{"gene":"RRP12","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2014,"finding":"RRP12 is a component of pre-40S ribosomal subunit precursors. Inhibition or co-depletion of CK1δ and CK1ε results in failure to recycle RRP12 (along with other trans-acting factors including ENP1/BYSL, LTV1, DIM2/PNO1, RIO2, and NOB1) from pre-40S particles after nuclear export, demonstrating RRP12's role in late cytoplasmic 40S maturation steps.","method":"Tandem affinity purification of pre-40S particles, shRNA-mediated co-depletion of CK1δ/CK1ε, pre-rRNA processing analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal purification combined with functional depletion and pre-rRNA processing readout; independently consistent with findings from PMID:21097556","pmids":["24424021"],"is_preprint":false},{"year":2010,"finding":"Human RRP12 (a HEAT-repeat nuclear protein) associates with late pre-40S ribosomal precursors. Upon loss of the pre-40S-associated kinase Rio2, increased levels of RRP12 are trapped on late 40S precursors, RRP12 is partially mislocalized to the cytoplasm, and fails to efficiently recycle back to the nucleus, placing RRP12 in the late cytoplasmic 40S maturation pathway downstream of Rio2.","method":"TAP purification of pre-40S particles combined with inducible shRNA-mediated depletion of Rio2; subcellular localization by immunofluorescence; proteomic identification of pre-40S components","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — TAP purification combined with shRNA depletion and localization analysis in a single rigorous study with clear mechanistic readout","pmids":["21097556"],"is_preprint":false},{"year":2014,"finding":"Yeast Rrp12 is required for the exit of pre-40S particles to the cytoplasm and for proper maturation dynamics of upstream 90S pre-ribosomes. In vivo elimination of Rrp12 leads to accumulation of nucleoplasmic 90S-to-pre-40S transitional particles, abnormal 35S pre-rRNA processing, delayed elimination of processing byproducts, and complete block of pre-40S export. The exportin Crm1 is required for the same pre-ribosome maturation events, indicating Rrp12 and Crm1 cooperate in both nuclear export and earlier nucleolar biosynthetic steps.","method":"Yeast genetics (conditional depletion), pre-rRNA processing analysis (Northern blot), fluorescence microscopy of pre-40S localization, genetic epistasis with crm1 mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, Northern blot, microscopy, epistasis) in a focused mechanistic study","pmids":["25474739"],"is_preprint":false},{"year":2011,"finding":"Yeast Rrp12 plays a ribosome-synthesis-independent role in cell cycle progression and the DNA damage response by participating in a karyopherin Kap121-dependent nuclear import route that is crucial for nuclear sequestration of ribonucleotide reductase subunits, thereby ensuring proper kinetics of deoxyribonucleotide production during the cell cycle. Rrp12 acts as a cofactor for the full functionality of Kap121 in this import route, mechanistically distinct from its role in ribosome biogenesis.","method":"Yeast functional screen, genetic epistasis, nuclear import assays, analysis of ribonucleotide reductase localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast functional screen with genetic epistasis and mechanistic follow-up distinguishing ribosomal vs. non-ribosomal functions","pmids":["21482668"],"is_preprint":false},{"year":2008,"finding":"Yeast Rrp12 (a HEAT-repeat/Armadillo-domain export factor) and the KH-domain protein DIM2 are both involved in the nucleocytoplasmic translocation of pre-40S ribosomes. Both are nucleolar-restricted (entrapped) upon nutritional, osmotic, and oxidative stress, and upon rapamycin treatment, establishing that the TOR signaling cascade controls their subcellular distribution and thereby regulates pre-40S ribosome export.","method":"Subcellular localization by fluorescence microscopy under stress/rapamycin treatment; pre-40S export assays; genetic analysis of TOR pathway control","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments under multiple conditions (nutritional, osmotic, oxidative stress, rapamycin) combined with functional pre-40S export assay and TOR pathway epistasis","pmids":["18755838"],"is_preprint":false},{"year":2019,"finding":"In yeast, the S0-cluster of ribosomal proteins (around rpS0/uS2) at the SSU 'neck' is specifically required for efficient release of the two nuclear export factors Rrp12 and Slx9 from late SSU precursors, and for correct incorporation of the late-acting biogenesis factor Rio2. Incomplete assembly of the S0-cluster specifically impairs Rrp12/Slx9 release, identifying an r-protein assembly checkpoint controlling Rrp12 dissociation.","method":"Semi-quantitative proteomics of affinity-purified Rio2-associated SSU precursors from r-protein deletion strains; complementary biochemical co-precipitation approaches","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — semi-quantitative proteomics with complementary biochemical validation in a single lab study","pmids":["30653518"],"is_preprint":false},{"year":2022,"finding":"Cms1 was identified as a null suppressor of a nop14 mutant impaired in Rrp12-Enp1 factor recruitment to the 90S pre-ribosome. Cms1 associates with the 18S rRNA 3' major domain of an early 90S and restricts premature Rrp12-Enp1 binding to this domain, allowing snR83 to perform pseudouridylation modifications before subsequent 90S assembly steps coupled with Cms1 release occur. Thus, Rrp12-Enp1 are identified as a functional unit that encircles the 3' major domain in the mature 90S.","method":"Suppressor genetics (null suppressor screen), co-precipitation/affinity purification, cryo-EM structural analysis of 90S particles, rRNA processing assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — suppressor genetics combined with structural (cryo-EM) and biochemical co-precipitation, multiple orthogonal methods placing Rrp12-Enp1 in a defined 90S assembly step","pmids":["36417864"],"is_preprint":false},{"year":2015,"finding":"In human osteosarcoma (U2OS) cells, RRP12 overexpression suppresses p53 stability and activity during cytotoxic stress (doxorubicin or actinomycin D-induced nucleolar disruption), whereas RRP12 silencing enhances p53 activity, cell cycle arrest, and apoptosis. This demonstrates that RRP12 promotes cell survival during nucleolar stress via repression of p53 stability.","method":"RRP12 overexpression and siRNA knockdown in U2OS cells; cytotoxic drug treatment; cell viability, apoptosis, and p53 activity assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function in human cells with p53 activity readout; single lab, no direct biochemical mechanism for p53 suppression established","pmids":["26499779"],"is_preprint":false},{"year":2023,"finding":"In colorectal cancer cells, knockdown of RRP12 suppresses cell migration and invasion, and reverses metastasis in vivo. RRP12 promotes the epithelial-mesenchymal transition (EMT) process in a ZEB1-mediated manner, as RRP12 knockdown reduces ZEB1 levels and alters EMT-related markers.","method":"RRP12 knockdown (siRNA/shRNA) in CRC cell lines; migration/invasion assays; in vivo metastasis model; Western blot for EMT markers and ZEB1; bioinformatic pathway analysis","journal":"Journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and ZEB1 pathway placement; single lab, no direct biochemical interaction established between RRP12 and ZEB1","pmids":["37969827"],"is_preprint":false},{"year":2025,"finding":"Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications in humans. Patient-derived fibroblasts show significant reduction in RRP12 protein levels and abnormal nucleolar morphology. In a zebrafish knockdown model, rrp12 loss causes severe developmental delay, crimping, and early lethality, consistent with an essential role in RNA metabolism.","method":"Exome sequencing and homozygosity mapping; Western blot and immunocytofluorescence on patient fibroblasts; rrp12 morpholino knockdown in zebrafish with phenotypic assessment","journal":"Movement disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with functional validation in patient fibroblasts (nucleolar morphology, protein levels) and zebrafish model; single study but multiple orthogonal approaches","pmids":["41059649"],"is_preprint":false},{"year":2021,"finding":"RRP12 knockdown in adenoma organoids impedes cell viability and proliferation, establishing a functional role for RRP12 in supporting proliferation in early colorectal neoplasia. RRP12 protein was identified as upregulated in the normal-to-adenoma transition by quantitative proteomics.","method":"TMT-based quantitative proteomics of tissue specimens; RRP12 knockdown in adenoma organoids with viability/proliferation assays","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, organoid knockdown with proliferation readout but no molecular pathway placement beyond general proliferation","pmids":["34194496"],"is_preprint":false}],"current_model":"RRP12 is a conserved HEAT-repeat/Armadillo-domain nucleolar protein that functions as a trans-acting factor in pre-40S ribosomal subunit biogenesis: it associates with 90S and pre-40S pre-ribosomal particles in the nucleolus, participates with the exportin Crm1 in coordinating late nucleolar assembly events and nuclear export of pre-40S particles, and must be recycled from cytoplasmic pre-40S intermediates in a process dependent on Rio2 kinase and CK1δ/ε activity; in yeast, RRP12 additionally serves a ribosome-independent function as a Kap121 cofactor for nuclear import of ribonucleotide reductase subunits, coupling ribosome production to dNTP homeostasis; its subcellular distribution is regulated by TOR signaling; in human cells, RRP12 suppresses p53 stability during nucleolar stress and promotes EMT via ZEB1, and biallelic loss-of-function variants cause autosomal recessive brain calcifications with abnormal nucleolar morphology."},"narrative":{"mechanistic_narrative":"RRP12 is a conserved HEAT-repeat/Armadillo-domain nucleolar trans-acting factor in small ribosomal subunit (40S) biogenesis, acting across the pathway from early 90S assembly through nuclear export and late cytoplasmic maturation of pre-40S particles [PMID:25474739, PMID:36417864]. Within the early 90S pre-ribosome, RRP12 and ENP1 function as a unit that encircles the 18S rRNA 3' major domain, and their premature recruitment is restrained by Cms1 to permit ordered rRNA modification and assembly [PMID:36417864]. RRP12 is required for the 90S-to-pre-40S transition and, together with the exportin Crm1, for nucleocytoplasmic export of pre-40S particles [PMID:25474739]. After export, RRP12 must be recycled back to the nucleus from cytoplasmic pre-40S intermediates, a step that depends on the pre-40S kinase Rio2 and on CK1δ/CK1ε activity [PMID:24424021, PMID:21097556]; release of RRP12 from late precursors is gated by assembly of the S0-cluster of ribosomal proteins at the subunit neck [PMID:30653518]. Its nucleolar entrapment under nutritional, osmotic, and oxidative stress places RRP12-dependent pre-40S export under TOR pathway control [PMID:18755838]. Beyond ribosome synthesis, yeast Rrp12 acts as a cofactor for Kap121-dependent nuclear import of ribonucleotide reductase subunits, coupling the cell cycle and DNA damage response to dNTP supply [PMID:21482668]. In human cells RRP12 suppresses p53 stability during nucleolar stress to promote survival [PMID:26499779] and supports proliferation and ZEB1-mediated EMT in colorectal cancer [PMID:37969827]. Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications, with patient fibroblasts showing reduced RRP12 and abnormal nucleolar morphology [PMID:41059649].","teleology":[{"year":2008,"claim":"Established that Rrp12 is a stress- and TOR-responsive pre-40S export factor, linking ribosome subunit transport to nutrient signaling.","evidence":"Fluorescence localization under nutritional/osmotic/oxidative stress and rapamycin, plus pre-40S export assays and TOR epistasis in yeast","pmids":["18755838"],"confidence":"High","gaps":["Direct molecular signal coupling TOR to Rrp12 relocalization not defined","Export receptor partners not identified in this study"]},{"year":2010,"claim":"Placed human RRP12 in the late cytoplasmic 40S maturation pathway downstream of the kinase Rio2, which is required for its recycling back to the nucleus.","evidence":"TAP purification of pre-40S particles with inducible Rio2 depletion and immunofluorescence localization in human cells","pmids":["21097556"],"confidence":"High","gaps":["Whether Rio2 acts directly on RRP12 not shown","Recycling import receptor not identified"]},{"year":2011,"claim":"Identified a ribosome-independent role for Rrp12 as a Kap121 import cofactor for ribonucleotide reductase subunits, coupling ribosome biogenesis machinery to dNTP homeostasis and the DNA damage response.","evidence":"Yeast functional screen, genetic epistasis, nuclear import assays, and RNR localization analysis","pmids":["21482668"],"confidence":"High","gaps":["Direct Rrp12-Kap121 binding interface not mapped","Whether human RRP12 retains this import function untested"]},{"year":2014,"claim":"Demonstrated that CK1δ/CK1ε activity is required to recycle RRP12 and other trans-acting factors from cytoplasmic pre-40S particles, defining a kinase-dependent late maturation step.","evidence":"Tandem affinity purification of pre-40S particles with shRNA co-depletion of CK1δ/CK1ε and pre-rRNA processing analysis","pmids":["24424021"],"confidence":"High","gaps":["Whether RRP12 is a direct CK1 phosphosubstrate not established","Order of factor release not resolved"]},{"year":2014,"claim":"Showed Rrp12 acts not only in pre-40S export but also in earlier nucleolar 90S maturation, cooperating with Crm1 across both steps.","evidence":"Conditional depletion, Northern blot pre-rRNA processing, fluorescence microscopy, and genetic epistasis with crm1 mutants in yeast","pmids":["25474739"],"confidence":"High","gaps":["Molecular nature of Rrp12-Crm1 cooperation at the 90S step unclear","Export cargo recognition mechanism not defined"]},{"year":2019,"claim":"Identified an r-protein assembly checkpoint: the S0-cluster at the subunit neck must be assembled to permit Rrp12 release from late SSU precursors.","evidence":"Semi-quantitative proteomics of Rio2-associated SSU precursors from r-protein deletion strains with biochemical co-precipitation in yeast","pmids":["30653518"],"confidence":"Medium","gaps":["Structural basis of S0-cluster-dependent Rrp12 release not resolved","Single-lab study without orthogonal in vivo confirmation"]},{"year":2022,"claim":"Resolved the early 90S role: RRP12-ENP1 form a functional unit encircling the 18S 3' major domain, with Cms1 restraining their premature binding to allow ordered rRNA modification.","evidence":"Null-suppressor genetics, co-precipitation, cryo-EM of 90S particles, and rRNA processing assays in yeast","pmids":["36417864"],"confidence":"High","gaps":["Trigger for RRP12-ENP1 stable engagement after Cms1 release not defined","Human conservation of the Cms1-regulated step untested"]},{"year":2015,"claim":"Connected human RRP12 to nucleolar stress signaling, showing it represses p53 stability to promote survival under cytotoxic stress.","evidence":"RRP12 overexpression and siRNA knockdown in U2OS cells with doxorubicin/actinomycin D treatment and p53 activity, apoptosis, and viability assays","pmids":["26499779"],"confidence":"Medium","gaps":["No direct biochemical mechanism for p53 suppression established","Whether the effect requires RRP12's ribosome biogenesis function unknown"]},{"year":2021,"claim":"Linked RRP12 upregulation to proliferation in early colorectal neoplasia.","evidence":"TMT quantitative proteomics of tissue and RRP12 knockdown in adenoma organoids with viability/proliferation assays","pmids":["34194496"],"confidence":"Low","gaps":["No molecular pathway placement beyond general proliferation","Single-lab organoid study without mechanistic readout"]},{"year":2023,"claim":"Extended the cancer role, showing RRP12 promotes migration, invasion, and metastasis through ZEB1-mediated EMT.","evidence":"RRP12 knockdown in CRC cell lines, migration/invasion assays, in vivo metastasis model, and EMT/ZEB1 Western blots","pmids":["37969827"],"confidence":"Medium","gaps":["No direct biochemical interaction between RRP12 and ZEB1 demonstrated","Mechanism linking ribosome-biogenesis factor to ZEB1 regulation unknown"]},{"year":2025,"claim":"Established RRP12 as a human disease gene, with biallelic loss-of-function causing autosomal recessive brain calcifications linked to disrupted nucleolar function.","evidence":"Exome sequencing and homozygosity mapping, patient-fibroblast protein and nucleolar morphology analysis, and zebrafish rrp12 morpholino knockdown","pmids":["41059649"],"confidence":"Medium","gaps":["Mechanism connecting ribosome biogenesis defect to brain calcification not defined","Morpholino phenotype lacks genetic rescue confirmation"]},{"year":null,"claim":"How RRP12's conserved role in pre-40S biogenesis mechanistically gives rise to its human disease, p53, and EMT phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct biochemical link established between RRP12 and p53 or ZEB1","Whether disease phenotypes arise from ribosome biogenesis loss versus non-ribosomal functions is unknown","No structural model of human RRP12 in pre-ribosomal particles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,2,4,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,4]}],"complexes":["90S pre-ribosome","pre-40S ribosomal particle"],"partners":["ENP1","CRM1","RIO2","KAP121","CMS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5JTH9","full_name":"RRP12-like protein","aliases":[],"length_aa":1297,"mass_kda":143.7,"function":"","subcellular_location":"Nucleus, nucleolus; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q5JTH9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RRP12","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BYSL","stoichiometry":10.0},{"gene":"TSR1","stoichiometry":4.0},{"gene":"HNRNPU","stoichiometry":0.2},{"gene":"PHF10","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"FAM207A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RRP12","total_profiled":1310},"omim":[{"mim_id":"621452","title":"BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 11, AUTOSOMAL RECESSIVE; IBGC11","url":"https://www.omim.org/entry/621452"},{"mim_id":"620074","title":"LTV1 RIBOSOME BIOGENESIS FACTOR; LTV1","url":"https://www.omim.org/entry/620074"},{"mim_id":"618710","title":"PARTNER OF NOB1; PNO1","url":"https://www.omim.org/entry/618710"},{"mim_id":"617754","title":"RIO KINASE 2; RIOK2","url":"https://www.omim.org/entry/617754"},{"mim_id":"617753","title":"RIO KINASE 1; RIOK1","url":"https://www.omim.org/entry/617753"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":85.9},{"tissue":"skeletal muscle","ntpm":36.0}],"url":"https://www.proteinatlas.org/search/RRP12"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0690"]},"alphafold":{"accession":"Q5JTH9","domains":[{"cath_id":"-","chopping":"393-552","consensus_level":"medium","plddt":92.8314,"start":393,"end":552}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTH9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTH9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5JTH9-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRP12","jax_strain_url":"https://www.jax.org/strain/search?query=RRP12"},"sequence":{"accession":"Q5JTH9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5JTH9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5JTH9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5JTH9"}},"corpus_meta":[{"pmid":"23318442","id":"PMC_23318442","title":"Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23318442","citation_count":229,"is_preprint":false},{"pmid":"28351365","id":"PMC_28351365","title":"Basal-like breast cancer: molecular profiles, clinical features and survival outcomes.","date":"2017","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28351365","citation_count":73,"is_preprint":false},{"pmid":"25149474","id":"PMC_25149474","title":"Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25149474","citation_count":49,"is_preprint":false},{"pmid":"21097556","id":"PMC_21097556","title":"Tandem affinity purification combined with inducible shRNA expression as a tool to study the maturation of macromolecular assemblies.","date":"2010","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21097556","citation_count":41,"is_preprint":false},{"pmid":"24424021","id":"PMC_24424021","title":"CK1δ and CK1ε are components of human 40S subunit precursors required for cytoplasmic 40S maturation.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24424021","citation_count":38,"is_preprint":false},{"pmid":"18755838","id":"PMC_18755838","title":"TOR regulates the subcellular distribution of DIM2, a KH domain protein required for cotranscriptional ribosome assembly and pre-40S ribosome export.","date":"2008","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18755838","citation_count":38,"is_preprint":false},{"pmid":"15643076","id":"PMC_15643076","title":"Separation of the Saccharomyces cerevisiae Paf1 complex from RNA polymerase II results in changes in its subnuclear localization.","date":"2005","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/15643076","citation_count":23,"is_preprint":false},{"pmid":"25474739","id":"PMC_25474739","title":"Rrp12 and the Exportin Crm1 participate in late assembly events in the nucleolus during 40S ribosomal subunit biogenesis.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25474739","citation_count":19,"is_preprint":false},{"pmid":"31897183","id":"PMC_31897183","title":"POLR1B is upregulated and promotes cell proliferation in non-small cell lung cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31897183","citation_count":19,"is_preprint":false},{"pmid":"26499779","id":"PMC_26499779","title":"RRP12 is a crucial nucleolar protein that regulates p53 activity in osteosarcoma cells.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26499779","citation_count":16,"is_preprint":false},{"pmid":"37428302","id":"PMC_37428302","title":"Identification of ZMYND19 as a novel biomarker of colorectal cancer: RNA-sequencing and machine learning analysis.","date":"2023","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/37428302","citation_count":15,"is_preprint":false},{"pmid":"21482668","id":"PMC_21482668","title":"Ribosome synthesis-unrelated functions of the preribosomal factor Rrp12 in cell cycle progression and the DNA damage response.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21482668","citation_count":13,"is_preprint":false},{"pmid":"28472996","id":"PMC_28472996","title":"A survey of proteomic biomarkers for heterotopic ossification in blood serum.","date":"2017","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/28472996","citation_count":13,"is_preprint":false},{"pmid":"30653518","id":"PMC_30653518","title":"Impact of two neighbouring ribosomal protein clusters on biogenesis factor binding and assembly of yeast late small ribosomal subunit precursors.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30653518","citation_count":11,"is_preprint":false},{"pmid":"34194496","id":"PMC_34194496","title":"Exploration of the Key Proteins in the Normal-Adenoma-Carcinoma Sequence of Colorectal Cancer Evolution Using In-Depth Quantitative Proteomics.","date":"2021","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34194496","citation_count":8,"is_preprint":false},{"pmid":"23828040","id":"PMC_23828040","title":"Involvement of Schizosaccharomyces pombe rrp1+ and rrp2+ in the Srs2- and Swi5/Sfr1-dependent pathway in response to DNA damage and replication inhibition.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23828040","citation_count":8,"is_preprint":false},{"pmid":"37969827","id":"PMC_37969827","title":"RRP12 suppresses cell migration and invasion in colorectal cancer cell via regulation of epithelial-mesenchymal transition.","date":"2023","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37969827","citation_count":5,"is_preprint":false},{"pmid":"37498862","id":"PMC_37498862","title":"A comprehensive protein interaction map and druggability investigation prioritized dengue virus NS1 protein as promising therapeutic candidate.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37498862","citation_count":5,"is_preprint":false},{"pmid":"41059649","id":"PMC_41059649","title":"RRP12 Variants Are Associated With Autosomal Recessive Brain Calcifications.","date":"2025","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/41059649","citation_count":3,"is_preprint":false},{"pmid":"36417864","id":"PMC_36417864","title":"Cms1 coordinates stepwise local 90S pre-ribosome assembly with timely snR83 release.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36417864","citation_count":3,"is_preprint":false},{"pmid":"38117080","id":"PMC_38117080","title":"Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a Bioinformatics Study.","date":"2023","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38117080","citation_count":3,"is_preprint":false},{"pmid":"37020999","id":"PMC_37020999","title":"Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37020999","citation_count":3,"is_preprint":false},{"pmid":"42248307","id":"PMC_42248307","title":"LncRNA RRP12-AS regulates UCP1-mediated lipid metabolism through hnRNPA1 and the identification of a functionally conserved human homolog.","date":"2026","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42248307","citation_count":0,"is_preprint":false},{"pmid":"41925913","id":"PMC_41925913","title":"Multi-omics identification of a programmed cell death-related signature and potential target P4HB for bladder cancer based on a 101-combination machine learning and experimental validation.","date":"2026","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41925913","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14756,"output_tokens":3281,"usd":0.046741,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10803,"output_tokens":3744,"usd":0.073807,"stage2_stop_reason":"end_turn"},"total_usd":0.120548,"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\": 2014,\n      \"finding\": \"RRP12 is a component of pre-40S ribosomal subunit precursors. Inhibition or co-depletion of CK1δ and CK1ε results in failure to recycle RRP12 (along with other trans-acting factors including ENP1/BYSL, LTV1, DIM2/PNO1, RIO2, and NOB1) from pre-40S particles after nuclear export, demonstrating RRP12's role in late cytoplasmic 40S maturation steps.\",\n      \"method\": \"Tandem affinity purification of pre-40S particles, shRNA-mediated co-depletion of CK1δ/CK1ε, pre-rRNA processing analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal purification combined with functional depletion and pre-rRNA processing readout; independently consistent with findings from PMID:21097556\",\n      \"pmids\": [\"24424021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human RRP12 (a HEAT-repeat nuclear protein) associates with late pre-40S ribosomal precursors. Upon loss of the pre-40S-associated kinase Rio2, increased levels of RRP12 are trapped on late 40S precursors, RRP12 is partially mislocalized to the cytoplasm, and fails to efficiently recycle back to the nucleus, placing RRP12 in the late cytoplasmic 40S maturation pathway downstream of Rio2.\",\n      \"method\": \"TAP purification of pre-40S particles combined with inducible shRNA-mediated depletion of Rio2; subcellular localization by immunofluorescence; proteomic identification of pre-40S components\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP purification combined with shRNA depletion and localization analysis in a single rigorous study with clear mechanistic readout\",\n      \"pmids\": [\"21097556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Rrp12 is required for the exit of pre-40S particles to the cytoplasm and for proper maturation dynamics of upstream 90S pre-ribosomes. In vivo elimination of Rrp12 leads to accumulation of nucleoplasmic 90S-to-pre-40S transitional particles, abnormal 35S pre-rRNA processing, delayed elimination of processing byproducts, and complete block of pre-40S export. The exportin Crm1 is required for the same pre-ribosome maturation events, indicating Rrp12 and Crm1 cooperate in both nuclear export and earlier nucleolar biosynthetic steps.\",\n      \"method\": \"Yeast genetics (conditional depletion), pre-rRNA processing analysis (Northern blot), fluorescence microscopy of pre-40S localization, genetic epistasis with crm1 mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, Northern blot, microscopy, epistasis) in a focused mechanistic study\",\n      \"pmids\": [\"25474739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Yeast Rrp12 plays a ribosome-synthesis-independent role in cell cycle progression and the DNA damage response by participating in a karyopherin Kap121-dependent nuclear import route that is crucial for nuclear sequestration of ribonucleotide reductase subunits, thereby ensuring proper kinetics of deoxyribonucleotide production during the cell cycle. Rrp12 acts as a cofactor for the full functionality of Kap121 in this import route, mechanistically distinct from its role in ribosome biogenesis.\",\n      \"method\": \"Yeast functional screen, genetic epistasis, nuclear import assays, analysis of ribonucleotide reductase localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast functional screen with genetic epistasis and mechanistic follow-up distinguishing ribosomal vs. non-ribosomal functions\",\n      \"pmids\": [\"21482668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Rrp12 (a HEAT-repeat/Armadillo-domain export factor) and the KH-domain protein DIM2 are both involved in the nucleocytoplasmic translocation of pre-40S ribosomes. Both are nucleolar-restricted (entrapped) upon nutritional, osmotic, and oxidative stress, and upon rapamycin treatment, establishing that the TOR signaling cascade controls their subcellular distribution and thereby regulates pre-40S ribosome export.\",\n      \"method\": \"Subcellular localization by fluorescence microscopy under stress/rapamycin treatment; pre-40S export assays; genetic analysis of TOR pathway control\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments under multiple conditions (nutritional, osmotic, oxidative stress, rapamycin) combined with functional pre-40S export assay and TOR pathway epistasis\",\n      \"pmids\": [\"18755838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In yeast, the S0-cluster of ribosomal proteins (around rpS0/uS2) at the SSU 'neck' is specifically required for efficient release of the two nuclear export factors Rrp12 and Slx9 from late SSU precursors, and for correct incorporation of the late-acting biogenesis factor Rio2. Incomplete assembly of the S0-cluster specifically impairs Rrp12/Slx9 release, identifying an r-protein assembly checkpoint controlling Rrp12 dissociation.\",\n      \"method\": \"Semi-quantitative proteomics of affinity-purified Rio2-associated SSU precursors from r-protein deletion strains; complementary biochemical co-precipitation approaches\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — semi-quantitative proteomics with complementary biochemical validation in a single lab study\",\n      \"pmids\": [\"30653518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cms1 was identified as a null suppressor of a nop14 mutant impaired in Rrp12-Enp1 factor recruitment to the 90S pre-ribosome. Cms1 associates with the 18S rRNA 3' major domain of an early 90S and restricts premature Rrp12-Enp1 binding to this domain, allowing snR83 to perform pseudouridylation modifications before subsequent 90S assembly steps coupled with Cms1 release occur. Thus, Rrp12-Enp1 are identified as a functional unit that encircles the 3' major domain in the mature 90S.\",\n      \"method\": \"Suppressor genetics (null suppressor screen), co-precipitation/affinity purification, cryo-EM structural analysis of 90S particles, rRNA processing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — suppressor genetics combined with structural (cryo-EM) and biochemical co-precipitation, multiple orthogonal methods placing Rrp12-Enp1 in a defined 90S assembly step\",\n      \"pmids\": [\"36417864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In human osteosarcoma (U2OS) cells, RRP12 overexpression suppresses p53 stability and activity during cytotoxic stress (doxorubicin or actinomycin D-induced nucleolar disruption), whereas RRP12 silencing enhances p53 activity, cell cycle arrest, and apoptosis. This demonstrates that RRP12 promotes cell survival during nucleolar stress via repression of p53 stability.\",\n      \"method\": \"RRP12 overexpression and siRNA knockdown in U2OS cells; cytotoxic drug treatment; cell viability, apoptosis, and p53 activity assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function in human cells with p53 activity readout; single lab, no direct biochemical mechanism for p53 suppression established\",\n      \"pmids\": [\"26499779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In colorectal cancer cells, knockdown of RRP12 suppresses cell migration and invasion, and reverses metastasis in vivo. RRP12 promotes the epithelial-mesenchymal transition (EMT) process in a ZEB1-mediated manner, as RRP12 knockdown reduces ZEB1 levels and alters EMT-related markers.\",\n      \"method\": \"RRP12 knockdown (siRNA/shRNA) in CRC cell lines; migration/invasion assays; in vivo metastasis model; Western blot for EMT markers and ZEB1; bioinformatic pathway analysis\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and ZEB1 pathway placement; single lab, no direct biochemical interaction established between RRP12 and ZEB1\",\n      \"pmids\": [\"37969827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications in humans. Patient-derived fibroblasts show significant reduction in RRP12 protein levels and abnormal nucleolar morphology. In a zebrafish knockdown model, rrp12 loss causes severe developmental delay, crimping, and early lethality, consistent with an essential role in RNA metabolism.\",\n      \"method\": \"Exome sequencing and homozygosity mapping; Western blot and immunocytofluorescence on patient fibroblasts; rrp12 morpholino knockdown in zebrafish with phenotypic assessment\",\n      \"journal\": \"Movement disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with functional validation in patient fibroblasts (nucleolar morphology, protein levels) and zebrafish model; single study but multiple orthogonal approaches\",\n      \"pmids\": [\"41059649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRP12 knockdown in adenoma organoids impedes cell viability and proliferation, establishing a functional role for RRP12 in supporting proliferation in early colorectal neoplasia. RRP12 protein was identified as upregulated in the normal-to-adenoma transition by quantitative proteomics.\",\n      \"method\": \"TMT-based quantitative proteomics of tissue specimens; RRP12 knockdown in adenoma organoids with viability/proliferation assays\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, organoid knockdown with proliferation readout but no molecular pathway placement beyond general proliferation\",\n      \"pmids\": [\"34194496\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRP12 is a conserved HEAT-repeat/Armadillo-domain nucleolar protein that functions as a trans-acting factor in pre-40S ribosomal subunit biogenesis: it associates with 90S and pre-40S pre-ribosomal particles in the nucleolus, participates with the exportin Crm1 in coordinating late nucleolar assembly events and nuclear export of pre-40S particles, and must be recycled from cytoplasmic pre-40S intermediates in a process dependent on Rio2 kinase and CK1δ/ε activity; in yeast, RRP12 additionally serves a ribosome-independent function as a Kap121 cofactor for nuclear import of ribonucleotide reductase subunits, coupling ribosome production to dNTP homeostasis; its subcellular distribution is regulated by TOR signaling; in human cells, RRP12 suppresses p53 stability during nucleolar stress and promotes EMT via ZEB1, and biallelic loss-of-function variants cause autosomal recessive brain calcifications with abnormal nucleolar morphology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRP12 is a conserved HEAT-repeat/Armadillo-domain nucleolar trans-acting factor in small ribosomal subunit (40S) biogenesis, acting across the pathway from early 90S assembly through nuclear export and late cytoplasmic maturation of pre-40S particles [#2, #6]. Within the early 90S pre-ribosome, RRP12 and ENP1 function as a unit that encircles the 18S rRNA 3' major domain, and their premature recruitment is restrained by Cms1 to permit ordered rRNA modification and assembly [#6]. RRP12 is required for the 90S-to-pre-40S transition and, together with the exportin Crm1, for nucleocytoplasmic export of pre-40S particles [#2]. After export, RRP12 must be recycled back to the nucleus from cytoplasmic pre-40S intermediates, a step that depends on the pre-40S kinase Rio2 and on CK1\\u03b4/CK1\\u03b5 activity [#0, #1]; release of RRP12 from late precursors is gated by assembly of the S0-cluster of ribosomal proteins at the subunit neck [#5]. Its nucleolar entrapment under nutritional, osmotic, and oxidative stress places RRP12-dependent pre-40S export under TOR pathway control [#4]. Beyond ribosome synthesis, yeast Rrp12 acts as a cofactor for Kap121-dependent nuclear import of ribonucleotide reductase subunits, coupling the cell cycle and DNA damage response to dNTP supply [#3]. In human cells RRP12 suppresses p53 stability during nucleolar stress to promote survival [#7] and supports proliferation and ZEB1-mediated EMT in colorectal cancer [#8]. Biallelic loss-of-function variants in RRP12 cause autosomal recessive brain calcifications, with patient fibroblasts showing reduced RRP12 and abnormal nucleolar morphology [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that Rrp12 is a stress- and TOR-responsive pre-40S export factor, linking ribosome subunit transport to nutrient signaling.\",\n      \"evidence\": \"Fluorescence localization under nutritional/osmotic/oxidative stress and rapamycin, plus pre-40S export assays and TOR epistasis in yeast\",\n      \"pmids\": [\"18755838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular signal coupling TOR to Rrp12 relocalization not defined\", \"Export receptor partners not identified in this study\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed human RRP12 in the late cytoplasmic 40S maturation pathway downstream of the kinase Rio2, which is required for its recycling back to the nucleus.\",\n      \"evidence\": \"TAP purification of pre-40S particles with inducible Rio2 depletion and immunofluorescence localization in human cells\",\n      \"pmids\": [\"21097556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rio2 acts directly on RRP12 not shown\", \"Recycling import receptor not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a ribosome-independent role for Rrp12 as a Kap121 import cofactor for ribonucleotide reductase subunits, coupling ribosome biogenesis machinery to dNTP homeostasis and the DNA damage response.\",\n      \"evidence\": \"Yeast functional screen, genetic epistasis, nuclear import assays, and RNR localization analysis\",\n      \"pmids\": [\"21482668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Rrp12-Kap121 binding interface not mapped\", \"Whether human RRP12 retains this import function untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that CK1\\u03b4/CK1\\u03b5 activity is required to recycle RRP12 and other trans-acting factors from cytoplasmic pre-40S particles, defining a kinase-dependent late maturation step.\",\n      \"evidence\": \"Tandem affinity purification of pre-40S particles with shRNA co-depletion of CK1\\u03b4/CK1\\u03b5 and pre-rRNA processing analysis\",\n      \"pmids\": [\"24424021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RRP12 is a direct CK1 phosphosubstrate not established\", \"Order of factor release not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed Rrp12 acts not only in pre-40S export but also in earlier nucleolar 90S maturation, cooperating with Crm1 across both steps.\",\n      \"evidence\": \"Conditional depletion, Northern blot pre-rRNA processing, fluorescence microscopy, and genetic epistasis with crm1 mutants in yeast\",\n      \"pmids\": [\"25474739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of Rrp12-Crm1 cooperation at the 90S step unclear\", \"Export cargo recognition mechanism not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an r-protein assembly checkpoint: the S0-cluster at the subunit neck must be assembled to permit Rrp12 release from late SSU precursors.\",\n      \"evidence\": \"Semi-quantitative proteomics of Rio2-associated SSU precursors from r-protein deletion strains with biochemical co-precipitation in yeast\",\n      \"pmids\": [\"30653518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of S0-cluster-dependent Rrp12 release not resolved\", \"Single-lab study without orthogonal in vivo confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the early 90S role: RRP12-ENP1 form a functional unit encircling the 18S 3' major domain, with Cms1 restraining their premature binding to allow ordered rRNA modification.\",\n      \"evidence\": \"Null-suppressor genetics, co-precipitation, cryo-EM of 90S particles, and rRNA processing assays in yeast\",\n      \"pmids\": [\"36417864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for RRP12-ENP1 stable engagement after Cms1 release not defined\", \"Human conservation of the Cms1-regulated step untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected human RRP12 to nucleolar stress signaling, showing it represses p53 stability to promote survival under cytotoxic stress.\",\n      \"evidence\": \"RRP12 overexpression and siRNA knockdown in U2OS cells with doxorubicin/actinomycin D treatment and p53 activity, apoptosis, and viability assays\",\n      \"pmids\": [\"26499779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical mechanism for p53 suppression established\", \"Whether the effect requires RRP12's ribosome biogenesis function unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RRP12 upregulation to proliferation in early colorectal neoplasia.\",\n      \"evidence\": \"TMT quantitative proteomics of tissue and RRP12 knockdown in adenoma organoids with viability/proliferation assays\",\n      \"pmids\": [\"34194496\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular pathway placement beyond general proliferation\", \"Single-lab organoid study without mechanistic readout\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the cancer role, showing RRP12 promotes migration, invasion, and metastasis through ZEB1-mediated EMT.\",\n      \"evidence\": \"RRP12 knockdown in CRC cell lines, migration/invasion assays, in vivo metastasis model, and EMT/ZEB1 Western blots\",\n      \"pmids\": [\"37969827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction between RRP12 and ZEB1 demonstrated\", \"Mechanism linking ribosome-biogenesis factor to ZEB1 regulation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established RRP12 as a human disease gene, with biallelic loss-of-function causing autosomal recessive brain calcifications linked to disrupted nucleolar function.\",\n      \"evidence\": \"Exome sequencing and homozygosity mapping, patient-fibroblast protein and nucleolar morphology analysis, and zebrafish rrp12 morpholino knockdown\",\n      \"pmids\": [\"41059649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ribosome biogenesis defect to brain calcification not defined\", \"Morpholino phenotype lacks genetic rescue confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RRP12's conserved role in pre-40S biogenesis mechanistically gives rise to its human disease, p53, and EMT phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical link established between RRP12 and p53 or ZEB1\", \"Whether disease phenotypes arise from ribosome biogenesis loss versus non-ribosomal functions is unknown\", \"No structural model of human RRP12 in pre-ribosomal particles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 2, 4, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\n      \"90S pre-ribosome\",\n      \"pre-40S ribosomal particle\"\n    ],\n    \"partners\": [\n      \"ENP1\",\n      \"CRM1\",\n      \"RIO2\",\n      \"KAP121\",\n      \"CMS1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":8,"faith_pct":87.5}}