{"gene":"RRP1B","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2007,"finding":"RRP1B physically and functionally interacts with the metastasis modifier SIPA1, as demonstrated by yeast two-hybrid, immunoprecipitation, and functional assays. Ectopic expression of RRP1B in mouse mammary tumor cells significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays.","method":"Yeast two-hybrid, co-immunoprecipitation, functional metastasis assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal yeast two-hybrid plus Co-IP plus functional assay, single lab, multiple orthogonal methods","pmids":["18081427"],"is_preprint":false},{"year":2009,"finding":"RRP1B is a chromatin-associated factor that physically interacts with nucleosome-binding proteins including histone H1X, PARP1, TRIM28 (KAP1), CSDA, heterochromatin protein-1α, and acetyl-histone H4 lysine 5, as shown by tandem affinity purification, co-immunofluorescence, and co-immunoprecipitation.","method":"Tandem affinity purification, co-immunofluorescence, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (TAP, co-IP, co-IF), single lab","pmids":["19710015"],"is_preprint":false},{"year":2009,"finding":"An RRP1B allelic variant associated with improved breast cancer survival differentially modulates transcription factors controlled by TRIM28 and CSDA compared with wild-type RRP1B, indicating RRP1B is a dynamic modulator of chromatin structure and transcription.","method":"Gene expression analysis comparing wild-type vs. variant RRP1B ectopic expression in HeLa cells","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (gene expression), no direct biochemical mechanism","pmids":["19710015"],"is_preprint":false},{"year":2009,"finding":"RRP1B is a transcriptional target of E2F1 and forms a complex with E2F1 on selective proapoptotic target gene promoters inside the nucleolus and nucleoplasmic punctates; RRP1B is required for E2F1-induced apoptosis and for the expression of certain E2F1 proapoptotic target genes in response to DNA-damaging agents.","method":"Promoter characterization, co-immunoprecipitation, ChIP, RRP1B knockdown with apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (promoter assay, Co-IP, ChIP, loss-of-function), single lab","pmids":["20040599"],"is_preprint":false},{"year":2010,"finding":"RRP1B acts as a novel nucleolar targeting subunit for PP1β and PP1γ (with isoform specificity), targeting PP1 to the granular component of the nucleolus in an RNase-dependent manner. Quantitative proteomics of RRP1B–PP1γ complexes revealed enrichment of large (60S) ribosomal subunit proteins and pre-60S nonribosomal proteins involved in mid-late rRNA processing.","method":"GFP-fusion live-cell fluorescence imaging, quantitative proteomics (SILAC-MS), co-immunoprecipitation, fractionation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP combined with quantitative MS proteomics and live-cell imaging, multiple orthogonal methods in a single study","pmids":["20926688"],"is_preprint":false},{"year":2013,"finding":"RRP1B physically interacts with the splicing regulator SRSF1 (SF2/ASF), and this interaction is increased by transcriptional inhibitors; knockdown of Rrp1b in mouse mammary tumor cells induces significant alternative isoform expression changes in over 600 genes, particularly in cell cycle and checkpoint regulation pathways.","method":"Co-immunoprecipitation, co-immunofluorescence, RNA-sequencing of knockdown vs. control cells, RT-PCR with isoform-specific primers","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus Co-IF plus RNA-seq, single lab, multiple orthogonal methods","pmids":["23604122"],"is_preprint":false},{"year":2014,"finding":"RRP1B binds chromatin genome-wide and co-occupies loci with TRIM28/KAP1 and HP1α (CBX5); RRP1B occupancy at these loci correlates with higher H3K9me3 levels (heterochromatinization) and transcriptional repression; RRP1B upregulation induces global changes in histone methylation.","method":"ChIP-seq (endogenous RRP1B in MDA-MB-231 and HeLa cells), ChIP-reChIP, gene expression analysis","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq in two cell lines with ChIP-reChIP validation and gene expression correlation, multiple orthogonal methods","pmids":["25092915"],"is_preprint":false},{"year":2015,"finding":"Upon influenza A virus infection, RRP1B translocates from the nucleolus to the nucleoplasm. RRP1B interacts with viral RdRp subunits PB1 and PB2, forms a co-immunoprecipitable complex with RdRp, and is required for RdRp binding to cellular capped mRNA; depletion of RRP1B significantly reduces IAV mRNA transcription.","method":"shRNA knockdown, co-immunoprecipitation, minireplicon assay, capped-mRNA association assay, immunofluorescence","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional minireplicon assay plus loss-of-function, single lab, multiple orthogonal methods","pmids":["26311876"],"is_preprint":false},{"year":2019,"finding":"RRP1B mediates the effect of DOCK1 knockdown on claudin-1 re-expression, cell viability, and motility in claudin-low breast cancer cells, placing RRP1B in a DOCK1–RRP1B–DNMT–claudin-1 pathway; DOCK1 knockdown decreased DNMT expression and increased claudin-1 promoter activity via RRP1B.","method":"shRNA knockdown of DOCK1 and RRP1B, claudin-1 promoter activity assay, cell viability and motility assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double knockdown) with promoter activity assay and functional readouts, single lab","pmids":["31717460"],"is_preprint":false},{"year":1997,"finding":"The NNP-1 protein (RRP1B) was shown by immunocytochemistry to have a nuclear localization and encodes a ~52 kDa protein with sequence similarity to C. elegans C47E12.7 and S. cerevisiae YD78.","method":"Immunocytochemistry, Northern blot, genomic mapping","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (immunocytochemistry) for localization, no functional consequence linked","pmids":["9192856"],"is_preprint":false}],"current_model":"RRP1B is a nucleolar/chromatin-associated protein that (1) targets PP1β/γ to the granular component of the nucleolus via a pre-60S ribosomal processing complex to regulate ribosome biogenesis through reversible phosphorylation; (2) suppresses metastasis-associated transcription by binding chromatin together with TRIM28/KAP1 and HP1α to promote H3K9me3-mediated heterochromatinization and gene repression; (3) regulates alternative mRNA splicing through a physical interaction with SRSF1; (4) is transcriptionally induced by E2F1 and forms a complex with E2F1 on proapoptotic target gene promoters to facilitate DNA-damage-induced apoptosis; (5) interacts with SIPA1 to modulate ECM gene expression and metastatic dissemination; and (6) upon influenza A virus infection, translocates to the nucleoplasm, associates with the viral RdRp (PB1/PB2), and facilitates viral mRNA transcription by promoting capped-mRNA recruitment."},"narrative":{"mechanistic_narrative":"RRP1B is a nucleolar and chromatin-associated protein that couples ribosome biogenesis to transcriptional and post-transcriptional gene regulation, with a recurrent role as a breast cancer metastasis modifier [PMID:18081427, PMID:25092915]. In the nucleolus it serves as a regulatory targeting subunit that recruits the catalytic phosphatases PP1β and PP1γ to the granular component in an RNase-dependent manner, within a complex enriched for large (60S) ribosomal subunit proteins and pre-60S nonribosomal factors involved in mid-to-late rRNA processing [PMID:20926688]. On chromatin, RRP1B binds genome-wide and co-occupies loci with TRIM28/KAP1 and HP1α (CBX5), where its occupancy correlates with elevated H3K9me3 and transcriptional repression, and its upregulation drives global histone methylation changes — establishing it as a heterochromatin-promoting transcriptional modulator [PMID:19710015, PMID:25092915]. RRP1B also influences gene output at the RNA level through a physical interaction with the splicing regulator SRSF1, with loss of RRP1B altering alternative isoform usage across hundreds of cell-cycle and checkpoint genes [PMID:23604122]. It is a transcriptional target of E2F1 and forms a complex with E2F1 on proapoptotic promoters, a function required for E2F1-induced, DNA-damage-associated apoptosis [PMID:20040599]. Beyond its endogenous roles, RRP1B is co-opted during influenza A virus infection, translocating to the nucleoplasm, binding the viral RdRp subunits PB1 and PB2, and facilitating viral capped-mRNA recruitment and mRNA transcription [PMID:26311876].","teleology":[{"year":1997,"claim":"Established the basic identity and subcellular address of the protein, defining RRP1B (NNP-1) as a nuclear ~52 kDa protein conserved from yeast to worm.","evidence":"Immunocytochemistry, Northern blot, and genomic mapping","pmids":["9192856"],"confidence":"Low","gaps":["Single localization method with no functional readout","No molecular activity or interaction partners defined","Nucleolar versus nucleoplasmic distribution not resolved"]},{"year":2007,"claim":"Linked RRP1B to metastasis biology by identifying it as a physical and functional partner of the metastasis modifier SIPA1 that alters ECM gene expression and tumor dissemination.","evidence":"Yeast two-hybrid, co-IP, and metastasis functional assays in mouse mammary tumor cells","pmids":["18081427"],"confidence":"Medium","gaps":["Molecular mechanism linking SIPA1 binding to ECM gene changes unresolved","Direct chromatin or transcriptional target not yet defined","Reliance on ectopic overexpression"]},{"year":2009,"claim":"Defined RRP1B as a chromatin-associated factor by cataloguing its nucleosome-binding partners (H1X, PARP1, TRIM28/KAP1, CSDA, HP1α, acetyl-H4K5), positioning it within heterochromatin machinery.","evidence":"Tandem affinity purification, co-immunofluorescence, co-IP","pmids":["19710015"],"confidence":"Medium","gaps":["Interactome from single lab without genome-wide occupancy yet","Functional consequence of each interaction not dissected","Direct versus indirect binding not distinguished for all partners"]},{"year":2009,"claim":"Connected an RRP1B survival-associated allelic variant to differential modulation of TRIM28/CSDA-controlled transcription, framing RRP1B as a dynamic chromatin and transcription modulator.","evidence":"Gene expression comparison of wild-type versus variant RRP1B ectopic expression in HeLa cells","pmids":["19710015"],"confidence":"Low","gaps":["Single method (expression profiling) with no direct biochemical mechanism","Causal link between variant and chromatin state not established","Clinical association is correlative"]},{"year":2009,"claim":"Placed RRP1B in the DNA-damage apoptotic response as an E2F1 transcriptional target that complexes with E2F1 on proapoptotic promoters and is required for E2F1-induced apoptosis.","evidence":"Promoter characterization, co-IP, ChIP, and knockdown apoptosis assays","pmids":["20040599"],"confidence":"Medium","gaps":["How RRP1B enhances E2F1 activity at promoters mechanistically unclear","Relationship between this nuclear pool and nucleolar functions undefined","Specific proapoptotic targets requiring RRP1B not fully mapped"]},{"year":2010,"claim":"Resolved a concrete molecular activity by showing RRP1B is a nucleolar targeting subunit for PP1β/PP1γ, linking it to reversible phosphorylation of the pre-60S rRNA processing machinery.","evidence":"GFP live-cell imaging, SILAC quantitative proteomics, reciprocal co-IP, fractionation","pmids":["20926688"],"confidence":"High","gaps":["Phosphatase substrates within the 60S processing complex not identified","Functional outcome of PP1 targeting on rRNA maturation not directly measured","Isoform specificity mechanism for PP1β/γ selection unresolved"]},{"year":2013,"claim":"Extended RRP1B regulation to the RNA level, showing it binds SRSF1 and shapes alternative splicing of hundreds of cell-cycle and checkpoint genes.","evidence":"Co-IP, co-IF, RNA-seq of knockdown cells, isoform-specific RT-PCR","pmids":["23604122"],"confidence":"Medium","gaps":["Direct RNA-binding by RRP1B versus SRSF1-mediated effect not separated","Mechanism by which transcriptional inhibition increases the interaction unclear","Splicing changes not linked to specific phenotypic outcomes"]},{"year":2014,"claim":"Provided genome-wide evidence that RRP1B promotes heterochromatinization, co-occupying loci with TRIM28/KAP1 and HP1α where it correlates with H3K9me3 and gene repression.","evidence":"ChIP-seq in MDA-MB-231 and HeLa, ChIP-reChIP, gene expression analysis","pmids":["25092915"],"confidence":"High","gaps":["Whether RRP1B recruits or is recruited by the H3K9 methylation machinery undetermined","Direct effector enzyme for H3K9me3 deposition not identified","Causal direction between occupancy and repression correlative"]},{"year":2015,"claim":"Revealed viral co-option: influenza A virus redistributes RRP1B to the nucleoplasm where it binds the viral RdRp (PB1/PB2) and is required for capped-mRNA recruitment and viral transcription.","evidence":"shRNA knockdown, co-IP, minireplicon assay, capped-mRNA association assay, immunofluorescence","pmids":["26311876"],"confidence":"Medium","gaps":["Trigger and machinery driving nucleolar-to-nucleoplasm relocalization unknown","Whether RRP1B directly contacts capped mRNA or bridges RdRp unclear","Relationship of this function to its endogenous chromatin roles unaddressed"]},{"year":2019,"claim":"Embedded RRP1B in a metastasis-suppression signaling axis, showing it mediates DOCK1-knockdown-driven claudin-1 re-expression through a DOCK1–RRP1B–DNMT–claudin-1 pathway.","evidence":"Double shRNA knockdown epistasis, claudin-1 promoter activity, viability and motility assays","pmids":["31717460"],"confidence":"Medium","gaps":["Direct biochemical link between RRP1B and DNMT regulation not shown","Whether RRP1B acts on the claudin-1 locus directly unresolved","Mechanism connecting cytoplasmic DOCK1 signaling to nuclear RRP1B undefined"]},{"year":null,"claim":"How RRP1B's distinct activities — nucleolar PP1 targeting in ribosome biogenesis, chromatin-based heterochromatin repression, splicing regulation, and E2F1-dependent apoptosis — are functionally integrated or switched between, and which is rate-limiting for its metastasis-modifier role, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model coordinating nucleolar versus chromatin pools","Direct catalytic substrates and RNA targets undefined","Structural basis for partner selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7]}],"complexes":["RRP1B-PP1 (PP1β/PP1γ) nucleolar complex","pre-60S ribosomal processing complex","TRIM28/KAP1-HP1α heterochromatin complex","influenza A virus RdRp (PB1/PB2) complex"],"partners":["SIPA1","TRIM28","CBX5","PARP1","SRSF1","E2F1","PB1","PB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14684","full_name":"Ribosomal RNA processing protein 1 homolog B","aliases":["RRP1-like protein B"],"length_aa":758,"mass_kda":84.4,"function":"Positively regulates DNA damage-induced apoptosis by acting as a transcriptional coactivator of proapoptotic target genes of the transcriptional activator E2F1 (PubMed:20040599). Likely to play a role in ribosome biogenesis by targeting serine/threonine protein phosphatase PP1 to the nucleolus (PubMed:20926688). Involved in regulation of mRNA splicing (By similarity). Inhibits SIPA1 GTPase activity (By similarity). Involved in regulating expression of extracellular matrix genes (By similarity). Associates with chromatin and may play a role in modulating chromatin structure (PubMed:19710015) (Microbial infection) Following influenza A virus (IAV) infection, promotes viral mRNA transcription by facilitating the binding of IAV RNA-directed RNA polymerase to capped mRNA","subcellular_location":"Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q14684/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RRP1B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"RRP1","ensg_id":"ENSG00000160214","cell_line_id":"CID000861","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"ATG4B","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP19","stoichiometry":0.2},{"gene":"SRP68","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000861","total_profiled":1310},"omim":[{"mim_id":"610654","title":"RIBOSOMAL RNA-PROCESSING 1B; RRP1B","url":"https://www.omim.org/entry/610654"},{"mim_id":"189971","title":"E2F TRANSCRIPTION FACTOR 1; E2F1","url":"https://www.omim.org/entry/189971"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRP1B"},"hgnc":{"alias_symbol":["Nnp1","RRP1","PPP1R136"],"prev_symbol":["KIAA0179"]},"alphafold":{"accession":"Q14684","domains":[{"cath_id":"-","chopping":"9-173","consensus_level":"high","plddt":91.7681,"start":9,"end":173},{"cath_id":"-","chopping":"185-228_295-337","consensus_level":"medium","plddt":85.992,"start":185,"end":337}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14684","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14684-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14684-F1-predicted_aligned_error_v6.png","plddt_mean":59.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRP1B","jax_strain_url":"https://www.jax.org/strain/search?query=RRP1B"},"sequence":{"accession":"Q14684","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14684.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14684/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14684"}},"corpus_meta":[{"pmid":"18081427","id":"PMC_18081427","title":"Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.","date":"2007","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18081427","citation_count":76,"is_preprint":false},{"pmid":"20926688","id":"PMC_20926688","title":"RRP1B targets PP1 to mammalian cell nucleoli and is associated with Pre-60S ribosomal subunits.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20926688","citation_count":37,"is_preprint":false},{"pmid":"19710015","id":"PMC_19710015","title":"The metastasis efficiency modifier ribosomal RNA processing 1 homolog B (RRP1B) is a chromatin-associated factor.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19710015","citation_count":30,"is_preprint":false},{"pmid":"20040599","id":"PMC_20040599","title":"Regulation of E2F1-induced apoptosis by the nucleolar protein RRP1B.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20040599","citation_count":29,"is_preprint":false},{"pmid":"26311876","id":"PMC_26311876","title":"A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26311876","citation_count":28,"is_preprint":false},{"pmid":"31717460","id":"PMC_31717460","title":"DOCK1 Regulates Growth and Motility through the RRP1B-Claudin-1 Pathway in Claudin-Low Breast Cancer Cells.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31717460","citation_count":21,"is_preprint":false},{"pmid":"23604122","id":"PMC_23604122","title":"RRP1B is a metastasis modifier that regulates the expression of alternative mRNA isoforms through interactions with SRSF1.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23604122","citation_count":19,"is_preprint":false},{"pmid":"15606508","id":"PMC_15606508","title":"Upregulation of the NNP-1 (novel nuclear protein-1, D21S2056E) gene in keloid tissue determined by cDNA microarray and in situ hybridization.","date":"2004","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15606508","citation_count":16,"is_preprint":false},{"pmid":"25092915","id":"PMC_25092915","title":"Metastasis-associated protein ribosomal RNA processing 1 homolog B (RRP1B) modulates metastasis through regulation of histone methylation.","date":"2014","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/25092915","citation_count":15,"is_preprint":false},{"pmid":"12209604","id":"PMC_12209604","title":"Novel products of the HUD, HUC, NNP-1 and alpha-internexin genes identified by autologous antibody screening of a pediatric neuroblastoma library.","date":"2002","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12209604","citation_count":13,"is_preprint":false},{"pmid":"9192856","id":"PMC_9192856","title":"The NNP-1 gene (D21S2056E), which encodes a novel nuclear protein, maps in close proximity to the cystatin B gene within the EPM1 and APECED critical region on 21q22.3.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9192856","citation_count":11,"is_preprint":false},{"pmid":"25277657","id":"PMC_25277657","title":"Rrp1B gene polymorphism (1307T>C) in metastatic progression of breast cancer.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25277657","citation_count":7,"is_preprint":false},{"pmid":"26901824","id":"PMC_26901824","title":"The contribution of SIPA1 and RRP1B germline polymorphisms to breast cancer phenotype, lymph node status and survival in a group of Lithuanian young breast cancer patients.","date":"2016","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/26901824","citation_count":7,"is_preprint":false},{"pmid":"38610928","id":"PMC_38610928","title":"Impact of RRP1B Variants on the Phenotype, Progression, and Metastasis of Cervical Cancer.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38610928","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9523,"output_tokens":2527,"usd":0.033237,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9726,"output_tokens":4016,"usd":0.074515,"stage2_stop_reason":"end_turn"},"total_usd":0.107752,"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\": 2007,\n      \"finding\": \"RRP1B physically and functionally interacts with the metastasis modifier SIPA1, as demonstrated by yeast two-hybrid, immunoprecipitation, and functional assays. Ectopic expression of RRP1B in mouse mammary tumor cells significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, functional metastasis assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal yeast two-hybrid plus Co-IP plus functional assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18081427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RRP1B is a chromatin-associated factor that physically interacts with nucleosome-binding proteins including histone H1X, PARP1, TRIM28 (KAP1), CSDA, heterochromatin protein-1α, and acetyl-histone H4 lysine 5, as shown by tandem affinity purification, co-immunofluorescence, and co-immunoprecipitation.\",\n      \"method\": \"Tandem affinity purification, co-immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (TAP, co-IP, co-IF), single lab\",\n      \"pmids\": [\"19710015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An RRP1B allelic variant associated with improved breast cancer survival differentially modulates transcription factors controlled by TRIM28 and CSDA compared with wild-type RRP1B, indicating RRP1B is a dynamic modulator of chromatin structure and transcription.\",\n      \"method\": \"Gene expression analysis comparing wild-type vs. variant RRP1B ectopic expression in HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (gene expression), no direct biochemical mechanism\",\n      \"pmids\": [\"19710015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RRP1B is a transcriptional target of E2F1 and forms a complex with E2F1 on selective proapoptotic target gene promoters inside the nucleolus and nucleoplasmic punctates; RRP1B is required for E2F1-induced apoptosis and for the expression of certain E2F1 proapoptotic target genes in response to DNA-damaging agents.\",\n      \"method\": \"Promoter characterization, co-immunoprecipitation, ChIP, RRP1B knockdown with apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (promoter assay, Co-IP, ChIP, loss-of-function), single lab\",\n      \"pmids\": [\"20040599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RRP1B acts as a novel nucleolar targeting subunit for PP1β and PP1γ (with isoform specificity), targeting PP1 to the granular component of the nucleolus in an RNase-dependent manner. Quantitative proteomics of RRP1B–PP1γ complexes revealed enrichment of large (60S) ribosomal subunit proteins and pre-60S nonribosomal proteins involved in mid-late rRNA processing.\",\n      \"method\": \"GFP-fusion live-cell fluorescence imaging, quantitative proteomics (SILAC-MS), co-immunoprecipitation, fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP combined with quantitative MS proteomics and live-cell imaging, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"20926688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RRP1B physically interacts with the splicing regulator SRSF1 (SF2/ASF), and this interaction is increased by transcriptional inhibitors; knockdown of Rrp1b in mouse mammary tumor cells induces significant alternative isoform expression changes in over 600 genes, particularly in cell cycle and checkpoint regulation pathways.\",\n      \"method\": \"Co-immunoprecipitation, co-immunofluorescence, RNA-sequencing of knockdown vs. control cells, RT-PCR with isoform-specific primers\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus Co-IF plus RNA-seq, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23604122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RRP1B binds chromatin genome-wide and co-occupies loci with TRIM28/KAP1 and HP1α (CBX5); RRP1B occupancy at these loci correlates with higher H3K9me3 levels (heterochromatinization) and transcriptional repression; RRP1B upregulation induces global changes in histone methylation.\",\n      \"method\": \"ChIP-seq (endogenous RRP1B in MDA-MB-231 and HeLa cells), ChIP-reChIP, gene expression analysis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq in two cell lines with ChIP-reChIP validation and gene expression correlation, multiple orthogonal methods\",\n      \"pmids\": [\"25092915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Upon influenza A virus infection, RRP1B translocates from the nucleolus to the nucleoplasm. RRP1B interacts with viral RdRp subunits PB1 and PB2, forms a co-immunoprecipitable complex with RdRp, and is required for RdRp binding to cellular capped mRNA; depletion of RRP1B significantly reduces IAV mRNA transcription.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, minireplicon assay, capped-mRNA association assay, immunofluorescence\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional minireplicon assay plus loss-of-function, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26311876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RRP1B mediates the effect of DOCK1 knockdown on claudin-1 re-expression, cell viability, and motility in claudin-low breast cancer cells, placing RRP1B in a DOCK1–RRP1B–DNMT–claudin-1 pathway; DOCK1 knockdown decreased DNMT expression and increased claudin-1 promoter activity via RRP1B.\",\n      \"method\": \"shRNA knockdown of DOCK1 and RRP1B, claudin-1 promoter activity assay, cell viability and motility assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double knockdown) with promoter activity assay and functional readouts, single lab\",\n      \"pmids\": [\"31717460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The NNP-1 protein (RRP1B) was shown by immunocytochemistry to have a nuclear localization and encodes a ~52 kDa protein with sequence similarity to C. elegans C47E12.7 and S. cerevisiae YD78.\",\n      \"method\": \"Immunocytochemistry, Northern blot, genomic mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (immunocytochemistry) for localization, no functional consequence linked\",\n      \"pmids\": [\"9192856\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRP1B is a nucleolar/chromatin-associated protein that (1) targets PP1β/γ to the granular component of the nucleolus via a pre-60S ribosomal processing complex to regulate ribosome biogenesis through reversible phosphorylation; (2) suppresses metastasis-associated transcription by binding chromatin together with TRIM28/KAP1 and HP1α to promote H3K9me3-mediated heterochromatinization and gene repression; (3) regulates alternative mRNA splicing through a physical interaction with SRSF1; (4) is transcriptionally induced by E2F1 and forms a complex with E2F1 on proapoptotic target gene promoters to facilitate DNA-damage-induced apoptosis; (5) interacts with SIPA1 to modulate ECM gene expression and metastatic dissemination; and (6) upon influenza A virus infection, translocates to the nucleoplasm, associates with the viral RdRp (PB1/PB2), and facilitates viral mRNA transcription by promoting capped-mRNA recruitment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRP1B is a nucleolar and chromatin-associated protein that couples ribosome biogenesis to transcriptional and post-transcriptional gene regulation, with a recurrent role as a breast cancer metastasis modifier [#0, #6]. In the nucleolus it serves as a regulatory targeting subunit that recruits the catalytic phosphatases PP1\\u03b2 and PP1\\u03b3 to the granular component in an RNase-dependent manner, within a complex enriched for large (60S) ribosomal subunit proteins and pre-60S nonribosomal factors involved in mid-to-late rRNA processing [#4]. On chromatin, RRP1B binds genome-wide and co-occupies loci with TRIM28/KAP1 and HP1\\u03b1 (CBX5), where its occupancy correlates with elevated H3K9me3 and transcriptional repression, and its upregulation drives global histone methylation changes \\u2014 establishing it as a heterochromatin-promoting transcriptional modulator [#1, #6]. RRP1B also influences gene output at the RNA level through a physical interaction with the splicing regulator SRSF1, with loss of RRP1B altering alternative isoform usage across hundreds of cell-cycle and checkpoint genes [#5]. It is a transcriptional target of E2F1 and forms a complex with E2F1 on proapoptotic promoters, a function required for E2F1-induced, DNA-damage-associated apoptosis [#3]. Beyond its endogenous roles, RRP1B is co-opted during influenza A virus infection, translocating to the nucleoplasm, binding the viral RdRp subunits PB1 and PB2, and facilitating viral capped-mRNA recruitment and mRNA transcription [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the basic identity and subcellular address of the protein, defining RRP1B (NNP-1) as a nuclear ~52 kDa protein conserved from yeast to worm.\",\n      \"evidence\": \"Immunocytochemistry, Northern blot, and genomic mapping\",\n      \"pmids\": [\"9192856\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single localization method with no functional readout\", \"No molecular activity or interaction partners defined\", \"Nucleolar versus nucleoplasmic distribution not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked RRP1B to metastasis biology by identifying it as a physical and functional partner of the metastasis modifier SIPA1 that alters ECM gene expression and tumor dissemination.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and metastasis functional assays in mouse mammary tumor cells\",\n      \"pmids\": [\"18081427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking SIPA1 binding to ECM gene changes unresolved\", \"Direct chromatin or transcriptional target not yet defined\", \"Reliance on ectopic overexpression\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined RRP1B as a chromatin-associated factor by cataloguing its nucleosome-binding partners (H1X, PARP1, TRIM28/KAP1, CSDA, HP1\\u03b1, acetyl-H4K5), positioning it within heterochromatin machinery.\",\n      \"evidence\": \"Tandem affinity purification, co-immunofluorescence, co-IP\",\n      \"pmids\": [\"19710015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactome from single lab without genome-wide occupancy yet\", \"Functional consequence of each interaction not dissected\", \"Direct versus indirect binding not distinguished for all partners\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected an RRP1B survival-associated allelic variant to differential modulation of TRIM28/CSDA-controlled transcription, framing RRP1B as a dynamic chromatin and transcription modulator.\",\n      \"evidence\": \"Gene expression comparison of wild-type versus variant RRP1B ectopic expression in HeLa cells\",\n      \"pmids\": [\"19710015\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (expression profiling) with no direct biochemical mechanism\", \"Causal link between variant and chromatin state not established\", \"Clinical association is correlative\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed RRP1B in the DNA-damage apoptotic response as an E2F1 transcriptional target that complexes with E2F1 on proapoptotic promoters and is required for E2F1-induced apoptosis.\",\n      \"evidence\": \"Promoter characterization, co-IP, ChIP, and knockdown apoptosis assays\",\n      \"pmids\": [\"20040599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RRP1B enhances E2F1 activity at promoters mechanistically unclear\", \"Relationship between this nuclear pool and nucleolar functions undefined\", \"Specific proapoptotic targets requiring RRP1B not fully mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved a concrete molecular activity by showing RRP1B is a nucleolar targeting subunit for PP1\\u03b2/PP1\\u03b3, linking it to reversible phosphorylation of the pre-60S rRNA processing machinery.\",\n      \"evidence\": \"GFP live-cell imaging, SILAC quantitative proteomics, reciprocal co-IP, fractionation\",\n      \"pmids\": [\"20926688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase substrates within the 60S processing complex not identified\", \"Functional outcome of PP1 targeting on rRNA maturation not directly measured\", \"Isoform specificity mechanism for PP1\\u03b2/\\u03b3 selection unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended RRP1B regulation to the RNA level, showing it binds SRSF1 and shapes alternative splicing of hundreds of cell-cycle and checkpoint genes.\",\n      \"evidence\": \"Co-IP, co-IF, RNA-seq of knockdown cells, isoform-specific RT-PCR\",\n      \"pmids\": [\"23604122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding by RRP1B versus SRSF1-mediated effect not separated\", \"Mechanism by which transcriptional inhibition increases the interaction unclear\", \"Splicing changes not linked to specific phenotypic outcomes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided genome-wide evidence that RRP1B promotes heterochromatinization, co-occupying loci with TRIM28/KAP1 and HP1\\u03b1 where it correlates with H3K9me3 and gene repression.\",\n      \"evidence\": \"ChIP-seq in MDA-MB-231 and HeLa, ChIP-reChIP, gene expression analysis\",\n      \"pmids\": [\"25092915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RRP1B recruits or is recruited by the H3K9 methylation machinery undetermined\", \"Direct effector enzyme for H3K9me3 deposition not identified\", \"Causal direction between occupancy and repression correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed viral co-option: influenza A virus redistributes RRP1B to the nucleoplasm where it binds the viral RdRp (PB1/PB2) and is required for capped-mRNA recruitment and viral transcription.\",\n      \"evidence\": \"shRNA knockdown, co-IP, minireplicon assay, capped-mRNA association assay, immunofluorescence\",\n      \"pmids\": [\"26311876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger and machinery driving nucleolar-to-nucleoplasm relocalization unknown\", \"Whether RRP1B directly contacts capped mRNA or bridges RdRp unclear\", \"Relationship of this function to its endogenous chromatin roles unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Embedded RRP1B in a metastasis-suppression signaling axis, showing it mediates DOCK1-knockdown-driven claudin-1 re-expression through a DOCK1\\u2013RRP1B\\u2013DNMT\\u2013claudin-1 pathway.\",\n      \"evidence\": \"Double shRNA knockdown epistasis, claudin-1 promoter activity, viability and motility assays\",\n      \"pmids\": [\"31717460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between RRP1B and DNMT regulation not shown\", \"Whether RRP1B acts on the claudin-1 locus directly unresolved\", \"Mechanism connecting cytoplasmic DOCK1 signaling to nuclear RRP1B undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRP1B's distinct activities \\u2014 nucleolar PP1 targeting in ribosome biogenesis, chromatin-based heterochromatin repression, splicing regulation, and E2F1-dependent apoptosis \\u2014 are functionally integrated or switched between, and which is rate-limiting for its metastasis-modifier role, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model coordinating nucleolar versus chromatin pools\", \"Direct catalytic substrates and RNA targets undefined\", \"Structural basis for partner selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\n      \"RRP1B-PP1 (PP1\\u03b2/PP1\\u03b3) nucleolar complex\",\n      \"pre-60S ribosomal processing complex\",\n      \"TRIM28/KAP1-HP1\\u03b1 heterochromatin complex\",\n      \"influenza A virus RdRp (PB1/PB2) complex\"\n    ],\n    \"partners\": [\n      \"SIPA1\",\n      \"TRIM28\",\n      \"CBX5\",\n      \"PARP1\",\n      \"SRSF1\",\n      \"E2F1\",\n      \"PB1\",\n      \"PB2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}