{"gene":"RPL6","run_date":"2026-06-10T07:46:26","timeline":{"discoveries":[{"year":1993,"finding":"RPL6 (TAXREB107) was identified as a DNA-binding protein that specifically binds to domain C of the tax-responsive enhancer element in the HTLV-I long terminal repeat, and its mRNA is transiently upregulated by TPA treatment in Jurkat cells.","method":"Yeast expression/beta-galactosidase fusion protein binding assay, Northern blot, immunoblot","journal":"AIDS research and human retroviruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNA-binding demonstrated with fusion protein assay and confirmed by immunoblot; single lab but multiple methods","pmids":["8457378"],"is_preprint":false},{"year":1998,"finding":"RPL6/TAXREB107 was identified as an intracellular binding partner for FGF-2; both high-molecular-weight (HMW) and 18-kDa forms of FGF-2 bind to RPL6, with deletion analysis revealing two binding sites for HMW FGF-2 and one for 18-kDa FGF-2 (the unique N-terminal extension of HMW FGF-2 constitutes one binding domain). High expression of FGF-2 stimulates Tax-mediated transactivation, suggesting RPL6 mediates this cross-talk.","method":"Yeast two-hybrid, in vitro binding assays, deletion analysis, transfection/transactivation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus in vitro binding plus deletion analysis in a single study; single lab","pmids":["9826564"],"is_preprint":false},{"year":2002,"finding":"RPL6 (TAXREB107) directly interacts with the HTLV-1 transcription activator Tax protein, as demonstrated by yeast two-hybrid and GST pull-down assays, suggesting RPL6 may regulate Tax function in HTLV-1 proliferation.","method":"Yeast two-hybrid, GST pull-down","journal":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal binding methods (yeast two-hybrid + GST pull-down) but single lab and abstract-level reporting","pmids":["12007002"],"is_preprint":false},{"year":2001,"finding":"Chicken TaxREB107 (RPL6 ortholog) localizes to both nuclear and cytoplasmic compartments, with distinct nucleolar localization consistent with its identity as a ribosomal protein. Overexpression in embryonic myoblasts increased troponin I reporter activity and MRF-directed transcription from a skeletal muscle E-box reporter, enhancing myogenic gene transcription independently of physical association with MyoD.","method":"Immunofluorescent staining, reporter gene transfection assay, subcellular fractionation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunofluorescence plus functional reporter assay; single lab, chicken ortholog","pmids":["11707324"],"is_preprint":false},{"year":2003,"finding":"Overexpression of RPL6 in gastric cancer SGC7901 cells reduced intracellular accumulation and retention of adriamycin (ADR) as detected by flow cytometry, demonstrating RPL6 contributes to multidrug resistance.","method":"Eukaryotic expression vector transfection, flow cytometry (drug accumulation assay)","journal":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (flow cytometry), abstract-level reporting","pmids":["12678981"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated knockdown of RPL6 in gastric cancer cell lines (SGC7901 and AGS) suppressed G1-to-S phase cell cycle progression and reduced cyclin E expression, placing RPL6 upstream of cyclin E in cell cycle regulation.","method":"siRNA knockdown, flow cytometry (cell cycle analysis), Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD in two cell lines with defined molecular readout (cyclin E downregulation); single lab, multiple orthogonal methods","pmids":["22043320"],"is_preprint":false},{"year":2018,"finding":"RPL6 directly interacts with histone H2A; upon DNA damage, RPL6 is recruited to DNA damage sites in a PARP-dependent manner, promotes MDC1–γH2AX interaction, and facilitates accumulation of MDC1 at damage sites. RPL6 depletion reduces RNF168 recruitment and H2AK15 ubiquitination, and impairs downstream recruitment of 53BP1 and BRCA1, as well as the DNA damage-induced G2-M checkpoint.","method":"Immunoprecipitation, subcellular fractionation, His-ubiquitin pulldown, immunofluorescence microscopy, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, pulldown, fractionation, microscopy, functional checkpoint assays) in a single focused study establishing a clear mechanism","pmids":["30598506"],"is_preprint":false},{"year":2019,"finding":"RPL6 is a closely interacting partner with the RNA methyltransferase NSUN2 in gallbladder carcinoma cells; silencing RPL6 results in reduced NSUN2 protein (translational) levels while increasing NSUN2 mRNA (transcriptional) levels, and exogenous NSUN2 expression partially rescues the growth-inhibitory effect of RPL6 silencing.","method":"Co-immunoprecipitation, siRNA knockdown, Western blot, qRT-PCR, rescue experiment","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional rescue; single lab","pmids":["31487418"],"is_preprint":false},{"year":2019,"finding":"In Drosophila testes, RpL6 (the RPL6 ortholog) binds to Srlp as identified by LC-MS/MS; Srlp regulates spliceosome and ribosome subunit expression and controls spliceosome/ribosome function via RpL6 signals, linking RpL6 to germline stem cell self-renewal and differentiation.","method":"LC-MS/MS interactome, genetic manipulation (Drosophila in vivo), in vitro S2 cell assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mass spectrometry-identified interaction with in vivo genetic validation in Drosophila ortholog; single lab","pmids":["30931935"],"is_preprint":false},{"year":2022,"finding":"The ubiquitin-conjugating enzyme UBE2T ubiquitinates RPL6 via K48-linked polyubiquitination in an E3 ligase-independent manner, leading to proteasomal degradation of RPL6. This degradation reduces wild-type p53 expression and enhances gain-of-function mutant p53 activity, promoting glioblastoma malignancy.","method":"Ubiquitination assay, Western blot, siRNA/overexpression, xenograft mouse model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay identifying K48-linkage and E3-independence; single lab, in vitro and in vivo validation","pmids":["36156329"],"is_preprint":false},{"year":2022,"finding":"RPL6 knockdown in lung cancer cells decreased p-AKT and p-S6 levels, and increased cleaved caspase-3 and Bax while decreasing Bcl-2, placing RPL6 upstream of the AKT signaling pathway in lung cancer cell survival and proliferation.","method":"siRNA knockdown, Western blot, proliferation/migration/apoptosis assays","journal":"Journal of thoracic disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Western blot correlation between RPL6 KD and AKT pathway markers without direct mechanistic link","pmids":["35280491"],"is_preprint":false},{"year":2025,"finding":"RPL6 directly binds to the 3'UTR of HMGCS1 mRNA, stabilizing HMGCS1 mRNA and increasing its protein expression. This elevates intracellular cholesterol levels, which in turn inhibit ubiquitin-dependent degradation of HIF-1α, activating HIF-1α signaling and promoting HCC invasion and metastasis.","method":"Co-immunoprecipitation/RNA pulldown (3'UTR binding), Western blot, in vitro invasion assays, in vivo mouse HCC model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA 3'UTR binding experiment plus in vitro and in vivo functional validation; single lab","pmids":["40650669"],"is_preprint":false},{"year":2025,"finding":"EIF2B5 directly interacts with RPL6 (identified by mass spectrometry and confirmed by co-immunoprecipitation); EIF2B5 overexpression promotes RPL6 expression, which activates the PI3K/AKT/mTOR pathway to increase HCC cell proliferation and invasion.","method":"Mass spectrometry, co-immunoprecipitation, Western blot, siRNA/overexpression, RNA sequencing, xenograft mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction validated by reciprocal Co-IP with in vivo confirmation; single lab","pmids":["40246131"],"is_preprint":false},{"year":2025,"finding":"RPL6 directly interacts with cGAS and initiates cGAS-STING signaling in pancreatic cancer cells, promoting interferon-β production. DIAPH3 reduces RPL6 protein levels by disrupting RPL6's interaction with the deubiquitinase OTUD4, thereby suppressing cGAS-STING activation.","method":"Co-immunoprecipitation, forced overexpression (IFN-β ELISA/reporter), Western blot, bioinformatics","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP-based interaction with limited mechanistic follow-up reported at abstract level","pmids":["41318619"],"is_preprint":false},{"year":2025,"finding":"CacyBP/SIP directly interacts with RPL6 as confirmed by multiple biochemical methods; in silico analysis defined the domains/fragments of both proteins involved in binding. In neuroblastoma cells with stably silenced CacyBP/SIP, perinuclear (rough ER) nascent polypeptide synthesis was reduced and heat-shock-induced Hsp70 production was impaired, suggesting CacyBP/SIP influences ribosome function and protein synthesis through RPL6.","method":"Mass spectrometry, multiple biochemical binding assays, in silico domain analysis, OPP labeling of nascent polypeptides, Western blot (Hsp70)","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by multiple orthogonal biochemical methods with functional consequence (nascent protein synthesis) in cell line; single lab","pmids":["40691326"],"is_preprint":false},{"year":2025,"finding":"Free (ribosome-unbound) RPL6 is one of the major targets of ADP-ribosylation by PARP1 and PARP2 among 60S ribosomal proteins in vitro; this modification is strongly HPF1-dependent and preferentially targets serine/tyrosine residues of RPL6. Ribosome-bound RPL6 was not detectably ADP-ribosylated.","method":"In vitro ADP-ribosylation assay with radioactively labeled NAD+, isolated ribosomal subunit proteins, HPF1 co-factor titration","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro biochemical assay with negative control (ribosome-bound RPs not modified); preprint, single lab","pmids":["bio_10.1101_2025.09.15.676193"],"is_preprint":true},{"year":2025,"finding":"In yeast (S. cerevisiae), the importin Kap114 was found in the proxiOME of Rpl6 (eL6), suggesting Kap114 mediates nuclear import of Rpl6 for ribosome assembly. This proximity was identified by TurboID-based proximity labeling.","method":"TurboID-based proximity labeling (BioID), mass spectrometry","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling only (not direct interaction confirmed), preprint, yeast ortholog, single lab","pmids":["bio_10.1101_2025.09.18.677003"],"is_preprint":true}],"current_model":"RPL6 (eL6/TAXREB107) is a 60S large ribosomal subunit protein with multiple extraribosomal functions: it binds the HTLV-1 Tax-responsive enhancer element and directly interacts with the Tax transactivator; it serves as an intracellular partner for FGF-2; it is recruited to DNA damage sites in a PARP-dependent manner where it promotes the MDC1–γH2AX interaction and the downstream DDR cascade (RNF168, H2AK15ub, 53BP1, BRCA1); it regulates cell cycle G1/S progression through cyclin E; it binds the HMGCS1 mRNA 3'UTR to stabilize cholesterol biosynthesis and thereby stabilize HIF-1α; it is ubiquitinated by UBE2T via K48-linked chains leading to proteasomal degradation and p53 modulation; it is directly ADP-ribosylated by PARP1/PARP2 in an HPF1-dependent manner when free of the ribosome; and it interacts with partners including NSUN2, EIF2B5, CacyBP/SIP, and cGAS to modulate RNA methylation, PI3K/AKT/mTOR signaling, protein synthesis, and innate immune signaling."},"narrative":{"mechanistic_narrative":"RPL6 (eL6/TAXREB107) is a 60S large ribosomal subunit protein that, beyond its core role in translation, carries out a range of extraribosomal regulatory functions in transcription, the DNA damage response, the cell cycle, and oncogenic signaling [PMID:8457378, PMID:30598506]. It was first identified as a sequence-specific DNA-binding protein recognizing domain C of the HTLV-1 Tax-responsive enhancer and as a direct interactor of the Tax transactivator and of intracellular FGF-2, positioning it within virus-induced and growth-factor transcriptional cross-talk [PMID:8457378, PMID:9826564, PMID:12007002]. In the DNA damage response, RPL6 binds histone H2A and is recruited to damage sites in a PARP-dependent manner, where it promotes the MDC1–γH2AX interaction and the downstream RNF168/H2AK15ub/53BP1/BRCA1 cascade and the G2-M checkpoint [PMID:30598506]; consistent with this PARP linkage, ribosome-free RPL6 is a major HPF1-dependent substrate of PARP1/PARP2 ADP-ribosylation in vitro [PMID:bio_10.1101_2025.09.15.676193]. RPL6 also supports cell-cycle G1/S progression by maintaining cyclin E expression [PMID:22043320], and stabilizes HMGCS1 mRNA through 3'UTR binding to elevate cholesterol and thereby HIF-1α signaling [PMID:40650669]. Its abundance is controlled post-translationally: UBE2T conjugates K48-linked polyubiquitin to RPL6 to drive proteasomal degradation, which modulates wild-type and mutant p53 activity [PMID:36156329]. Through direct partners NSUN2, EIF2B5, CacyBP/SIP, and cGAS, RPL6 is further coupled to RNA methylation, PI3K/AKT/mTOR signaling, nascent protein synthesis, and cGAS-STING innate immune signaling [PMID:31487418, PMID:40246131, PMID:40691326, PMID:41318619].","teleology":[{"year":1993,"claim":"Established that RPL6 has a sequence-specific DNA-binding activity at the HTLV-1 enhancer, the first hint of an extraribosomal transcriptional role.","evidence":"Yeast fusion-protein DNA-binding assay and Northern/immunoblot in Jurkat cells","pmids":["8457378"],"confidence":"Medium","gaps":["No structural basis for DNA recognition","Whether endogenous full-length RPL6 binds this element in vivo not shown"]},{"year":1998,"claim":"Defined RPL6 as an intracellular FGF-2 binding partner with mapped binding domains, linking it to growth-factor signaling and Tax transactivation.","evidence":"Yeast two-hybrid, in vitro binding, deletion mapping, transactivation assay","pmids":["9826564"],"confidence":"Medium","gaps":["Functional consequence of FGF-2 binding not mechanistically resolved","Single lab"]},{"year":2002,"claim":"Showed RPL6 directly binds the HTLV-1 Tax protein, suggesting it modulates viral transactivation.","evidence":"Yeast two-hybrid and GST pull-down","pmids":["12007002"],"confidence":"Medium","gaps":["No demonstration of effect on Tax-driven transcription in this study","Abstract-level reporting"]},{"year":2011,"claim":"Placed RPL6 upstream of cyclin E in driving G1/S progression, establishing a cell-cycle role.","evidence":"siRNA knockdown with flow cytometry and Western blot in two gastric cancer lines","pmids":["22043320"],"confidence":"Medium","gaps":["Mechanism linking RPL6 to cyclin E expression unresolved","Confined to gastric cancer cells"]},{"year":2018,"claim":"Defined a clear DNA-damage-response function: RPL6 is PARP-dependently recruited to damage sites and is required for the MDC1–γH2AX axis and downstream RNF168/53BP1/BRCA1 signaling.","evidence":"Co-IP, fractionation, His-ubiquitin pulldown, immunofluorescence, siRNA, checkpoint assays","pmids":["30598506"],"confidence":"High","gaps":["Direct structural mode of damage-site recruitment unknown","How ribosomal vs extraribosomal RPL6 pools are partitioned not defined"]},{"year":2019,"claim":"Connected RPL6 to RNA methylation and germline biology through partners NSUN2 (human) and Srlp (Drosophila), implicating it in translational control of partner proteins.","evidence":"Reciprocal Co-IP and rescue in gallbladder carcinoma cells; LC-MS/MS interactome and genetics in Drosophila","pmids":["31487418","30931935"],"confidence":"Medium","gaps":["Whether RPL6 directly controls NSUN2 translation not proven","Drosophila ortholog generalization uncertain"]},{"year":2022,"claim":"Identified post-translational control of RPL6 abundance and its link to p53: UBE2T drives K48-linked degradation that modulates p53 activity.","evidence":"Ubiquitination assays, knockdown/overexpression, xenografts (UBE2T); AKT pathway marker analysis (lung cancer)","pmids":["36156329","35280491"],"confidence":"Medium","gaps":["E3-independent ubiquitination mechanism unusual and not fully explained","AKT linkage is correlative without direct mechanism"]},{"year":2025,"claim":"Expanded RPL6 functions into mRNA stabilization, multiple oncogenic signaling axes, and innate immunity through direct partner interactions.","evidence":"RNA pulldown/3'UTR binding and HCC models (HMGCS1/HIF-1α); MS+Co-IP with EIF2B5 (PI3K/AKT/mTOR); biochemical binding and OPP labeling with CacyBP/SIP; Co-IP with cGAS (cGAS-STING/IFN-β)","pmids":["40650669","40246131","40691326","41318619"],"confidence":"Medium","gaps":["Whether these distinct functions involve the same or different RPL6 pools unresolved","cGAS interaction reported at abstract level with limited follow-up"]},{"year":2025,"claim":"Showed that ribosome-free RPL6 is a preferred HPF1-dependent PARP1/2 ADP-ribosylation substrate, providing a biochemical basis for regulation of its extraribosomal pool.","evidence":"Reconstituted in vitro ADP-ribosylation with labeled NAD+ and ribosome-bound negative control (preprint)","pmids":["bio_10.1101_2025.09.15.676193"],"confidence":"Medium","gaps":["In vivo occurrence and functional consequence of RPL6 ADP-ribosylation not established","Preprint, single lab"]},{"year":null,"claim":"How RPL6 is partitioned and regulated between its ribosomal role and its many extraribosomal functions, and the structural basis for its diverse DNA, RNA, and protein interactions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for the extraribosomal interactions","Mechanism controlling the free vs ribosome-bound RPL6 pool unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,15]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]}],"complexes":["60S large ribosomal subunit"],"partners":["TAX","FGF2","MDC1","NSUN2","UBE2T","EIF2B5","CACYBP","CGAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02878","full_name":"Large ribosomal subunit protein eL6","aliases":["60S ribosomal protein L6","Neoplasm-related protein C140","Tax-responsive enhancer element-binding protein 107","TaxREB107"],"length_aa":288,"mass_kda":32.7,"function":"Component of the large ribosomal subunit (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547). The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell (PubMed:12962325, PubMed:23636399, PubMed:25901680, PubMed:25957688, PubMed:32669547) (Microbial infection) Specifically binds to domain C of the Tax-responsive enhancer element in the long terminal repeat of HTLV-I (PubMed:8457378)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm; Rough endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q02878/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RPL6","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":"DRG1","stoichiometry":10.0},{"gene":"EIF2S3","stoichiometry":10.0},{"gene":"NPM1","stoichiometry":10.0},{"gene":"RACK1","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}],"url":"https://opencell.sf.czbiohub.org/search/RPL6","total_profiled":1310},"omim":[{"mim_id":"603703","title":"RIBOSOMAL PROTEIN L6; RPL6","url":"https://www.omim.org/entry/603703"},{"mim_id":"600206","title":"EPIDERMAL GROWTH FACTOR RECEPTOR PATHWAY SUBSTRATE 8; EPS8","url":"https://www.omim.org/entry/600206"},{"mim_id":"163950","title":"NOONAN SYNDROME 1; NS1","url":"https://www.omim.org/entry/163950"},{"mim_id":"125255","title":"DECORIN; DCN","url":"https://www.omim.org/entry/125255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RPL6"},"hgnc":{"alias_symbol":["TAXREB107","L6","eL6"],"prev_symbol":["TXREB1"]},"alphafold":{"accession":"Q02878","domains":[{"cath_id":"2.30.30.30","chopping":"134-221_241-288","consensus_level":"medium","plddt":95.91,"start":134,"end":288}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02878","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02878-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02878-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RPL6","jax_strain_url":"https://www.jax.org/strain/search?query=RPL6"},"sequence":{"accession":"Q02878","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02878.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02878/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02878"}},"corpus_meta":[{"pmid":"31487418","id":"PMC_31487418","title":"NOP2/Sun RNA methyltransferase 2 promotes tumor progression via its interacting partner RPL6 in gallbladder carcinoma.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/31487418","citation_count":79,"is_preprint":false},{"pmid":"32396839","id":"PMC_32396839","title":"A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver TRM Cell-Mediated Immunity against Malaria in Mice.","date":"2020","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/32396839","citation_count":57,"is_preprint":false},{"pmid":"22043320","id":"PMC_22043320","title":"Downregulation of RPL6 by siRNA inhibits proliferation and cell cycle progression of human gastric cancer cell lines.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22043320","citation_count":53,"is_preprint":false},{"pmid":"30598506","id":"PMC_30598506","title":"Ribosomal protein L6 (RPL6) is recruited to DNA damage sites in a poly(ADP-ribose) polymerase-dependent manner and regulates the DNA damage response.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30598506","citation_count":50,"is_preprint":false},{"pmid":"9826564","id":"PMC_9826564","title":"Intracellular association of FGF-2 with the ribosomal protein L6/TAXREB107.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9826564","citation_count":26,"is_preprint":false},{"pmid":"8457378","id":"PMC_8457378","title":"Isolation of a cDNA clone encoding DNA-binding protein (TAXREB107) that binds specifically to domain C of the tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I.","date":"1993","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/8457378","citation_count":22,"is_preprint":false},{"pmid":"30931935","id":"PMC_30931935","title":"Srlp is crucial for the self-renewal and differentiation of germline stem cells via RpL6 signals in Drosophila testes.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30931935","citation_count":20,"is_preprint":false},{"pmid":"36156329","id":"PMC_36156329","title":"UBE2T promotes glioblastoma malignancy through ubiquitination-mediated degradation of RPL6.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36156329","citation_count":18,"is_preprint":false},{"pmid":"33790735","id":"PMC_33790735","title":"RPL6: A Key Molecule Regulating Zinc- and Magnesium-Bound Metalloproteins of Parkinson's Disease.","date":"2021","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33790735","citation_count":13,"is_preprint":false},{"pmid":"7537974","id":"PMC_7537974","title":"The mouse homologue of the HTLV-I tax responsive element binding protein TAXREB107 is a highly conserved gene which may regulate some basal cellular functions.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7537974","citation_count":12,"is_preprint":false},{"pmid":"35280491","id":"PMC_35280491","title":"Downregulated RPL6 inhibits lung cancer cell proliferation and migration and promotes cell apoptosis by regulating the AKT signaling pathway.","date":"2022","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/35280491","citation_count":10,"is_preprint":false},{"pmid":"10082121","id":"PMC_10082121","title":"Identification of TAXREB107 as an erythropoietin early response gene.","date":"1999","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/10082121","citation_count":5,"is_preprint":false},{"pmid":"12678981","id":"PMC_12678981","title":"[Differential expression of RPL6/Taxreb107 in drug resistant gastric cancer cell line SGC7901/ADR and its correlation with multiple-drug resistance].","date":"2003","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/12678981","citation_count":4,"is_preprint":false},{"pmid":"40650669","id":"PMC_40650669","title":"RPL6 Interacts with HMGCS1 to Stabilize HIF-1α by Promoting Cholesterol Production in Hepatocellular Carcinoma.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40650669","citation_count":3,"is_preprint":false},{"pmid":"11707324","id":"PMC_11707324","title":"Isolation and characterization of chicken TaxREB107, a putative DNA binding protein abundantly expressed in muscle.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11707324","citation_count":2,"is_preprint":false},{"pmid":"14572897","id":"PMC_14572897","title":"Identification of Taxreb107 as a lactogenic hormone responsive gene in mammary epithelial cells.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/14572897","citation_count":1,"is_preprint":false},{"pmid":"40246131","id":"PMC_40246131","title":"EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40246131","citation_count":1,"is_preprint":false},{"pmid":"12007002","id":"PMC_12007002","title":"[Interaction between HTLV-1 transcription activator tax and Taxreb107].","date":"2002","source":"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12007002","citation_count":1,"is_preprint":false},{"pmid":"41318619","id":"PMC_41318619","title":"The DIAPH3/RPL6 axis regulates the cGAS-STING pathway in pancreatic cancer.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41318619","citation_count":0,"is_preprint":false},{"pmid":"40691326","id":"PMC_40691326","title":"CacyBP/SIP - RPL6 interaction: potential influence on ribosome function.","date":"2025","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/40691326","citation_count":0,"is_preprint":false},{"pmid":"40385018","id":"PMC_40385018","title":"Downregulated TRAF3IP2-AS1 promotes hepatocellular carcinoma progression through the miR-374a-5p/SEL1L1/RPL6 axis to enhance DNA damage repair.","date":"2025","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/40385018","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.15.676193","title":"Interplay between human ribosomal proteins, PARP1, PARP2, HPF1 and histones","date":"2025-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.15.676193","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.18.677003","title":"Exploration of the proxiOME of large subunit ribosomal proteins reveals Acl1 and Bcl1 as cooperating dedicated chaperones of Rpl1","date":"2025-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.677003","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.22.666032","title":"Chemovaccination with a novel antimalarial targeting the late liver stage induces durable immunity against malaria","date":"2025-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.22.666032","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13927,"output_tokens":4241,"usd":0.052698,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12173,"output_tokens":3385,"usd":0.072745,"stage2_stop_reason":"end_turn"},"total_usd":0.125443,"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\": \"RPL6 (TAXREB107) was identified as a DNA-binding protein that specifically binds to domain C of the tax-responsive enhancer element in the HTLV-I long terminal repeat, and its mRNA is transiently upregulated by TPA treatment in Jurkat cells.\",\n      \"method\": \"Yeast expression/beta-galactosidase fusion protein binding assay, Northern blot, immunoblot\",\n      \"journal\": \"AIDS research and human retroviruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNA-binding demonstrated with fusion protein assay and confirmed by immunoblot; single lab but multiple methods\",\n      \"pmids\": [\"8457378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RPL6/TAXREB107 was identified as an intracellular binding partner for FGF-2; both high-molecular-weight (HMW) and 18-kDa forms of FGF-2 bind to RPL6, with deletion analysis revealing two binding sites for HMW FGF-2 and one for 18-kDa FGF-2 (the unique N-terminal extension of HMW FGF-2 constitutes one binding domain). High expression of FGF-2 stimulates Tax-mediated transactivation, suggesting RPL6 mediates this cross-talk.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, deletion analysis, transfection/transactivation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus in vitro binding plus deletion analysis in a single study; single lab\",\n      \"pmids\": [\"9826564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RPL6 (TAXREB107) directly interacts with the HTLV-1 transcription activator Tax protein, as demonstrated by yeast two-hybrid and GST pull-down assays, suggesting RPL6 may regulate Tax function in HTLV-1 proliferation.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down\",\n      \"journal\": \"Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal binding methods (yeast two-hybrid + GST pull-down) but single lab and abstract-level reporting\",\n      \"pmids\": [\"12007002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Chicken TaxREB107 (RPL6 ortholog) localizes to both nuclear and cytoplasmic compartments, with distinct nucleolar localization consistent with its identity as a ribosomal protein. Overexpression in embryonic myoblasts increased troponin I reporter activity and MRF-directed transcription from a skeletal muscle E-box reporter, enhancing myogenic gene transcription independently of physical association with MyoD.\",\n      \"method\": \"Immunofluorescent staining, reporter gene transfection assay, subcellular fractionation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunofluorescence plus functional reporter assay; single lab, chicken ortholog\",\n      \"pmids\": [\"11707324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of RPL6 in gastric cancer SGC7901 cells reduced intracellular accumulation and retention of adriamycin (ADR) as detected by flow cytometry, demonstrating RPL6 contributes to multidrug resistance.\",\n      \"method\": \"Eukaryotic expression vector transfection, flow cytometry (drug accumulation assay)\",\n      \"journal\": \"Zhonghua zhong liu za zhi [Chinese journal of oncology]\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (flow cytometry), abstract-level reporting\",\n      \"pmids\": [\"12678981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated knockdown of RPL6 in gastric cancer cell lines (SGC7901 and AGS) suppressed G1-to-S phase cell cycle progression and reduced cyclin E expression, placing RPL6 upstream of cyclin E in cell cycle regulation.\",\n      \"method\": \"siRNA knockdown, flow cytometry (cell cycle analysis), Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD in two cell lines with defined molecular readout (cyclin E downregulation); single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22043320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RPL6 directly interacts with histone H2A; upon DNA damage, RPL6 is recruited to DNA damage sites in a PARP-dependent manner, promotes MDC1–γH2AX interaction, and facilitates accumulation of MDC1 at damage sites. RPL6 depletion reduces RNF168 recruitment and H2AK15 ubiquitination, and impairs downstream recruitment of 53BP1 and BRCA1, as well as the DNA damage-induced G2-M checkpoint.\",\n      \"method\": \"Immunoprecipitation, subcellular fractionation, His-ubiquitin pulldown, immunofluorescence microscopy, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, pulldown, fractionation, microscopy, functional checkpoint assays) in a single focused study establishing a clear mechanism\",\n      \"pmids\": [\"30598506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RPL6 is a closely interacting partner with the RNA methyltransferase NSUN2 in gallbladder carcinoma cells; silencing RPL6 results in reduced NSUN2 protein (translational) levels while increasing NSUN2 mRNA (transcriptional) levels, and exogenous NSUN2 expression partially rescues the growth-inhibitory effect of RPL6 silencing.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blot, qRT-PCR, rescue experiment\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional rescue; single lab\",\n      \"pmids\": [\"31487418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila testes, RpL6 (the RPL6 ortholog) binds to Srlp as identified by LC-MS/MS; Srlp regulates spliceosome and ribosome subunit expression and controls spliceosome/ribosome function via RpL6 signals, linking RpL6 to germline stem cell self-renewal and differentiation.\",\n      \"method\": \"LC-MS/MS interactome, genetic manipulation (Drosophila in vivo), in vitro S2 cell assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mass spectrometry-identified interaction with in vivo genetic validation in Drosophila ortholog; single lab\",\n      \"pmids\": [\"30931935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The ubiquitin-conjugating enzyme UBE2T ubiquitinates RPL6 via K48-linked polyubiquitination in an E3 ligase-independent manner, leading to proteasomal degradation of RPL6. This degradation reduces wild-type p53 expression and enhances gain-of-function mutant p53 activity, promoting glioblastoma malignancy.\",\n      \"method\": \"Ubiquitination assay, Western blot, siRNA/overexpression, xenograft mouse model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay identifying K48-linkage and E3-independence; single lab, in vitro and in vivo validation\",\n      \"pmids\": [\"36156329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RPL6 knockdown in lung cancer cells decreased p-AKT and p-S6 levels, and increased cleaved caspase-3 and Bax while decreasing Bcl-2, placing RPL6 upstream of the AKT signaling pathway in lung cancer cell survival and proliferation.\",\n      \"method\": \"siRNA knockdown, Western blot, proliferation/migration/apoptosis assays\",\n      \"journal\": \"Journal of thoracic disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Western blot correlation between RPL6 KD and AKT pathway markers without direct mechanistic link\",\n      \"pmids\": [\"35280491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL6 directly binds to the 3'UTR of HMGCS1 mRNA, stabilizing HMGCS1 mRNA and increasing its protein expression. This elevates intracellular cholesterol levels, which in turn inhibit ubiquitin-dependent degradation of HIF-1α, activating HIF-1α signaling and promoting HCC invasion and metastasis.\",\n      \"method\": \"Co-immunoprecipitation/RNA pulldown (3'UTR binding), Western blot, in vitro invasion assays, in vivo mouse HCC model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA 3'UTR binding experiment plus in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"40650669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EIF2B5 directly interacts with RPL6 (identified by mass spectrometry and confirmed by co-immunoprecipitation); EIF2B5 overexpression promotes RPL6 expression, which activates the PI3K/AKT/mTOR pathway to increase HCC cell proliferation and invasion.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, Western blot, siRNA/overexpression, RNA sequencing, xenograft mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction validated by reciprocal Co-IP with in vivo confirmation; single lab\",\n      \"pmids\": [\"40246131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPL6 directly interacts with cGAS and initiates cGAS-STING signaling in pancreatic cancer cells, promoting interferon-β production. DIAPH3 reduces RPL6 protein levels by disrupting RPL6's interaction with the deubiquitinase OTUD4, thereby suppressing cGAS-STING activation.\",\n      \"method\": \"Co-immunoprecipitation, forced overexpression (IFN-β ELISA/reporter), Western blot, bioinformatics\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP-based interaction with limited mechanistic follow-up reported at abstract level\",\n      \"pmids\": [\"41318619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CacyBP/SIP directly interacts with RPL6 as confirmed by multiple biochemical methods; in silico analysis defined the domains/fragments of both proteins involved in binding. In neuroblastoma cells with stably silenced CacyBP/SIP, perinuclear (rough ER) nascent polypeptide synthesis was reduced and heat-shock-induced Hsp70 production was impaired, suggesting CacyBP/SIP influences ribosome function and protein synthesis through RPL6.\",\n      \"method\": \"Mass spectrometry, multiple biochemical binding assays, in silico domain analysis, OPP labeling of nascent polypeptides, Western blot (Hsp70)\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by multiple orthogonal biochemical methods with functional consequence (nascent protein synthesis) in cell line; single lab\",\n      \"pmids\": [\"40691326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Free (ribosome-unbound) RPL6 is one of the major targets of ADP-ribosylation by PARP1 and PARP2 among 60S ribosomal proteins in vitro; this modification is strongly HPF1-dependent and preferentially targets serine/tyrosine residues of RPL6. Ribosome-bound RPL6 was not detectably ADP-ribosylated.\",\n      \"method\": \"In vitro ADP-ribosylation assay with radioactively labeled NAD+, isolated ribosomal subunit proteins, HPF1 co-factor titration\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro biochemical assay with negative control (ribosome-bound RPs not modified); preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.15.676193\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In yeast (S. cerevisiae), the importin Kap114 was found in the proxiOME of Rpl6 (eL6), suggesting Kap114 mediates nuclear import of Rpl6 for ribosome assembly. This proximity was identified by TurboID-based proximity labeling.\",\n      \"method\": \"TurboID-based proximity labeling (BioID), mass spectrometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling only (not direct interaction confirmed), preprint, yeast ortholog, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.18.677003\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RPL6 (eL6/TAXREB107) is a 60S large ribosomal subunit protein with multiple extraribosomal functions: it binds the HTLV-1 Tax-responsive enhancer element and directly interacts with the Tax transactivator; it serves as an intracellular partner for FGF-2; it is recruited to DNA damage sites in a PARP-dependent manner where it promotes the MDC1–γH2AX interaction and the downstream DDR cascade (RNF168, H2AK15ub, 53BP1, BRCA1); it regulates cell cycle G1/S progression through cyclin E; it binds the HMGCS1 mRNA 3'UTR to stabilize cholesterol biosynthesis and thereby stabilize HIF-1α; it is ubiquitinated by UBE2T via K48-linked chains leading to proteasomal degradation and p53 modulation; it is directly ADP-ribosylated by PARP1/PARP2 in an HPF1-dependent manner when free of the ribosome; and it interacts with partners including NSUN2, EIF2B5, CacyBP/SIP, and cGAS to modulate RNA methylation, PI3K/AKT/mTOR signaling, protein synthesis, and innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RPL6 (eL6/TAXREB107) is a 60S large ribosomal subunit protein that, beyond its core role in translation, carries out a range of extraribosomal regulatory functions in transcription, the DNA damage response, the cell cycle, and oncogenic signaling [#0, #6]. It was first identified as a sequence-specific DNA-binding protein recognizing domain C of the HTLV-1 Tax-responsive enhancer and as a direct interactor of the Tax transactivator and of intracellular FGF-2, positioning it within virus-induced and growth-factor transcriptional cross-talk [#0, #1, #2]. In the DNA damage response, RPL6 binds histone H2A and is recruited to damage sites in a PARP-dependent manner, where it promotes the MDC1\\u2013\\u03b3H2AX interaction and the downstream RNF168/H2AK15ub/53BP1/BRCA1 cascade and the G2-M checkpoint [#6]; consistent with this PARP linkage, ribosome-free RPL6 is a major HPF1-dependent substrate of PARP1/PARP2 ADP-ribosylation in vitro [#15]. RPL6 also supports cell-cycle G1/S progression by maintaining cyclin E expression [#5], and stabilizes HMGCS1 mRNA through 3'UTR binding to elevate cholesterol and thereby HIF-1\\u03b1 signaling [#11]. Its abundance is controlled post-translationally: UBE2T conjugates K48-linked polyubiquitin to RPL6 to drive proteasomal degradation, which modulates wild-type and mutant p53 activity [#9]. Through direct partners NSUN2, EIF2B5, CacyBP/SIP, and cGAS, RPL6 is further coupled to RNA methylation, PI3K/AKT/mTOR signaling, nascent protein synthesis, and cGAS-STING innate immune signaling [#7, #12, #14, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that RPL6 has a sequence-specific DNA-binding activity at the HTLV-1 enhancer, the first hint of an extraribosomal transcriptional role.\",\n      \"evidence\": \"Yeast fusion-protein DNA-binding assay and Northern/immunoblot in Jurkat cells\",\n      \"pmids\": [\"8457378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for DNA recognition\", \"Whether endogenous full-length RPL6 binds this element in vivo not shown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined RPL6 as an intracellular FGF-2 binding partner with mapped binding domains, linking it to growth-factor signaling and Tax transactivation.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, deletion mapping, transactivation assay\",\n      \"pmids\": [\"9826564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FGF-2 binding not mechanistically resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed RPL6 directly binds the HTLV-1 Tax protein, suggesting it modulates viral transactivation.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down\",\n      \"pmids\": [\"12007002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of effect on Tax-driven transcription in this study\", \"Abstract-level reporting\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed RPL6 upstream of cyclin E in driving G1/S progression, establishing a cell-cycle role.\",\n      \"evidence\": \"siRNA knockdown with flow cytometry and Western blot in two gastric cancer lines\",\n      \"pmids\": [\"22043320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking RPL6 to cyclin E expression unresolved\", \"Confined to gastric cancer cells\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a clear DNA-damage-response function: RPL6 is PARP-dependently recruited to damage sites and is required for the MDC1\\u2013\\u03b3H2AX axis and downstream RNF168/53BP1/BRCA1 signaling.\",\n      \"evidence\": \"Co-IP, fractionation, His-ubiquitin pulldown, immunofluorescence, siRNA, checkpoint assays\",\n      \"pmids\": [\"30598506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural mode of damage-site recruitment unknown\", \"How ribosomal vs extraribosomal RPL6 pools are partitioned not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected RPL6 to RNA methylation and germline biology through partners NSUN2 (human) and Srlp (Drosophila), implicating it in translational control of partner proteins.\",\n      \"evidence\": \"Reciprocal Co-IP and rescue in gallbladder carcinoma cells; LC-MS/MS interactome and genetics in Drosophila\",\n      \"pmids\": [\"31487418\", \"30931935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RPL6 directly controls NSUN2 translation not proven\", \"Drosophila ortholog generalization uncertain\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-translational control of RPL6 abundance and its link to p53: UBE2T drives K48-linked degradation that modulates p53 activity.\",\n      \"evidence\": \"Ubiquitination assays, knockdown/overexpression, xenografts (UBE2T); AKT pathway marker analysis (lung cancer)\",\n      \"pmids\": [\"36156329\", \"35280491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3-independent ubiquitination mechanism unusual and not fully explained\", \"AKT linkage is correlative without direct mechanism\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded RPL6 functions into mRNA stabilization, multiple oncogenic signaling axes, and innate immunity through direct partner interactions.\",\n      \"evidence\": \"RNA pulldown/3'UTR binding and HCC models (HMGCS1/HIF-1\\u03b1); MS+Co-IP with EIF2B5 (PI3K/AKT/mTOR); biochemical binding and OPP labeling with CacyBP/SIP; Co-IP with cGAS (cGAS-STING/IFN-\\u03b2)\",\n      \"pmids\": [\"40650669\", \"40246131\", \"40691326\", \"41318619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these distinct functions involve the same or different RPL6 pools unresolved\", \"cGAS interaction reported at abstract level with limited follow-up\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that ribosome-free RPL6 is a preferred HPF1-dependent PARP1/2 ADP-ribosylation substrate, providing a biochemical basis for regulation of its extraribosomal pool.\",\n      \"evidence\": \"Reconstituted in vitro ADP-ribosylation with labeled NAD+ and ribosome-bound negative control (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.15.676193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo occurrence and functional consequence of RPL6 ADP-ribosylation not established\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RPL6 is partitioned and regulated between its ribosomal role and its many extraribosomal functions, and the structural basis for its diverse DNA, RNA, and protein interactions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model for the extraribosomal interactions\", \"Mechanism controlling the free vs ribosome-bound RPL6 pool unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"60S large ribosomal subunit\"],\n    \"partners\": [\"Tax\", \"FGF2\", \"MDC1\", \"NSUN2\", \"UBE2T\", \"EIF2B5\", \"CacyBP\", \"cGAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}