{"gene":"RRS1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2000,"finding":"RRS1 (yeast Rrs1p) is an essential nuclear protein required for ribosome biogenesis; depletion of Rrs1p causes defects in pre-rRNA processing and assembly of ribosomal subunits. The rrs1-1 mutation also greatly reduced transcriptional repression of rRNA and ribosomal protein genes caused by a secretory defect, placing Rrs1 in a signaling pathway coupling secretion to ribosome synthesis.","method":"Conditional null mutant (GAL1 promoter depletion), cold-sensitive mutant analysis, transcriptional repression assays in S. cerevisiae","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and functional approaches in yeast, replicated by subsequent studies","pmids":["10688653"],"is_preprint":false},{"year":2007,"finding":"Yeast assembly factors Rpf2 and Rrs1 form a ribonucleoprotein neighborhood in preribosomes together with ribosomal proteins rpL5, rpL11, and 5S rRNA. Rpf2 and Rrs1 are required for recruiting rpL5, rpL11, and 5S rRNA into nascent 90S preribosomes; in their absence, 27SB pre-rRNA processing is blocked and abortive 66S pre-rRNPs are prematurely released from the nucleolus.","method":"In vitro binding assays, co-immunoprecipitation, genetic depletion, pre-rRNA processing analysis, subcellular fractionation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, Co-IP, genetic depletion with specific processing phenotype), replicated by structural studies","pmids":["17938242"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the Rpf2-Rrs1 core complex from Aspergillus nidulans at 1.5 Å reveals that the Brix domain of Rpf2 is completed by Rrs1 to form two anticodon-binding domain-like modules. The Rpf2-Rrs1 heterodimer makes specific contacts with 5S rRNA, RpL5, and the biogenesis factor Rsa4. Two helices in the Rrs1 C-terminal tail occupy a strategic position to block rotation of 25S rRNA and the 5S RNP, explaining why removal of Rpf2-Rrs1 is required for 60S maturation rearrangements.","method":"X-ray crystallography (1.5 Å), fitting into cryo-EM density, biochemical interaction data","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional interpretation supported by cryo-EM fitting and biochemical data, independently confirmed by a second crystal structure paper","pmids":["26117542"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the Aspergillus nidulans Rpf2-Rrs1 core complex shows the Rrs1 long α-helix joins the C-terminal half of the Rpf2 Brix domain as part of a single structural unit; the proline-rich linker of Rrs1 wraps around Rpf2. Gel shift analysis demonstrated that the Rpf2-Rrs1 complex binds directly to 5S rRNA, and mutagenesis of Rpf2 R236 (equivalent to ScRpf2 R238) significantly impairs this binding.","method":"X-ray crystallography, gel shift (EMSA), site-directed mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with EMSA and mutagenesis in a single study, independently corroborated by Kharde et al. 2015","pmids":["25855814"],"is_preprint":false},{"year":2009,"finding":"Human RRS1 localizes in the nucleolus during interphase and redistributes to the chromosome periphery during mitosis. RNAi-mediated depletion of RRS1 causes abnormal chromosome alignment, spindle disorganization, mitotic delay, loss of centromeric Shugoshin 1 localization, and premature separation of sister chromatids, establishing a role for RRS1 in chromosome congression.","method":"Immunofluorescence microscopy, RNA interference, flow cytometry","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, RNAi with specific phenotypic readouts, single lab","pmids":["19465021"],"is_preprint":false},{"year":2009,"finding":"Mammalian Rrs1 localizes both in the nucleolus and in the endoplasmic reticulum of neurons. Its molecular partner 3D3/lyric shares this dual localization. Both Rrs1 and 3D3/lyric are induced by ER stress in neurons, and ER stress occurs as an early presymptomatic event in a Huntington disease knock-in mouse model.","method":"Subcellular fractionation, immunofluorescence co-localization, ER stress induction assays, HD mouse model analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization by fractionation and imaging tied to functional ER stress response, co-partner identified, single lab","pmids":["19433866"],"is_preprint":false},{"year":2015,"finding":"The essential function of Rrs1 in 60S ribosomal subunit biogenesis is conserved between S. cerevisiae and S. pombe. Two-hybrid analysis showed that Rrs1 interactions with Rpf2 (Rfp2) and Ebp2 are conserved in both yeasts.","method":"Temperature-sensitive mutant complementation, yeast two-hybrid","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic complementation across species and two-hybrid interactions, single lab","pmids":["26122634"],"is_preprint":false},{"year":2019,"finding":"In Trypanosoma brucei, TbRrs1 is an essential component of the 5S RNP complex. It directly interacts with trypanosome-specific proteins P34/P37, 5S rRNA, TbL5, and TbRpf2. RNAi knockdown of TbRrs1 impairs ribosome subunit formation and 25/28S and 5.8S rRNA processing.","method":"RNA interference, co-immunoprecipitation, direct binding assays","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with specific rRNA processing phenotype plus direct binding assays, single lab, ortholog study","pmids":["31391282"],"is_preprint":false},{"year":2021,"finding":"RRS1 genomic gain drives overexpression of RRS1 in hepatocellular carcinoma. Mechanistically, RRS1 retains RPL11 in the nucleolus, preventing RPL11 from inhibiting MDM2; this potentiates MDM2-mediated ubiquitination and degradation of p53, thereby promoting HCC cell growth.","method":"Integrative genomic analysis, in vitro and in vivo tumor growth assays, subcellular fractionation, co-immunoprecipitation, ubiquitination assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, Co-IP, ubiquitination assay, in vivo xenograft), mechanistic pathway clearly defined, single lab with convergent evidence","pmids":["34433556"],"is_preprint":false},{"year":2017,"finding":"RRS1 knockdown in colorectal cancer cells causes G2/M cell cycle arrest, reduces expression of CDC25C and CDK1, increases p53 and CDKN1A/p21 protein levels, and suppresses angiogenesis, establishing RRS1 as a regulator of the G2/M checkpoint and p53 pathway.","method":"RNAi knockdown, flow cytometry, Western blot, in vivo xenograft assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with specific cell cycle and molecular phenotype, in vivo validation, single lab","pmids":["29137316"],"is_preprint":false},{"year":2018,"finding":"RRS1 knockdown in breast cancer cells activates p53 and p21, increases ribosome-free RPL11, and co-immunoprecipitation experiments showed that RRS1 knockdown facilitates direct contact between MDM2 and RPL11/RPL5, thereby activating p53 through the RPL11/MDM2 axis.","method":"RNAi knockdown, Western blot, co-immunoprecipitation, in vivo xenograft assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with mechanistic pathway placement, multiple cancer cell lines, single lab","pmids":["30320499"],"is_preprint":false},{"year":2022,"finding":"RRS1 knockdown in breast cancer BT549 cells reduces RPL11 accumulation in the nucleolus, causing RPL11 to migrate to the nucleoplasm where it binds c-Myc, inhibiting c-Myc-mediated transactivation of SNAIL and decreasing invasion and metastasis. This defines an RRS1-RPL11-c-Myc-SNAIL axis.","method":"Lentiviral shRNA knockdown, co-immunoprecipitation (COIP), dual-luciferase reporter assay, subcellular fractionation","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — COIP with reporter assay defining pathway, single lab with two orthogonal methods","pmids":["35179222"],"is_preprint":false},{"year":2022,"finding":"RRS1 knockdown inhibits neuroblastoma cell proliferation via dephosphorylation of key PI3K/Akt/NF-κB pathway proteins. Co-immunoprecipitation and mass spectrometry identified RRS1 as physically associating with components of the PI3K/Akt and NF-κB pathways.","method":"RNAi knockdown, co-immunoprecipitation, mass spectrometry, Western blot, RT-qPCR","journal":"Pediatric research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS interaction data combined with pathway-specific protein phosphorylation readouts, single lab","pmids":["35523884"],"is_preprint":false},{"year":2023,"finding":"RRS1 binds to and stabilizes AEG-1 by inhibiting its ubiquitination and proteasomal degradation, which then promotes MDR1-mediated drug efflux. RRS1 also promotes apoptosis resistance through the ERK/Bcl-2/BAX signaling pathway in breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, cell viability assays","journal":"Molecules (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP combined with ubiquitination assay defining stabilization mechanism, single lab","pmids":["49267538","37049702"],"is_preprint":false},{"year":2024,"finding":"RRS1 directly interacts with GRP78 (co-immunoprecipitation + mass spectrometry). RRS1 inhibits ubiquitin-proteasome-mediated degradation of GRP78, stabilizing it and activating GRP78-mediated PI3K/AKT signaling to promote breast cancer progression.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, Western blot, lentiviral knockdown/overexpression","journal":"Molecules (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS interaction combined with ubiquitination assay and signaling pathway readout, single lab","pmids":["38474562"],"is_preprint":false},{"year":2026,"finding":"DCAF13 directly binds RRS1 and catalyzes K27-linked polyubiquitination of RRS1, a non-degradative modification that enhances RRS1 protein stability. DCAF13 deficiency disrupts ribosome assembly and protein synthesis in hematopoietic stem cells, and the defects are only partially rescued by p53 ablation, indicating p53-independent mechanisms also operate downstream.","method":"Conditional knockout mouse model, Co-immunoprecipitation, ubiquitination assays, ribosome assembly profiling, protein synthesis assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding identified, specific ubiquitin linkage type characterized, in vivo genetic model with multiple mechanistic readouts, single study with convergent orthogonal methods","pmids":["41787937"],"is_preprint":false},{"year":2025,"finding":"RRS1 silencing in lung cancer cells activates p53, increases lipid ROS, reduces SLC7A11 and GPX4, and increases ACSL4, triggering ferroptosis. This reduces angiogenesis and cisplatin resistance. Silencing p53 reverses these effects, placing RRS1 upstream of p53 in a ferroptosis-regulatory pathway.","method":"siRNA knockdown, lipid ROS measurement (BODIPY C11), iron quantification, Western blot, apoptosis flow cytometry, p53 rescue experiment","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis experiment (p53 rescue) with multiple ferroptosis markers, single lab","pmids":["39983385"],"is_preprint":false},{"year":2024,"finding":"In the plant Arabidopsis RRS1/RPS4 immune receptor complex, the E3 ligase RARE directly binds and ubiquitinates the integrated WRKY domain of RRS1 to promote proteasomal degradation of RRS1, indirectly destabilizing RPS4 and compromising complex function. Deubiquitinases UBP12/UBP13 counteract this by deubiquitinating RRS1's WRKY domain, maintaining complex homeostasis.","method":"Proximity labelling, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, genetic epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labelling with biochemical validation of ubiquitination, preprint not yet peer-reviewed, multiple orthogonal methods","pmids":["bio_10.1101_2024.07.01.599856"],"is_preprint":true},{"year":2025,"finding":"The plant RPS4 and RRS1 TIR-NLR proteins form an oligomeric complex whose size does not change upon effector provision. Oligomerization requires TIR domain interactions and nucleotide-binding capacity in RPS4. A cysteine in the RPS4 LRR domain contributes to oligomer stabilization. RPS4 TIR NADase activity is required for immune activation but not for oligomerization, consistent with a model where RRS1 TIR domains suppress RPS4 TIR NADase activity until effector recognition causes conformational relief.","method":"Size-exclusion chromatography, co-immunoprecipitation, mutagenesis of TIR domains and LRR cysteine, NADase activity assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutagenesis and biochemical approaches defining oligomer composition and activity, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.04.11.646618"],"is_preprint":true}],"current_model":"Human/mammalian RRS1 (ribosome biogenesis regulatory protein homolog, KIAA0112) is an essential nucleolar protein that, together with Rpf2, recruits 5S rRNA, RPL5, and RPL11 into nascent 60S preribosomes; its stability is controlled by DCAF13-mediated K27-linked polyubiquitination; in the nucleolus it sequesters RPL11 away from MDM2, thereby sustaining MDM2-mediated p53 degradation and cell proliferation, while its depletion releases RPL11 to activate the RPL11-MDM2-p53 axis, induce G2/M arrest and ferroptosis, and — through an RPL11-c-Myc-SNAIL axis — reduce cancer cell invasion."},"narrative":{"mechanistic_narrative":"RRS1 is an essential nucleolar ribosome biogenesis factor that, in partnership with Rpf2, recruits 5S rRNA, RPL5, and RPL11 into nascent 60S (90S/66S) preribosomes, a function conserved from budding and fission yeast through trypanosomes [PMID:10688653, PMID:17938242, PMID:26122634, PMID:31391282]. Structurally, Rrs1 completes the Brix domain of Rpf2 to form a heterodimer that contacts 5S rRNA, RpL5, and the maturation factor Rsa4, while its C-terminal helices wedge against 25S rRNA and the 5S RNP to lock subunit conformation until the Rpf2-Rrs1 module is removed for late 60S maturation rearrangements [PMID:26117542, PMID:25855814]. In human cells RRS1 occupies the nucleolus during interphase and relocalizes to the chromosome periphery in mitosis, where its depletion disrupts chromosome congression, spindle organization, and centromeric Shugoshin retention [PMID:19465021]. Beyond assembly, RRS1 governs the RPL11-MDM2-p53 surveillance axis: by retaining RPL11 in the nucleolus it prevents RPL11 from inhibiting MDM2, sustaining MDM2-mediated p53 ubiquitination and degradation and promoting tumor growth, whereas RRS1 loss releases ribosome-free RPL11 to engage MDM2/RPL5, activate p53 and p21, and impose G2/M arrest and ferroptosis [PMID:34433556, PMID:29137316, PMID:30320499, PMID:39983385]. Liberated RPL11 also binds c-Myc to suppress SNAIL transactivation and invasion, defining an RRS1-RPL11-c-Myc-SNAIL axis [PMID:35179222]. RRS1 additionally stabilizes client proteins by blocking their ubiquitin-proteasomal degradation, including GRP78 to activate PI3K/AKT signaling [PMID:38474562], and its own stability is enhanced by DCAF13-catalyzed non-degradative K27-linked polyubiquitination required for ribosome assembly in hematopoietic stem cells [PMID:41787937].","teleology":[{"year":2000,"claim":"Established RRS1 as an essential nuclear factor for ribosome biogenesis and linked it to the signaling circuit coupling secretory status to rRNA/ribosomal protein gene transcription.","evidence":"Conditional GAL1-depletion, cold-sensitive mutants, and transcriptional repression assays in S. cerevisiae","pmids":["10688653"],"confidence":"High","gaps":["No molecular partners or structural basis defined","Mechanism coupling secretion to ribosome synthesis not resolved"]},{"year":2007,"claim":"Resolved RRS1's molecular role by placing it with Rpf2 in a preribosomal neighborhood that recruits RpL5, RpL11, and 5S rRNA into nascent 90S particles.","evidence":"In vitro binding, Co-IP, genetic depletion with pre-rRNA processing analysis and fractionation in yeast","pmids":["17938242"],"confidence":"High","gaps":["Atomic geometry of contacts not determined","Trigger for Rpf2-Rrs1 release during maturation unknown"]},{"year":2015,"claim":"Defined the atomic architecture of the Rpf2-Rrs1 heterodimer, showing Rrs1 completes the Rpf2 Brix domain and that its C-terminal helices physically block subunit rotation, explaining why module removal gates 60S maturation.","evidence":"X-ray crystallography of the A. nidulans complex, cryo-EM fitting, EMSA, and site-directed mutagenesis (two independent structures)","pmids":["26117542","25855814"],"confidence":"High","gaps":["Mechanism that displaces Rpf2-Rrs1 during maturation not captured","Human complex structure not solved"]},{"year":2009,"claim":"Extended RRS1 function beyond the nucleolus, revealing a mitotic role in chromosome congression and a neuronal ER-stress-associated localization with a 3D3/lyric partner.","evidence":"Immunofluorescence, RNAi with mitotic phenotyping, subcellular fractionation, and ER stress assays including an HD mouse model","pmids":["19465021","19433866"],"confidence":"Medium","gaps":["Molecular basis of mitotic and ER roles unresolved","Relationship to ribosome biogenesis function unclear","Single-lab observations"]},{"year":2019,"claim":"Confirmed conservation of the 5S-RNP assembly role across deep eukaryotic divergence by demonstrating TbRrs1 as an essential 5S RNP component in trypanosomes.","evidence":"RNAi knockdown, Co-IP, and direct binding assays in T. brucei","pmids":["31391282"],"confidence":"Medium","gaps":["Trypanosome-specific P34/P37 contribution to assembly not fully mapped","Ortholog study, single lab"]},{"year":2021,"claim":"Identified the mechanism by which RRS1 overexpression promotes cancer: nucleolar sequestration of RPL11 to free MDM2 and accelerate p53 degradation.","evidence":"Integrative genomics, fractionation, Co-IP, ubiquitination assays, and xenografts in hepatocellular carcinoma","pmids":["34433556"],"confidence":"High","gaps":["Quantitative threshold of RPL11 sequestration not defined","Direct RRS1-RPL11 interaction surface unmapped"]},{"year":2018,"claim":"Showed RRS1 loss activates the RPL11/RPL5-MDM2-p53 axis and triggers G2/M arrest across multiple cancers, establishing it as a tunable regulator of ribosomal-stress p53 signaling.","evidence":"RNAi knockdown, Co-IP, Western blot, and xenografts in colorectal and breast cancer cells","pmids":["29137316","30320499"],"confidence":"Medium","gaps":["Whether p53 activation is purely RPL11-dependent not isolated","Single-lab studies per cancer type"]},{"year":2022,"claim":"Expanded the RRS1-RPL11 output to additional effectors, including c-Myc/SNAIL suppression of invasion and physical association with PI3K/Akt/NF-kB components.","evidence":"shRNA knockdown, Co-IP/MS, dual-luciferase reporter, and fractionation in breast cancer and neuroblastoma cells","pmids":["35179222","35523884"],"confidence":"Medium","gaps":["Directness of PI3K/Akt/NF-kB association versus indirect effect unresolved","Single-lab data"]},{"year":2024,"claim":"Revealed a non-ribosomal RRS1 activity: stabilizing client proteins (AEG-1, GRP78) by blocking their ubiquitin-proteasomal degradation to drive drug resistance and PI3K/AKT signaling.","evidence":"Co-IP/MS, ubiquitination assays, and knockdown/overexpression in breast cancer cells","pmids":["37049702","38474562"],"confidence":"Medium","gaps":["Whether RRS1 acts as a deubiquitinase recruiter or competitor is unknown","Single-lab studies"]},{"year":2026,"claim":"Defined upstream control of RRS1 itself: DCAF13 catalyzes non-degradative K27-linked polyubiquitination that stabilizes RRS1 and is required for ribosome assembly in hematopoietic stem cells through p53-dependent and -independent routes.","evidence":"Conditional knockout mouse, Co-IP, linkage-specific ubiquitination assays, and ribosome/protein-synthesis profiling","pmids":["41787937"],"confidence":"High","gaps":["The p53-independent downstream effectors not identified","Site of K27 modification on RRS1 not mapped"]},{"year":2025,"claim":"Linked RRS1 loss directly to ferroptosis via a p53-dependent pathway, broadening its role in cell-death regulation and chemoresistance.","evidence":"siRNA knockdown, lipid ROS/iron quantification, ferroptosis marker profiling, and p53 rescue in lung cancer cells","pmids":["39983385"],"confidence":"Medium","gaps":["Whether ferroptosis is RPL11-MDM2-dependent not tested","Single-lab epistasis"]},{"year":null,"claim":"How RRS1's conserved ribosome-assembly function is mechanistically integrated with its extra-ribosomal roles in p53/RPL11 surveillance, client-protein stabilization, mitosis, and ER stress remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting nucleolar assembly to RPL11 sequestration kinetics","Human Rpf2-RRS1 structure and its regulation by DCAF13 ubiquitination not determined","Mechanistic basis of mitotic chromosome-periphery role undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,3,7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,10,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,13,14,15]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,5,8,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,9]}],"complexes":["Rpf2-Rrs1 heterodimer","5S RNP / 90S preribosome","RPS4/RRS1 TIR-NLR immune complex (plant)"],"partners":["RPF2","RPL5","RPL11","EBP2","DCAF13","GRP78","AEG-1","MTDH/3D3/LYRIC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15050","full_name":"Ribosome biogenesis regulatory protein homolog","aliases":[],"length_aa":365,"mass_kda":41.2,"function":"Involved in ribosomal large subunit assembly. May regulate the localization of the 5S RNP/5S ribonucleoprotein particle to the nucleolus","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q15050/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RRS1","classification":"Common Essential","n_dependent_lines":1189,"n_total_lines":1208,"dependency_fraction":0.984271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GDI2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RRS1","total_profiled":1310},"omim":[{"mim_id":"618529","title":"ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 2; RRS2","url":"https://www.omim.org/entry/618529"},{"mim_id":"618471","title":"RIBOSOME PRODUCTION FACTOR 2 HOMOLOG; RPF2","url":"https://www.omim.org/entry/618471"},{"mim_id":"618311","title":"RIBOSOME BIOGENESIS REGULATOR 1 HOMOLOG; RRS1","url":"https://www.omim.org/entry/618311"},{"mim_id":"616331","title":"ROBINOW SYNDROME, AUTOSOMAL DOMINANT 2; DRS2","url":"https://www.omim.org/entry/616331"},{"mim_id":"602337","title":"RECEPTOR TYROSINE KINASE-LIKE ORPHAN RECEPTOR 2; ROR2","url":"https://www.omim.org/entry/602337"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRS1"},"hgnc":{"alias_symbol":["KIAA0112"],"prev_symbol":[]},"alphafold":{"accession":"Q15050","domains":[{"cath_id":"-","chopping":"8-91","consensus_level":"high","plddt":89.9282,"start":8,"end":91},{"cath_id":"-","chopping":"262-296","consensus_level":"medium","plddt":81.3011,"start":262,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15050","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15050-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15050-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRS1","jax_strain_url":"https://www.jax.org/strain/search?query=RRS1"},"sequence":{"accession":"Q15050","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15050.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15050/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15050"}},"corpus_meta":[{"pmid":"12788974","id":"PMC_12788974","title":"Physical interaction between RRS1-R, a protein conferring resistance to bacterial wilt, and PopP2, a type III effector targeted to the plant nucleus.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12788974","citation_count":500,"is_preprint":false},{"pmid":"19519800","id":"PMC_19519800","title":"RRS1 and RPS4 provide a dual Resistance-gene system against fungal and bacterial pathogens.","date":"2009","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19519800","citation_count":302,"is_preprint":false},{"pmid":"17938242","id":"PMC_17938242","title":"Assembly factors Rpf2 and Rrs1 recruit 5S rRNA and ribosomal proteins rpL5 and rpL11 into nascent ribosomes.","date":"2007","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/17938242","citation_count":167,"is_preprint":false},{"pmid":"7556057","id":"PMC_7556057","title":"The race-specific elicitor, NIP1, from the barley pathogen, Rhynchosporium secalis, determines avirulence on host plants of the Rrs1 resistance genotype.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7556057","citation_count":138,"is_preprint":false},{"pmid":"19433866","id":"PMC_19433866","title":"Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19433866","citation_count":134,"is_preprint":false},{"pmid":"28475615","id":"PMC_28475615","title":"Protein-protein interactions in the RPS4/RRS1 immune receptor complex.","date":"2017","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/28475615","citation_count":95,"is_preprint":false},{"pmid":"10688653","id":"PMC_10688653","title":"RRS1, a conserved essential gene, encodes a novel regulatory protein required for ribosome biogenesis in Saccharomyces cerevisiae.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10688653","citation_count":73,"is_preprint":false},{"pmid":"36862074","id":"PMC_36862074","title":"RRS1 shapes robust root system to enhance drought resistance in rice.","date":"2023","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/36862074","citation_count":50,"is_preprint":false},{"pmid":"26117542","id":"PMC_26117542","title":"The structure of Rpf2-Rrs1 explains its role in ribosome biogenesis.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26117542","citation_count":49,"is_preprint":false},{"pmid":"25855814","id":"PMC_25855814","title":"Structural and functional analysis of the Rpf2-Rrs1 complex in ribosome biogenesis.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25855814","citation_count":40,"is_preprint":false},{"pmid":"31952549","id":"PMC_31952549","title":"Down-regulated lncRNA SBF2-AS1 inhibits tumorigenesis and progression of breast cancer by sponging microRNA-143 and repressing RRS1.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31952549","citation_count":38,"is_preprint":false},{"pmid":"34433556","id":"PMC_34433556","title":"Genomic gain of RRS1 promotes hepatocellular carcinoma through reducing the RPL11-MDM2-p53 signaling.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34433556","citation_count":35,"is_preprint":false},{"pmid":"29137316","id":"PMC_29137316","title":"RRS1 silencing suppresses colorectal cancer cell proliferation and tumorigenesis by inhibiting G2/M progression and angiogenesis.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29137316","citation_count":35,"is_preprint":false},{"pmid":"19465021","id":"PMC_19465021","title":"A nucleolar protein RRS1 contributes to chromosome congression.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19465021","citation_count":35,"is_preprint":false},{"pmid":"30320499","id":"PMC_30320499","title":"Functional role of RRS1 in breast cancer cell proliferation.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30320499","citation_count":24,"is_preprint":false},{"pmid":"31438772","id":"PMC_31438772","title":"MicroRNA-598 inhibits the growth and maintenance of gastric cancer stem-like cells by down-regulating RRS1.","date":"2019","source":"Cell cycle (Georgetown, 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Theoretical and applied genetics. 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evolution","url":"https://pubmed.ncbi.nlm.nih.gov/21424546","citation_count":9,"is_preprint":false},{"pmid":"37049702","id":"PMC_37049702","title":"Ribosome Biogenesis Regulator 1 Homolog (RRS1) Promotes Cisplatin Resistance by Regulating AEG-1 Abundance in Breast Cancer Cells.","date":"2023","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37049702","citation_count":7,"is_preprint":false},{"pmid":"37090698","id":"PMC_37090698","title":"Integrated bioinformatics and machine-learning screening for immune-related genes in diagnosing non-alcoholic fatty liver disease with ischemic stroke and RRS1 pan-cancer analysis.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37090698","citation_count":6,"is_preprint":false},{"pmid":"31391282","id":"PMC_31391282","title":"Trypanosoma brucei Homologue of Regulator of Ribosome Synthesis 1 (Rrs1) Has Direct Interactions with Essential Trypanosome-Specific Proteins.","date":"2019","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/31391282","citation_count":6,"is_preprint":false},{"pmid":"28277970","id":"PMC_28277970","title":"Analyses of natural variation indicates that the absence of RPS4/RRS1 and amino acid change in RPS4 cause loss of their functions and resistance to pathogens.","date":"2017","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/28277970","citation_count":5,"is_preprint":false},{"pmid":"32264934","id":"PMC_32264934","title":"Correction to: Down-regulated lncRNA SBF2-AS1 inhibits tumorigenesis and progression of breast cancer by sponging microRNA-143 and repressing RRS1.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32264934","citation_count":5,"is_preprint":false},{"pmid":"37705317","id":"PMC_37705317","title":"Genomic gain/methylation modification/hsa-miR-132-3p increases RRS1 overexpression in liver 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38474562","citation_count":3,"is_preprint":false},{"pmid":"25484219","id":"PMC_25484219","title":"Crystallization and preliminary X-ray crystallographic analysis of ribosome assembly factors: the Rpf2-Rrs1 complex.","date":"2014","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/25484219","citation_count":3,"is_preprint":false},{"pmid":"39267538","id":"PMC_39267538","title":"The role of RRS1 in breast cancer cells metastasis and AEG-1/AKT/c-Myc signaling pathway.","date":"2024","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/39267538","citation_count":1,"is_preprint":false},{"pmid":"40165491","id":"PMC_40165491","title":"M2 Macrophage-Extracellular Vesicle-Derived lncRNA-NEAT1 Regulates miR-204-5p/RRS1-mediated Cell Cycle to Promote the Occurrence and Development of Colorectal Cancer.","date":"2025","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/40165491","citation_count":1,"is_preprint":false},{"pmid":"40957517","id":"PMC_40957517","title":"The miR-125 targeting ARFIP2 and the miR-3770 targeting Rrs1_0 are involved in beta-cypermethrin resistance in cockroach.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40957517","citation_count":1,"is_preprint":false},{"pmid":"41787937","id":"PMC_41787937","title":"DCAF13 Safeguards Hematopoietic Stem Cells via RRS1-Regulated Ribosome Biogenesis.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41787937","citation_count":0,"is_preprint":false},{"pmid":"41162766","id":"PMC_41162766","title":"RRS1 regulates proliferation, migration, and invasion of HTR-8/SVneo human trophoblasts.","date":"2025","source":"Frontiers of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41162766","citation_count":0,"is_preprint":false},{"pmid":"40339202","id":"PMC_40339202","title":"Study on the role and function of RRS1 in cutaneous squamous cell carcinoma.","date":"2025","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/40339202","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.11.646618","title":"Recognition-dependent activation of the RRS1-R/RPS4 immune receptor complex","date":"2025-04-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.11.646618","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.01.599856","title":"Reversible ubiquitination of integrated domain controls paired NLR immune receptor complex homeostasis","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.01.599856","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23221,"output_tokens":4852,"usd":0.071221,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13011,"output_tokens":4091,"usd":0.083665,"stage2_stop_reason":"end_turn"},"total_usd":0.154886,"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\": 2000,\n      \"finding\": \"RRS1 (yeast Rrs1p) is an essential nuclear protein required for ribosome biogenesis; depletion of Rrs1p causes defects in pre-rRNA processing and assembly of ribosomal subunits. The rrs1-1 mutation also greatly reduced transcriptional repression of rRNA and ribosomal protein genes caused by a secretory defect, placing Rrs1 in a signaling pathway coupling secretion to ribosome synthesis.\",\n      \"method\": \"Conditional null mutant (GAL1 promoter depletion), cold-sensitive mutant analysis, transcriptional repression assays in S. cerevisiae\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and functional approaches in yeast, replicated by subsequent studies\",\n      \"pmids\": [\"10688653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast assembly factors Rpf2 and Rrs1 form a ribonucleoprotein neighborhood in preribosomes together with ribosomal proteins rpL5, rpL11, and 5S rRNA. Rpf2 and Rrs1 are required for recruiting rpL5, rpL11, and 5S rRNA into nascent 90S preribosomes; in their absence, 27SB pre-rRNA processing is blocked and abortive 66S pre-rRNPs are prematurely released from the nucleolus.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, genetic depletion, pre-rRNA processing analysis, subcellular fractionation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, Co-IP, genetic depletion with specific processing phenotype), replicated by structural studies\",\n      \"pmids\": [\"17938242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the Rpf2-Rrs1 core complex from Aspergillus nidulans at 1.5 Å reveals that the Brix domain of Rpf2 is completed by Rrs1 to form two anticodon-binding domain-like modules. The Rpf2-Rrs1 heterodimer makes specific contacts with 5S rRNA, RpL5, and the biogenesis factor Rsa4. Two helices in the Rrs1 C-terminal tail occupy a strategic position to block rotation of 25S rRNA and the 5S RNP, explaining why removal of Rpf2-Rrs1 is required for 60S maturation rearrangements.\",\n      \"method\": \"X-ray crystallography (1.5 Å), fitting into cryo-EM density, biochemical interaction data\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional interpretation supported by cryo-EM fitting and biochemical data, independently confirmed by a second crystal structure paper\",\n      \"pmids\": [\"26117542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the Aspergillus nidulans Rpf2-Rrs1 core complex shows the Rrs1 long α-helix joins the C-terminal half of the Rpf2 Brix domain as part of a single structural unit; the proline-rich linker of Rrs1 wraps around Rpf2. Gel shift analysis demonstrated that the Rpf2-Rrs1 complex binds directly to 5S rRNA, and mutagenesis of Rpf2 R236 (equivalent to ScRpf2 R238) significantly impairs this binding.\",\n      \"method\": \"X-ray crystallography, gel shift (EMSA), site-directed mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with EMSA and mutagenesis in a single study, independently corroborated by Kharde et al. 2015\",\n      \"pmids\": [\"25855814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human RRS1 localizes in the nucleolus during interphase and redistributes to the chromosome periphery during mitosis. RNAi-mediated depletion of RRS1 causes abnormal chromosome alignment, spindle disorganization, mitotic delay, loss of centromeric Shugoshin 1 localization, and premature separation of sister chromatids, establishing a role for RRS1 in chromosome congression.\",\n      \"method\": \"Immunofluorescence microscopy, RNA interference, flow cytometry\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, RNAi with specific phenotypic readouts, single lab\",\n      \"pmids\": [\"19465021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian Rrs1 localizes both in the nucleolus and in the endoplasmic reticulum of neurons. Its molecular partner 3D3/lyric shares this dual localization. Both Rrs1 and 3D3/lyric are induced by ER stress in neurons, and ER stress occurs as an early presymptomatic event in a Huntington disease knock-in mouse model.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence co-localization, ER stress induction assays, HD mouse model analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization by fractionation and imaging tied to functional ER stress response, co-partner identified, single lab\",\n      \"pmids\": [\"19433866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The essential function of Rrs1 in 60S ribosomal subunit biogenesis is conserved between S. cerevisiae and S. pombe. Two-hybrid analysis showed that Rrs1 interactions with Rpf2 (Rfp2) and Ebp2 are conserved in both yeasts.\",\n      \"method\": \"Temperature-sensitive mutant complementation, yeast two-hybrid\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic complementation across species and two-hybrid interactions, single lab\",\n      \"pmids\": [\"26122634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Trypanosoma brucei, TbRrs1 is an essential component of the 5S RNP complex. It directly interacts with trypanosome-specific proteins P34/P37, 5S rRNA, TbL5, and TbRpf2. RNAi knockdown of TbRrs1 impairs ribosome subunit formation and 25/28S and 5.8S rRNA processing.\",\n      \"method\": \"RNA interference, co-immunoprecipitation, direct binding assays\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with specific rRNA processing phenotype plus direct binding assays, single lab, ortholog study\",\n      \"pmids\": [\"31391282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRS1 genomic gain drives overexpression of RRS1 in hepatocellular carcinoma. Mechanistically, RRS1 retains RPL11 in the nucleolus, preventing RPL11 from inhibiting MDM2; this potentiates MDM2-mediated ubiquitination and degradation of p53, thereby promoting HCC cell growth.\",\n      \"method\": \"Integrative genomic analysis, in vitro and in vivo tumor growth assays, subcellular fractionation, co-immunoprecipitation, ubiquitination assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, Co-IP, ubiquitination assay, in vivo xenograft), mechanistic pathway clearly defined, single lab with convergent evidence\",\n      \"pmids\": [\"34433556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RRS1 knockdown in colorectal cancer cells causes G2/M cell cycle arrest, reduces expression of CDC25C and CDK1, increases p53 and CDKN1A/p21 protein levels, and suppresses angiogenesis, establishing RRS1 as a regulator of the G2/M checkpoint and p53 pathway.\",\n      \"method\": \"RNAi knockdown, flow cytometry, Western blot, in vivo xenograft assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with specific cell cycle and molecular phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"29137316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RRS1 knockdown in breast cancer cells activates p53 and p21, increases ribosome-free RPL11, and co-immunoprecipitation experiments showed that RRS1 knockdown facilitates direct contact between MDM2 and RPL11/RPL5, thereby activating p53 through the RPL11/MDM2 axis.\",\n      \"method\": \"RNAi knockdown, Western blot, co-immunoprecipitation, in vivo xenograft assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with mechanistic pathway placement, multiple cancer cell lines, single lab\",\n      \"pmids\": [\"30320499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRS1 knockdown in breast cancer BT549 cells reduces RPL11 accumulation in the nucleolus, causing RPL11 to migrate to the nucleoplasm where it binds c-Myc, inhibiting c-Myc-mediated transactivation of SNAIL and decreasing invasion and metastasis. This defines an RRS1-RPL11-c-Myc-SNAIL axis.\",\n      \"method\": \"Lentiviral shRNA knockdown, co-immunoprecipitation (COIP), dual-luciferase reporter assay, subcellular fractionation\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — COIP with reporter assay defining pathway, single lab with two orthogonal methods\",\n      \"pmids\": [\"35179222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRS1 knockdown inhibits neuroblastoma cell proliferation via dephosphorylation of key PI3K/Akt/NF-κB pathway proteins. Co-immunoprecipitation and mass spectrometry identified RRS1 as physically associating with components of the PI3K/Akt and NF-κB pathways.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, mass spectrometry, Western blot, RT-qPCR\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS interaction data combined with pathway-specific protein phosphorylation readouts, single lab\",\n      \"pmids\": [\"35523884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RRS1 binds to and stabilizes AEG-1 by inhibiting its ubiquitination and proteasomal degradation, which then promotes MDR1-mediated drug efflux. RRS1 also promotes apoptosis resistance through the ERK/Bcl-2/BAX signaling pathway in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, cell viability assays\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP combined with ubiquitination assay defining stabilization mechanism, single lab\",\n      \"pmids\": [\"49267538\", \"37049702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRS1 directly interacts with GRP78 (co-immunoprecipitation + mass spectrometry). RRS1 inhibits ubiquitin-proteasome-mediated degradation of GRP78, stabilizing it and activating GRP78-mediated PI3K/AKT signaling to promote breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, Western blot, lentiviral knockdown/overexpression\",\n      \"journal\": \"Molecules (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS interaction combined with ubiquitination assay and signaling pathway readout, single lab\",\n      \"pmids\": [\"38474562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DCAF13 directly binds RRS1 and catalyzes K27-linked polyubiquitination of RRS1, a non-degradative modification that enhances RRS1 protein stability. DCAF13 deficiency disrupts ribosome assembly and protein synthesis in hematopoietic stem cells, and the defects are only partially rescued by p53 ablation, indicating p53-independent mechanisms also operate downstream.\",\n      \"method\": \"Conditional knockout mouse model, Co-immunoprecipitation, ubiquitination assays, ribosome assembly profiling, protein synthesis assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding identified, specific ubiquitin linkage type characterized, in vivo genetic model with multiple mechanistic readouts, single study with convergent orthogonal methods\",\n      \"pmids\": [\"41787937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RRS1 silencing in lung cancer cells activates p53, increases lipid ROS, reduces SLC7A11 and GPX4, and increases ACSL4, triggering ferroptosis. This reduces angiogenesis and cisplatin resistance. Silencing p53 reverses these effects, placing RRS1 upstream of p53 in a ferroptosis-regulatory pathway.\",\n      \"method\": \"siRNA knockdown, lipid ROS measurement (BODIPY C11), iron quantification, Western blot, apoptosis flow cytometry, p53 rescue experiment\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis experiment (p53 rescue) with multiple ferroptosis markers, single lab\",\n      \"pmids\": [\"39983385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the plant Arabidopsis RRS1/RPS4 immune receptor complex, the E3 ligase RARE directly binds and ubiquitinates the integrated WRKY domain of RRS1 to promote proteasomal degradation of RRS1, indirectly destabilizing RPS4 and compromising complex function. Deubiquitinases UBP12/UBP13 counteract this by deubiquitinating RRS1's WRKY domain, maintaining complex homeostasis.\",\n      \"method\": \"Proximity labelling, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, genetic epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labelling with biochemical validation of ubiquitination, preprint not yet peer-reviewed, multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.599856\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The plant RPS4 and RRS1 TIR-NLR proteins form an oligomeric complex whose size does not change upon effector provision. Oligomerization requires TIR domain interactions and nucleotide-binding capacity in RPS4. A cysteine in the RPS4 LRR domain contributes to oligomer stabilization. RPS4 TIR NADase activity is required for immune activation but not for oligomerization, consistent with a model where RRS1 TIR domains suppress RPS4 TIR NADase activity until effector recognition causes conformational relief.\",\n      \"method\": \"Size-exclusion chromatography, co-immunoprecipitation, mutagenesis of TIR domains and LRR cysteine, NADase activity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutagenesis and biochemical approaches defining oligomer composition and activity, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.11.646618\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Human/mammalian RRS1 (ribosome biogenesis regulatory protein homolog, KIAA0112) is an essential nucleolar protein that, together with Rpf2, recruits 5S rRNA, RPL5, and RPL11 into nascent 60S preribosomes; its stability is controlled by DCAF13-mediated K27-linked polyubiquitination; in the nucleolus it sequesters RPL11 away from MDM2, thereby sustaining MDM2-mediated p53 degradation and cell proliferation, while its depletion releases RPL11 to activate the RPL11-MDM2-p53 axis, induce G2/M arrest and ferroptosis, and — through an RPL11-c-Myc-SNAIL axis — reduce cancer cell invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRS1 is an essential nucleolar ribosome biogenesis factor that, in partnership with Rpf2, recruits 5S rRNA, RPL5, and RPL11 into nascent 60S (90S/66S) preribosomes, a function conserved from budding and fission yeast through trypanosomes [#0, #1, #6, #7]. Structurally, Rrs1 completes the Brix domain of Rpf2 to form a heterodimer that contacts 5S rRNA, RpL5, and the maturation factor Rsa4, while its C-terminal helices wedge against 25S rRNA and the 5S RNP to lock subunit conformation until the Rpf2-Rrs1 module is removed for late 60S maturation rearrangements [#2, #3]. In human cells RRS1 occupies the nucleolus during interphase and relocalizes to the chromosome periphery in mitosis, where its depletion disrupts chromosome congression, spindle organization, and centromeric Shugoshin retention [#4]. Beyond assembly, RRS1 governs the RPL11-MDM2-p53 surveillance axis: by retaining RPL11 in the nucleolus it prevents RPL11 from inhibiting MDM2, sustaining MDM2-mediated p53 ubiquitination and degradation and promoting tumor growth, whereas RRS1 loss releases ribosome-free RPL11 to engage MDM2/RPL5, activate p53 and p21, and impose G2/M arrest and ferroptosis [#8, #9, #10, #16]. Liberated RPL11 also binds c-Myc to suppress SNAIL transactivation and invasion, defining an RRS1-RPL11-c-Myc-SNAIL axis [#11]. RRS1 additionally stabilizes client proteins by blocking their ubiquitin-proteasomal degradation, including GRP78 to activate PI3K/AKT signaling [#14], and its own stability is enhanced by DCAF13-catalyzed non-degradative K27-linked polyubiquitination required for ribosome assembly in hematopoietic stem cells [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established RRS1 as an essential nuclear factor for ribosome biogenesis and linked it to the signaling circuit coupling secretory status to rRNA/ribosomal protein gene transcription.\",\n      \"evidence\": \"Conditional GAL1-depletion, cold-sensitive mutants, and transcriptional repression assays in S. cerevisiae\",\n      \"pmids\": [\"10688653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular partners or structural basis defined\", \"Mechanism coupling secretion to ribosome synthesis not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved RRS1's molecular role by placing it with Rpf2 in a preribosomal neighborhood that recruits RpL5, RpL11, and 5S rRNA into nascent 90S particles.\",\n      \"evidence\": \"In vitro binding, Co-IP, genetic depletion with pre-rRNA processing analysis and fractionation in yeast\",\n      \"pmids\": [\"17938242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic geometry of contacts not determined\", \"Trigger for Rpf2-Rrs1 release during maturation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the atomic architecture of the Rpf2-Rrs1 heterodimer, showing Rrs1 completes the Rpf2 Brix domain and that its C-terminal helices physically block subunit rotation, explaining why module removal gates 60S maturation.\",\n      \"evidence\": \"X-ray crystallography of the A. nidulans complex, cryo-EM fitting, EMSA, and site-directed mutagenesis (two independent structures)\",\n      \"pmids\": [\"26117542\", \"25855814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism that displaces Rpf2-Rrs1 during maturation not captured\", \"Human complex structure not solved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended RRS1 function beyond the nucleolus, revealing a mitotic role in chromosome congression and a neuronal ER-stress-associated localization with a 3D3/lyric partner.\",\n      \"evidence\": \"Immunofluorescence, RNAi with mitotic phenotyping, subcellular fractionation, and ER stress assays including an HD mouse model\",\n      \"pmids\": [\"19465021\", \"19433866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of mitotic and ER roles unresolved\", \"Relationship to ribosome biogenesis function unclear\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed conservation of the 5S-RNP assembly role across deep eukaryotic divergence by demonstrating TbRrs1 as an essential 5S RNP component in trypanosomes.\",\n      \"evidence\": \"RNAi knockdown, Co-IP, and direct binding assays in T. brucei\",\n      \"pmids\": [\"31391282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trypanosome-specific P34/P37 contribution to assembly not fully mapped\", \"Ortholog study, single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the mechanism by which RRS1 overexpression promotes cancer: nucleolar sequestration of RPL11 to free MDM2 and accelerate p53 degradation.\",\n      \"evidence\": \"Integrative genomics, fractionation, Co-IP, ubiquitination assays, and xenografts in hepatocellular carcinoma\",\n      \"pmids\": [\"34433556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative threshold of RPL11 sequestration not defined\", \"Direct RRS1-RPL11 interaction surface unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed RRS1 loss activates the RPL11/RPL5-MDM2-p53 axis and triggers G2/M arrest across multiple cancers, establishing it as a tunable regulator of ribosomal-stress p53 signaling.\",\n      \"evidence\": \"RNAi knockdown, Co-IP, Western blot, and xenografts in colorectal and breast cancer cells\",\n      \"pmids\": [\"29137316\", \"30320499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 activation is purely RPL11-dependent not isolated\", \"Single-lab studies per cancer type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the RRS1-RPL11 output to additional effectors, including c-Myc/SNAIL suppression of invasion and physical association with PI3K/Akt/NF-kB components.\",\n      \"evidence\": \"shRNA knockdown, Co-IP/MS, dual-luciferase reporter, and fractionation in breast cancer and neuroblastoma cells\",\n      \"pmids\": [\"35179222\", \"35523884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of PI3K/Akt/NF-kB association versus indirect effect unresolved\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-ribosomal RRS1 activity: stabilizing client proteins (AEG-1, GRP78) by blocking their ubiquitin-proteasomal degradation to drive drug resistance and PI3K/AKT signaling.\",\n      \"evidence\": \"Co-IP/MS, ubiquitination assays, and knockdown/overexpression in breast cancer cells\",\n      \"pmids\": [\"37049702\", \"38474562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RRS1 acts as a deubiquitinase recruiter or competitor is unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined upstream control of RRS1 itself: DCAF13 catalyzes non-degradative K27-linked polyubiquitination that stabilizes RRS1 and is required for ribosome assembly in hematopoietic stem cells through p53-dependent and -independent routes.\",\n      \"evidence\": \"Conditional knockout mouse, Co-IP, linkage-specific ubiquitination assays, and ribosome/protein-synthesis profiling\",\n      \"pmids\": [\"41787937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The p53-independent downstream effectors not identified\", \"Site of K27 modification on RRS1 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked RRS1 loss directly to ferroptosis via a p53-dependent pathway, broadening its role in cell-death regulation and chemoresistance.\",\n      \"evidence\": \"siRNA knockdown, lipid ROS/iron quantification, ferroptosis marker profiling, and p53 rescue in lung cancer cells\",\n      \"pmids\": [\"39983385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ferroptosis is RPL11-MDM2-dependent not tested\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRS1's conserved ribosome-assembly function is mechanistically integrated with its extra-ribosomal roles in p53/RPL11 surveillance, client-protein stabilization, mitosis, and ER stress remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting nucleolar assembly to RPL11 sequestration kinetics\", \"Human Rpf2-RRS1 structure and its regulation by DCAF13 ubiquitination not determined\", \"Mechanistic basis of mitotic chromosome-periphery role undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 3, 7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 13, 14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 5, 8, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [\n      \"Rpf2-Rrs1 heterodimer\",\n      \"5S RNP / 90S preribosome\",\n      \"RPS4/RRS1 TIR-NLR immune complex (plant)\"\n    ],\n    \"partners\": [\n      \"RPF2\",\n      \"RPL5\",\n      \"RPL11\",\n      \"EBP2\",\n      \"DCAF13\",\n      \"GRP78\",\n      \"AEG-1\",\n      \"MTDH/3D3/lyric\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}