrative":"RPL23A encodes uL23, a conserved structural protein of the 60S large ribosomal subunit that is essential for ribosome assembly and provides a functional docking platform at the ribosomal tunnel exit [PMID:8428950, PMID:17584789]. Genetic complementation in yeast established that the ribosomal assembly role is conserved across species: the Drosophila ortholog substitutes for yeast L25 to support viability and proper 27S→25S rRNA processing [PMID:17584789]. At the tunnel exit, uL23 serves as the contact point for ribosome-associated factors that act cotranslationally, including the signal recognition particle, which engages the intra-tunnel loop of uL23 via its signal-sequence-binding domain to scan translating ribosomes for substrate selection [PMID:28134917]. Beyond its ribosomal role, RPL23A participates in p53 regulation through multiple routes: it binds RPL11 to restrain the RPL11–MDM2–p53 axis, such that loss of RPL23A releases RPL11 to inhibit MDM2 and drive p53 accumulation and apoptosis [PMID:34782045], and a native peptide derived from RPL23A (PDRL23A) competes with RPL26 to suppress p53 translation under hypoxic stress [PMID:34808368]. RPL23A protein abundance is controlled by the E3 ubiquitin ligase HERC3, which directly binds RPL23A and catalyzes K48-linked polyubiquitination and proteasomal degradation through its HECT domain, thereby influencing the c-Myc/p21 axis and cell-cycle progression [PMID:35637966]. Consistent with an essential cellular role, suppression of RPL23A expression is antiproliferative [PMID:9053844].","teleology":[{"year":1993,"claim":"Established RPL23A as a defined molecular entity — a conserved 60S large-subunit ribosomal protein — placing it within the L23 family before any functional dissection.","evidence":"cDNA sequencing and hybridization analysis of rat L23a with cross-species homology comparison","pmids":["8428950"],"confidence":"Medium","gaps":["Sequence identity alone did not demonstrate ribosomal assembly function","No mechanistic role at the tunnel exit established"]},{"year":1997,"claim":"Showed that reducing RPL23A has a direct antiproliferative consequence, linking the gene's expression to cell growth rather than being a passive structural component.","evidence":"Antisense knockdown in HeLa cells with colony formation assay; IFN-beta-dependent downregulation","pmids":["9053844"],"confidence":"Medium","gaps":["Did not distinguish loss of ribosome function from extra-ribosomal signaling effects","Mechanism connecting RPL23A to proliferation unresolved"]},{"year":2007,"claim":"Demonstrated that RPL23A's ribosomal assembly role is functionally conserved, settling that the protein is genuinely required for large-subunit biogenesis and rRNA maturation.","evidence":"Yeast chromosomal disruption/complementation with Drosophila L23a and pulse-chase rRNA processing","pmids":["17584789"],"confidence":"High","gaps":["Reduced growth rate of the complemented strain indicates incomplete functional equivalence","Specific structural contacts within assembling ribosome not defined"]},{"year":2017,"claim":"Defined a specific cotranslational targeting function for the uL23 tunnel-exit loop, showing it is the SRP docking site that enables early substrate scanning.","evidence":"In vivo crosslinking and mutational analysis of bacterial uL23–SRP contact","pmids":["28134917"],"confidence":"High","gaps":["Demonstrated in bacterial system; eukaryotic RPL23A–SRP contact not directly shown","Does not address other tunnel-exit factor interactions"]},{"year":2021,"claim":"Placed RPL23A in p53 control by two distinct routes — sequestering RPL11 to restrain MDM2-p53, and generating a peptide that competes with RPL26 to suppress p53 translation.","evidence":"Knockdown, co-IP and apoptosis assays in spermatogonia; intracellular peptidomics, co-IP and I/R rescue for PDRL23A","pmids":["34782045","34808368"],"confidence":"Medium","gaps":["Each pathway shown in a single tissue context (germ cells; cardiomyocytes)","Stoichiometry and physiological balance between ribosomal vs free RPL23A pools unclear"]},{"year":2022,"claim":"Identified the mechanism controlling RPL23A protein levels — HERC3-mediated K48 ubiquitination and degradation — and linked this turnover to c-Myc/p21 and cell-cycle control in cancer.","evidence":"Reciprocal Co-IP, GST-pulldown, in vivo ubiquitylation, cycloheximide chase, and rescue in colorectal cancer cells","pmids":["35637966"],"confidence":"High","gaps":["How RPL23A regulates the c-Myc/p21 axis mechanistically not fully resolved","Whether degradation targets ribosomal vs extra-ribosomal RPL23A unknown"]},{"year":2025,"claim":"Directly visualized uL23 as a dynamic docking site for the chaperone Trigger Factor selectively on translating ribosomes, refining the tunnel-exit factor recruitment model.","evidence":"High-speed atomic force microscopy and molecular dynamics on bacterial ribosome-nascent chain complexes (preprint)","pmids":["bio_10.1101_2025.05.16.654432"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Bacterial system; eukaryotic RPL23A–chaperone dynamics not shown"]},{"year":null,"claim":"How the ribosomal and extra-ribosomal (p53-regulatory) pools of RPL23A are partitioned and coordinated in human cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model of free vs ribosome-bound RPL23A","Eukaryotic structural validation of tunnel-exit factor contacts lacking","Integration of HERC3-controlled abundance with p53 pathway output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8]}],"complexes":["60S large ribosomal subunit"],"partners":["RPL11","RPL26","HERC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62750","full_name":"Large ribosomal subunit protein uL23","aliases":["60S ribosomal protein L23a"],"length_aa":156,"mass_kda":17.7,"function":"Component of the large ribosomal subunit (PubMed:23636399, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:23636399, PubMed:32669547). Binds a specific region on the 26S rRNA (PubMed:23636399, PubMed:32669547). May promote p53/TP53 degradation possibly through the stimulation of MDM2-mediated TP53 polyubiquitination (PubMed:26203195)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P62750/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL23A","classification":"Common Essential","n_dependent_lines":381,"n_total_lines":381,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"EIF3B","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":10.0},{"gene":"RBM8A","stoichiometry":10.0},{"gene":"RPL11","stoichiometry":10.0},{"gene":"RPL4","stoichiometry":10.0},{"gene":"RPL5","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"SRP72","stoichiometry":10.0},{"gene":"CAPRIN1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/RPL23A","total_profiled":1310},"omim":[{"mim_id":"610889","title":"IMPORTIN 11; IPO11","url":"https://www.omim.org/entry/610889"},{"mim_id":"602326","title":"RIBOSOMAL PROTEIN L23A; RPL23A","url":"https://www.omim.org/entry/602326"},{"mim_id":"180300","title":"RHEUMATOID ARTHRITIS; RA","url":"https://www.omim.org/entry/180300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL23A"},"hgnc":{"alias_symbol":["L23A","uL23"],"prev_symbol":[]},"alphafold":{"accession":"P62750","domains":[{"cath_id":"3.30.70.330","chopping":"72-147","consensus_level":"high","plddt":96.4963,"start":72,"end":147}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62750","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62750-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62750-F1-predicted_aligned_error_v6.png","plddt_mean":89.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL23A","jax_strain_url":"https://www.jax.org/strain/search?query=RPL23A"},"sequence":{"accession":"P62750","fasta_url":"https://rest.uniprot.org/uniprotkb/P62750.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62750/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62750"}},"corpus_meta":[{"pmid":"20733037","id":"PMC_20733037","title":"Genotypic characterization of UL23 thymidine kinase and UL30 DNA polymerase of clinical isolates of herpes simplex virus: natural polymorphism and mutations associated with resistance to antivirals.","date":"2010","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/20733037","citation_count":111,"is_preprint":false},{"pmid":"11724303","id":"PMC_11724303","title":"Enhanced expression of S8, L12, L23a, L27 and L30 ribosomal protein mRNAs in human hepatocellular carcinoma.","date":"2001","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11724303","citation_count":69,"is_preprint":false},{"pmid":"29184886","id":"PMC_29184886","title":"Expression Profiling of Ribosomal Protein Gene Family in Dehydration Stress Responses and Characterization of Transgenic Rice Plants Overexpressing RPL23A for Water-Use Efficiency and Tolerance to Drought and Salt Stresses.","date":"2017","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29184886","citation_count":57,"is_preprint":false},{"pmid":"29377960","id":"PMC_29377960","title":"Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29377960","citation_count":43,"is_preprint":false},{"pmid":"9053844","id":"PMC_9053844","title":"Suppression of human ribosomal protein L23A expression during cell growth inhibition by interferon-beta.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9053844","citation_count":39,"is_preprint":false},{"pmid":"28134917","id":"PMC_28134917","title":"The signal recognition particle contacts uL23 and scans substrate translation inside the ribosomal tunnel.","date":"2017","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28134917","citation_count":39,"is_preprint":false},{"pmid":"12029146","id":"PMC_12029146","title":"The products of human cytomegalovirus genes UL23, UL24, UL43 and US22 are tegument components.","date":"2002","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/12029146","citation_count":38,"is_preprint":false},{"pmid":"9931508","id":"PMC_9931508","title":"Poly(ADP-ribose) polymerase interacts with novel Drosophila ribosomal proteins, L22 and l23a, with unique histone-like amino-terminal extensions.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9931508","citation_count":33,"is_preprint":false},{"pmid":"8428950","id":"PMC_8428950","title":"The primary structure of rat ribosomal protein L23a. 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Ribosomes","date":"2025-05-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.16.654432","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21318,"output_tokens":2402,"usd":0.049992,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9548,"output_tokens":2689,"usd":0.057482,"stage2_stop_reason":"end_turn"},"total_usd":0.107474,"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\": 1993,\n      \"finding\": \"Rat RPL23A (L23a) was identified as a 156 amino acid component of the 60S ribosomal large subunit, with sequence conservation across mammals, yeast (S. cerevisiae L25), archaebacteria (M. vannielii L23), and E. coli L23, establishing it as a member of the conserved L23 ribosomal protein family.\",\n      \"method\": \"cDNA sequencing, Northern blot, genomic Southern blot, sequence homology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary sequence determination and hybridization analysis in a single study, multiple orthogonal methods\",\n      \"pmids\": [\"8428950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Reduction of RPL23A mRNA by antisense expression in HeLa cells directly reduced colony formation, demonstrating a direct antiproliferative consequence of inhibiting RPL23A expression; RPL23A mRNA was specifically downregulated by IFN-beta treatment independently of general growth arrest.\",\n      \"method\": \"Subtraction hybridization, Northern blot, antisense transfection with colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (antisense) with defined cellular phenotype, single lab, two methods\",\n      \"pmids\": [\"9053844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Drosophila RPL23A (PBP-3) was identified as a binding partner of Poly(ADP-ribose) polymerase (PARP) via its auto-modification domain, and Drosophila L23a contains a unique N-terminal Ala/Lys/Pro-rich extension resembling histone H1, suggesting dual DNA-binding and ribosomal functions.\",\n      \"method\": \"Far-Western screening of Drosophila cDNA library, sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Far-Western pulldown, single lab, Drosophila ortholog\",\n      \"pmids\": [\"9931508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human RPL23A was identified as a binding partner of vaccinia virus E3L protein in a yeast two-hybrid screen using a HeLa cDNA library.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Virus genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid, not confirmed by orthogonal method\",\n      \"pmids\": [\"11129635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Drosophila L23a can functionally substitute for yeast L25 (the S. cerevisiae ortholog) in ribosome biogenesis: a yeast strain with chromosomal L25 disruption and fly L23a as the sole copy was viable, though with a reduced growth rate and delay in 27S→25S rRNA processing, demonstrating functional conservation of the ribosomal assembly role.\",\n      \"method\": \"Yeast chromosomal gene disruption/complementation, pulse-chase rRNA processing assay, genetic epistasis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic complementation with in vivo functional readout (rRNA processing) and growth rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17584789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bacterial SRP contacts the intra-tunnel loop of ribosomal protein uL23 (RPL23A ortholog) via the C-terminal helix of SRP's signal-sequence-binding domain, allowing SRP to scan translating ribosomes for substrate selection before signal sequence emerges from the tunnel.\",\n      \"method\": \"In vivo crosslinking, mutational analysis, ribosome biochemistry\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct crosslinking and mutagenesis establishing specific contact between SRP C-terminal helix and uL23 tunnel loop, mechanistically rigorous single study\",\n      \"pmids\": [\"28134917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ionizing radiation reduces RPL23A expression in mouse spermatogonia, weakening the RPL23A–RPL11 interaction; loss of this interaction releases RPL11 to inhibit MDM2, leading to p53 accumulation and apoptosis via the RPL23A–RPL11–MDM2–p53 pathway.\",\n      \"method\": \"RPL23A knockdown, immunoprecipitation, immunofluorescence, immunoblotting, flow cytometry (apoptosis/cell cycle), TUNEL in vivo\",\n      \"journal\": \"Biomedical and environmental sciences : BES\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function plus co-IP establishing protein interaction and pathway placement, single lab, multiple methods\",\n      \"pmids\": [\"34782045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A native peptide derived from RPL23A (PDRL23A) interacts with ribosomal protein L26 (RPL26), blocking RPL26-governed p53 translation and reducing p53 protein levels, thereby decreasing p53-mediated apoptosis under hypoxic conditions and protecting cardiomyocytes from ischemia-reperfusion injury.\",\n      \"method\": \"Intracellular peptidomics, co-immunoprecipitation (PDRL23A–RPL26 interaction), in vitro cardiomyocyte injury assay, in vivo I/R model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue in vitro and in vivo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34808368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E3 ubiquitin ligase HERC3 directly interacts with RPL23A (identified by Co-IP and GST-pulldown) and targets it for K48-linked polyubiquitination and proteasomal degradation via HERC3's HECT domain; RPL23A in turn regulates the c-Myc/p21 axis and cell cycle progression in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GST-pulldown, in vivo ubiquitylation assay, cycloheximide chase, loss- and gain-of-function experiments, rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted ubiquitination, reciprocal Co-IP, GST-pulldown, cycloheximide chase, and functional rescue with multiple orthogonal methods in one study\",\n      \"pmids\": [\"35637966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using high-speed atomic force microscopy, bacterial ribosomal protein uL23 (RPL23A ortholog) was directly visualized making stable and transient contacts with chaperone Trigger Factor (TF) on translating 70S ribosomes (ribosome-nascent chain complexes), with TF exhibiting dynamic extended-to-compact conformational transitions; TF binding was not observed on non-translating ribosomes.\",\n      \"method\": \"High-speed atomic force microscopy, molecular dynamics simulations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct structural visualization by HS-AFM with MD support, single study not yet peer-reviewed (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.16.654432\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPL23A encodes a conserved 60S ribosomal large subunit protein (uL23) that is an essential structural component of the ribosomal tunnel exit where it serves as a docking site for ribosome-associated factors (SRP, chaperones such as Trigger Factor) to facilitate cotranslational targeting and folding; outside the ribosome, RPL23A interacts with RPL11 to suppress the RPL11–MDM2–p53 apoptotic pathway, is directly ubiquitinated and degraded by E3 ligase HERC3 (K48-linked, via the HECT domain) to regulate the c-Myc/p21 axis and cell cycle, and a native peptide derived from it (PDRL23A) competes with RPL26 to suppress p53 translation under hypoxic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL23A encodes uL23, a conserved structural protein of the 60S large ribosomal subunit that is essential for ribosome assembly and provides a functional docking platform at the ribosomal tunnel exit [#0, #4]. Genetic complementation in yeast established that the ribosomal assembly role is conserved across species: the Drosophila ortholog substitutes for yeast L25 to support viability and proper 27S\\u219225S rRNA processing [#4]. At the tunnel exit, uL23 serves as the contact point for ribosome-associated factors that act cotranslationally, including the signal recognition particle, which engages the intra-tunnel loop of uL23 via its signal-sequence-binding domain to scan translating ribosomes for substrate selection [#5]. Beyond its ribosomal role, RPL23A participates in p53 regulation through multiple routes: it binds RPL11 to restrain the RPL11\\u2013MDM2\\u2013p53 axis, such that loss of RPL23A releases RPL11 to inhibit MDM2 and drive p53 accumulation and apoptosis [#6], and a native peptide derived from RPL23A (PDRL23A) competes with RPL26 to suppress p53 translation under hypoxic stress [#7]. RPL23A protein abundance is controlled by the E3 ubiquitin ligase HERC3, which directly binds RPL23A and catalyzes K48-linked polyubiquitination and proteasomal degradation through its HECT domain, thereby influencing the c-Myc/p21 axis and cell-cycle progression [#8]. Consistent with an essential cellular role, suppression of RPL23A expression is antiproliferative [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established RPL23A as a defined molecular entity \\u2014 a conserved 60S large-subunit ribosomal protein \\u2014 placing it within the L23 family before any functional dissection.\",\n      \"evidence\": \"cDNA sequencing and hybridization analysis of rat L23a with cross-species homology comparison\",\n      \"pmids\": [\"8428950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequence identity alone did not demonstrate ribosomal assembly function\", \"No mechanistic role at the tunnel exit established\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that reducing RPL23A has a direct antiproliferative consequence, linking the gene's expression to cell growth rather than being a passive structural component.\",\n      \"evidence\": \"Antisense knockdown in HeLa cells with colony formation assay; IFN-beta-dependent downregulation\",\n      \"pmids\": [\"9053844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not distinguish loss of ribosome function from extra-ribosomal signaling effects\", \"Mechanism connecting RPL23A to proliferation unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that RPL23A's ribosomal assembly role is functionally conserved, settling that the protein is genuinely required for large-subunit biogenesis and rRNA maturation.\",\n      \"evidence\": \"Yeast chromosomal disruption/complementation with Drosophila L23a and pulse-chase rRNA processing\",\n      \"pmids\": [\"17584789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reduced growth rate of the complemented strain indicates incomplete functional equivalence\", \"Specific structural contacts within assembling ribosome not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a specific cotranslational targeting function for the uL23 tunnel-exit loop, showing it is the SRP docking site that enables early substrate scanning.\",\n      \"evidence\": \"In vivo crosslinking and mutational analysis of bacterial uL23\\u2013SRP contact\",\n      \"pmids\": [\"28134917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated in bacterial system; eukaryotic RPL23A\\u2013SRP contact not directly shown\", \"Does not address other tunnel-exit factor interactions\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed RPL23A in p53 control by two distinct routes \\u2014 sequestering RPL11 to restrain MDM2-p53, and generating a peptide that competes with RPL26 to suppress p53 translation.\",\n      \"evidence\": \"Knockdown, co-IP and apoptosis assays in spermatogonia; intracellular peptidomics, co-IP and I/R rescue for PDRL23A\",\n      \"pmids\": [\"34782045\", \"34808368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each pathway shown in a single tissue context (germ cells; cardiomyocytes)\", \"Stoichiometry and physiological balance between ribosomal vs free RPL23A pools unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the mechanism controlling RPL23A protein levels \\u2014 HERC3-mediated K48 ubiquitination and degradation \\u2014 and linked this turnover to c-Myc/p21 and cell-cycle control in cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, GST-pulldown, in vivo ubiquitylation, cycloheximide chase, and rescue in colorectal cancer cells\",\n      \"pmids\": [\"35637966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RPL23A regulates the c-Myc/p21 axis mechanistically not fully resolved\", \"Whether degradation targets ribosomal vs extra-ribosomal RPL23A unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Directly visualized uL23 as a dynamic docking site for the chaperone Trigger Factor selectively on translating ribosomes, refining the tunnel-exit factor recruitment model.\",\n      \"evidence\": \"High-speed atomic force microscopy and molecular dynamics on bacterial ribosome-nascent chain complexes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.16.654432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Bacterial system; eukaryotic RPL23A\\u2013chaperone dynamics not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the ribosomal and extra-ribosomal (p53-regulatory) pools of RPL23A are partitioned and coordinated in human cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of free vs ribosome-bound RPL23A\", \"Eukaryotic structural validation of tunnel-exit factor contacts lacking\", \"Integration of HERC3-controlled abundance with p53 pathway output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"60S large ribosomal subunit\"],\n    \"partners\": [\"RPL11\", \"RPL26\", \"HERC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}