{"gene":"MYBBP1A","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"MYBBP1A (p160 Myb-binding protein) was cloned and found to localize predominantly in the nucleolus by immunofluorescence. The p67 N-terminal fragment (generated by proteolytic cleavage in some cell types) but not full-length p160 can inhibit transactivation by c-Myb, indicating that the Myb-binding site lies within the N-terminal 580 residues and the Jun-binding site is C-terminal to that region.","method":"Molecular cloning, immunofluorescence localization, transactivation assays, proteolytic cleavage characterization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cloning and functional characterization with multiple orthogonal methods (immunofluorescence, binding specificity assays, transactivation reporter assays) in the foundational paper","pmids":["9447996"],"is_preprint":false},{"year":2004,"finding":"MYBBP1A (p160MBP) was identified as a direct repressor of PGC-1alpha. MYBBP1A binds PGC-1alpha and suppresses its transcriptional activity, reducing mitochondrial respiration and electron transport gene expression in myoblasts. p38 MAPK phosphorylation of PGC-1alpha disrupts the MYBBP1A–PGC-1alpha interaction, providing a mechanism for p38-mediated activation of PGC-1alpha.","method":"Co-immunoprecipitation, adenoviral overexpression in myoblasts, mitochondrial respiration assay, reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional overexpression with phenotypic readout (respiration), and p38 phosphorylation mechanistic link, single lab but multiple orthogonal methods","pmids":["14744933"],"is_preprint":false},{"year":2006,"finding":"MYBBP1A acts as a co-repressor of NF-κB by directly binding the transcription activation domain of RelA/p65. MYBBP1A repressed NF-κB-dependent transcription from chromatinized templates in vitro at a step before pre-initiation complex formation without affecting RelA/p65 nuclear translocation or DNA binding. MYBBP1A competed with the histone acetyltransferase p300 for interaction with the RelA/p65 transactivation domain.","method":"Co-immunoprecipitation, in vitro transcription from chromatinized templates, reporter assays, competition binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro chromatin transcription assay plus co-IP competition assay, single lab with multiple orthogonal methods","pmids":["17196614"],"is_preprint":false},{"year":2007,"finding":"MYBBP1A (p160) interacts with the homeodomain transcription factor Prep1 and competes with Pbx1 for Prep1 binding in vitro. The N-terminal p67 fragment of p160 binds the HR1 domain of Prep1 at residues LFPLL (L63/L66). MYBBP1A inhibits Prep1-dependent HoxB2 expression. Actinomycin D-induced translocation of p160 from the nucleolus to the nucleoplasm promotes endogenous co-localization and co-immunoprecipitation with Prep1.","method":"Co-immunoprecipitation, in vitro competition binding, reporter assays, immunofluorescence co-localization, mutagenesis of Prep1 binding motif","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis, and functional reporter assays in single lab with multiple orthogonal methods","pmids":["17875935"],"is_preprint":false},{"year":2008,"finding":"MYBBP1A (Mybbp1a) is present in two distinct complexes in cells: a smaller complex containing the processed p67/p140 fragments (lacking nucleolar localization sequences) and a larger complex containing intact p160 associated with ribosomal subunits. Treatment with actinomycin D, cisplatin, or UV (all inhibitors of ribosome biogenesis) induced proteolytic processing of p160 into p140 and p67 and caused translocation of Mybbp1a from the nucleolus to the nucleoplasm. Both complexes contain nucleophosmin and nucleolin; nucleostemin is only in the large complex.","method":"Biochemical purification of complexes, mass spectrometry, immunofluorescence, western blot of processed forms","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Moderate — complex purification with mass spectrometry identification plus cellular localization experiments, single lab multiple methods","pmids":["18173745"],"is_preprint":false},{"year":2009,"finding":"MYBBP1A functions as a co-repressor on the Period2 (Per2) circadian clock gene promoter by interacting with mouse CRY1 (mCRY1). Chromatin immunoprecipitation showed endogenous Mybbp1a binding to the Per2 promoter temporally coinciding with mCRY1 binding and correlated with down-regulation of Per2 expression and dimethylation of histone H3 Lys9.","method":"Affinity purification of mCRY1 complexes, co-immunoprecipitation, reporter assays, chromatin immunoprecipitation (ChIP)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRY1 complex purification, ChIP on endogenous promoter, functional reporter assay, single lab with multiple methods","pmids":["19129230"],"is_preprint":false},{"year":2010,"finding":"MYBBP1A is a substrate of Aurora B kinase; serine 1303 was identified as the major phosphorylation site by mass spectrometry. MYBBP1A is phosphorylated at S1303 in nocodazole-arrested mitotic cells and dephosphorylated upon Aurora B silencing or treatment with the Aurora kinase inhibitor Danusertib. Depletion of MYBBP1A by RNAi causes mitotic progression delay and spindle assembly defects.","method":"In vitro kinase assay, mass spectrometry identification of phosphosite, RNAi knockdown with mitotic phenotype, inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with MS phosphosite identification, confirmed in cells with inhibitor and knockdown, single lab multiple methods","pmids":["20177074"],"is_preprint":false},{"year":2011,"finding":"MYBBP1A is tethered to the nucleolus through nucleolar RNA. Upon nucleolar stress (suppression of rRNA transcription), nucleolar RNA content decreases, MYBBP1A translocates from the nucleolus to the nucleoplasm, and then facilitates p53–p300 interaction to enhance p53 acetylation and p53 accumulation. Depletion of RPL5 or RPL11 blocked rRNA export, maintained nucleolar RNA levels, and thereby prevented MYBBP1A translocation and p53 activation.","method":"RNAi knockdown, immunofluorescence tracking of MYBBP1A localization, co-immunoprecipitation of p53-p300 complex, western blot of p53 acetylation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockdown conditions, localization imaging, and co-IP with functional p53 acetylation readout replicated across perturbations","pmids":["21297583"],"is_preprint":false},{"year":2011,"finding":"Quantitative proteomics identified MYBBP1A (p160 Myb-binding protein) as a novel substrate/target of the VHL ubiquitin ligase complex, suggesting VHL regulates MYBBP1A protein levels.","method":"Quantitative proteomics (SILAC-based ubiquitin ligase substrate identification)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomics screen, no functional validation of ubiquitination mechanism described in abstract","pmids":["21386990"],"is_preprint":false},{"year":2012,"finding":"MYBBP1A is essential for early mouse embryonic development (required prior to blastocyst formation). In HeLa cells, MYBBP1A down-regulation promotes apoptosis, causes G2/M arrest or anomalous mitosis, and affects expression of genes controlling chromosomal segregation. At mitosis, MYBBP1A localizes to a parachromosomal region. In NIH3T3 cells, MYBBP1A down-regulation increases susceptibility to Ras-induced transformation, indicating tumor suppressor activity.","method":"Conditional knockout (embryonic lethal phenotype), siRNA knockdown, gene-expression profiling, cell cycle analysis, immunofluorescence at mitosis, transformation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout in mouse, multiple cell line KD experiments with defined phenotypic readouts, single lab with multiple orthogonal methods","pmids":["23056166"],"is_preprint":false},{"year":2012,"finding":"Mybbp1a associates with the RNA Polymerase I transcription complex and ribosome biogenesis machinery. Mybbp1a represses rRNA gene transcription (shown by reporter assay decoupling transcription from processing) and reduces RNA Pol I loading on rDNA genes (ChIP). Depletion of Mybbp1a causes accumulation of unprocessed rRNA precursor and growth arrest, indicating a dual role in rRNA transcription repression and pre-rRNA processing.","method":"Co-immunoprecipitation with Pol I complex, ChIP for Pol I loading, Pol I reporter assay, siRNA knockdown with rRNA precursor analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, and knockdown with molecular phenotype, single lab multiple orthogonal methods","pmids":["22645127"],"is_preprint":false},{"year":2012,"finding":"Mybbp1a binds to the chromatin around hypermethylated/inactive rDNA gene promoters and maintains rDNA repeats in a silenced state by associating with HDAC1/2. Knockdown of Mybbp1a abrogates local DNA methylation and histone silencing marks, displaces UBF and HDACs from the promoter, and elevates rRNA expression.","method":"ChIP, siRNA knockdown, bisulfite sequencing/methylation analysis, western blot","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP and methylation analysis with knockdown, single lab single set of experiments","pmids":["22686419"],"is_preprint":false},{"year":2013,"finding":"MYBBP1A enhances p53 tetramerization and subsequent p300-mediated acetylation in response to nucleolar stress. MYBBP1A has two regions that directly bind lysine residues of the p53 C-terminal regulatory domain. MYBBP1A forms self-assembled complexes that provide a molecular platform for p53 tetramer formation, and tetramerization is required for efficient p53 acetylation and cell death.","method":"Co-immunoprecipitation, in vitro binding assays, size-exclusion chromatography for tetramer analysis, deletion mapping, cell death assays with actinomycin D","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding mapping with deletion mutants, in vitro tetramerization assay, and functional cell death readout, single lab multiple methods","pmids":["24375404"],"is_preprint":false},{"year":2013,"finding":"MYBBP1A binds to Sirt7 in vitro and in vivo (co-IP), and inhibits Sirt7-mediated deacetylation of histone H3K18. The N- and C-terminal regions of Sirt7 and the C-terminal region of Mybbp1a are required for this interaction.","method":"Co-immunoprecipitation (in vivo), in vitro binding assay, serial deletion mapping, histone deacetylation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding and co-IP with functional deacetylation assay, single lab single study","pmids":["24134843"],"is_preprint":false},{"year":2013,"finding":"MYBBP1A binds p53 and enhances p53 target gene transcription under anoikis conditions. MYBBP1A knockdown in breast cancer cells with wild-type p53 (MCF-7, ZR-75-1) enhanced tumorigenesis, colony formation, and anoikis resistance.","method":"Co-immunoprecipitation, siRNA knockdown, colony formation assay, xenograft assay, anoikis assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus multiple functional assays (anoikis, colony formation, xenograft), single lab","pmids":["23388179"],"is_preprint":false},{"year":2014,"finding":"ANK (progressive ankylosis protein) interacts with MYBBP1a via its cytoplasmic C-terminal loop. MYBBP1a nuclear levels are regulated by the ANK interaction; loss of ANK/MYBBP1a interaction (in ank/ank chondrocytes) increases nuclear MYBBP1a, decreases NF-κB activity, and reduces catabolic marker expression and cartilage degradation in IL-1β-treated chondrocytes.","method":"Yeast two-hybrid screening, co-immunoprecipitation, immunohistochemistry/immunoblotting for MYBBP1a nuclear/cytoplasmic distribution, NF-κB reporter assay, transfection with mutant ank constructs","journal":"Osteoarthritis and cartilage","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, functional rescue with mutant constructs, single lab","pmids":["24747173"],"is_preprint":false},{"year":2015,"finding":"Gradual reduction in rRNA transcription (not rRNA processing inhibition) triggers MYBBP1A translocation from the nucleolus to the nucleoplasm. MYBBP1A translocation correlates with increased p53 acetylation, p21 and BAX induction, and apoptosis. In contrast, when rRNA processing is inhibited (nucleolar RNA levels maintained), MYBBP1A remains in the nucleolus, p53 accumulates without acetylation, and cells undergo G1 arrest rather than apoptosis.","method":"RNAi depletion of rRNA transcription/processing factors, immunofluorescence for MYBBP1A localization, western blot for p53 acetylation and p21/BAX, flow cytometry for cell cycle/apoptosis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic comparison of multiple perturbations with paired localization and functional readouts, mechanistically distinguishes two distinct nucleolar stress responses","pmids":["26044764"],"is_preprint":false},{"year":2019,"finding":"MYBBP1A directly represses PGC-1α and also represses c-MYB, which in turn regulates PGC-1α mRNA levels. Loss of MYBBP1A simultaneously relieves both modes of repression, causing a metabolic switch from glycolysis to OXPHOS in renal cancer cells. This effect is selective to cells expressing high c-MYB levels.","method":"siRNA knockdown, gene expression analysis, metabolic assays (glycolysis vs OXPHOS), xenograft models","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockdown with metabolic phenotype and in vivo xenograft, single lab","pmids":["31066170"],"is_preprint":false},{"year":2019,"finding":"MYBBP1A loss increases c-MYB transcriptional activity, leading to expansion of the cancer stem cell population in renal carcinoma cells expressing high c-MYB. This increases tumorigenic properties in vitro and in vivo.","method":"siRNA knockdown, stem cell sphere assay, xenograft, gene expression analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional knockdown with defined phenotype, single lab","pmids":["30781655"],"is_preprint":false},{"year":2019,"finding":"MYBBP1A forms a complex with DNMT1 (shown by co-IP) and induces aberrant hypermethylation of CpG islands in the IGFBP5 promoter, suppressing IGFBP5 secretion and thereby activating the IGF1/AKT signaling pathway in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ChIP, bisulfite sequencing/pyrosequencing for CpG methylation, siRNA knockdown with proliferation/migration readout","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and methylation assays with functional pathway readout, single lab multiple methods","pmids":["31109829"],"is_preprint":false},{"year":2024,"finding":"NAT10 induces ac4C modification of Mybbp1a mRNA, increasing Mybbp1a protein stability. Elevated Mybbp1a in turn activates p53 and represses transcription of the anti-ferroptotic gene SLC7A11, promoting cardiomyocyte ferroptosis during ischemia/reperfusion injury. Knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on ferroptosis.","method":"ac4C RNA modification assay, western blot for Mybbp1a stability, co-immunoprecipitation, siRNA knockdown, ferroptosis assay, cardiac I/R mouse model with cardiomyocyte-specific NAT10 KO","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C modification assay, co-IP, and in vivo cardiac model with KO, single lab","pmids":["38583415"],"is_preprint":false},{"year":2024,"finding":"GAS5 lncRNA stabilizes p53 by directly binding to MYBBP1A and facilitating the MYBBP1A–p53 interaction, enhancing p53-mediated transcription of IRF1 and activating type I interferon signaling (CXCL10, CCL5 production) in NSCLC cells.","method":"RNA immunoprecipitation, co-immunoprecipitation, reporter assays, overexpression/knockdown experiments, in vivo tumor models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and RNA-IP with functional downstream readout, single lab","pmids":["38762546"],"is_preprint":false},{"year":1999,"finding":"Human MYBBP1A cDNA was cloned; the protein was mapped to chromosome 17p13.3 by FISH. The gene physically links with the ALOX15 gene locus.","method":"cDNA cloning, fluorescence in situ hybridization (FISH), radiation hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and chromosomal mapping by FISH, standard genomics methods","pmids":["10644447"],"is_preprint":false},{"year":2008,"finding":"In Prep1-hypomorphic mice, reduced Prep1 causes reduced p160 (MYBBP1A) protein levels in skeletal muscle (Prep1 controls p160 protein stability). This reduction in p160 increases PGC-1α and GLUT4 expression in muscle, enhancing insulin sensitivity and glucose uptake. Overexpression of p160 (but not Pbx1) in L6 muscle cells or in vivo reversed the phenotype, confirming that p160 mediates the Prep1 effect on PGC-1α/GLUT4.","method":"Hypomorphic mouse model, in vivo muscle delivery of p160 cDNA, L6 cell overexpression, glucose uptake assay, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model plus in vivo rescue with p160 cDNA and cell line overexpression, multiple orthogonal approaches","pmids":["18644868"],"is_preprint":false}],"current_model":"MYBBP1A is a predominantly nucleolar protein that is tethered to the nucleolus via nucleolar RNA; upon nucleolar stress (reduced rRNA transcription), it translocates to the nucleoplasm where it directly binds and promotes p53 tetramerization and p300-mediated p53 acetylation to trigger apoptosis, represses NF-κB by competing with p300 for RelA/p65, represses PGC-1α and c-MYB transcriptional activity, acts as a co-repressor on circadian (Per2) and ribosomal RNA gene promoters in association with HDACs and CRY1, is phosphorylated by Aurora B kinase at S1303 during mitosis (required for proper spindle assembly), and is subject to ac4C modification by NAT10 (regulating its stability), with its nucleolar-to-nucleoplasmic shuttling serving as a stress-sensing switch that links ribosome biogenesis status to p53 activation and cell fate."},"narrative":{"mechanistic_narrative":"MYBBP1A is a predominantly nucleolar protein that functions as a stress-sensing transcriptional co-repressor coupling ribosome biogenesis status to p53 activation and cell fate [PMID:9447996, PMID:21297583]. Within the nucleolus it associates with the RNA Polymerase I transcription complex and ribosome biogenesis machinery, repressing rRNA gene transcription and reducing Pol I loading on rDNA while also being required for pre-rRNA processing [PMID:22645127], and it maintains silenced rDNA repeats through association with HDAC1/2 and preservation of DNA methylation and histone silencing marks [PMID:22686419]. MYBBP1A is tethered to the nucleolus by nucleolar RNA; when rRNA transcription falls during nucleolar stress, nucleolar RNA content drops and MYBBP1A translocates to the nucleoplasm [PMID:21297583], where it acts as a self-assembling platform that directly binds the p53 C-terminal regulatory domain to promote p53 tetramerization and p300-mediated acetylation, driving p21/BAX induction and apoptosis [PMID:21297583, PMID:24375404]. The nature of the nucleolar insult determines outcome: graded loss of rRNA transcription drives translocation, p53 acetylation and apoptosis, whereas processing inhibition that preserves nucleolar RNA retains MYBBP1A in the nucleolus and yields p53 accumulation without acetylation and G1 arrest [PMID:26044764]. Beyond p53, MYBBP1A is a direct repressor of multiple transcription factors: it binds and represses PGC-1α to limit mitochondrial respiration [PMID:14744933], represses c-MYB transactivation via its N-terminal Myb-binding region [PMID:9447996, PMID:31066170], and competes with p300 for the RelA/p65 transactivation domain to repress NF-κB before pre-initiation complex formation [PMID:17196614]. It also acts as a co-repressor on the Per2 circadian promoter in concert with CRY1 and H3K9 dimethylation [PMID:19129230]. Consistent with these growth-restraining activities, MYBBP1A is essential for early mouse embryonic development and behaves as a tumor suppressor whose loss increases susceptibility to Ras-induced transformation [PMID:23056166]. MYBBP1A is phosphorylated by Aurora B at serine 1303 during mitosis, with its depletion causing spindle assembly defects and mitotic delay [PMID:20177074], and its protein abundance is regulated post-transcriptionally through NAT10-mediated ac4C modification of its mRNA [PMID:38583415].","teleology":[{"year":1998,"claim":"Established MYBBP1A as a nucleolar protein with defined transcription-factor-binding architecture, answering where it resides and what it binds.","evidence":"Molecular cloning, immunofluorescence, and transactivation assays mapping the N-terminal Myb-binding region","pmids":["9447996"],"confidence":"High","gaps":["Did not establish how nucleolar localization relates to function","Physiological role of proteolytic p67 fragment unclear"]},{"year":2004,"claim":"Identified MYBBP1A as a direct repressor of PGC-1α, linking it to metabolic/mitochondrial control and to a p38 MAPK regulatory switch.","evidence":"Reciprocal co-IP, adenoviral overexpression in myoblasts, mitochondrial respiration and reporter assays","pmids":["14744933"],"confidence":"High","gaps":["Binding interface on PGC-1α not mapped","Whether repression occurs at promoter chromatin not addressed"]},{"year":2006,"claim":"Defined a co-repressor mechanism for NF-κB, showing MYBBP1A competes with p300 rather than blocking RelA nuclear entry or DNA binding.","evidence":"In vitro transcription from chromatinized templates plus co-IP competition assays","pmids":["17196614"],"confidence":"High","gaps":["Endogenous NF-κB target genes not profiled","Stimulus dependence of repression untested"]},{"year":2007,"claim":"Showed MYBBP1A extends its co-repressor role to homeodomain factor Prep1 and that actinomycin D-driven nucleoplasmic translocation enables endogenous interaction.","evidence":"Reciprocal co-IP, in vitro competition with Pbx1, binding-motif mutagenesis, and reporter assays","pmids":["17875935"],"confidence":"High","gaps":["Functional consequence on broader Hox program unclear","Translocation trigger mechanism not yet defined"]},{"year":2008,"claim":"Resolved MYBBP1A into distinct full-length and processed complexes and linked ribosome-biogenesis stress to its proteolytic processing and nucleolar-to-nucleoplasmic relocation.","evidence":"Biochemical complex purification with mass spectrometry, immunofluorescence, and processing immunoblots under actinomycin D/cisplatin/UV","pmids":["18173745"],"confidence":"High","gaps":["Protease responsible for processing not identified","Functional difference between complexes not fully defined"]},{"year":2008,"claim":"Genetic mouse model placed MYBBP1A downstream of Prep1 in metabolic control, showing Prep1 controls p160 stability to set PGC-1α/GLUT4 levels and insulin sensitivity.","evidence":"Prep1-hypomorphic mice with in vivo and L6 cell p160 rescue and glucose uptake assays","pmids":["18644868"],"confidence":"High","gaps":["Mechanism by which Prep1 stabilizes p160 unknown","Tissue specificity of metabolic effect not fully delineated"]},{"year":2010,"claim":"Connected MYBBP1A to mitosis by identifying it as an Aurora B substrate at S1303 required for proper spindle assembly.","evidence":"In vitro kinase assay with MS phosphosite mapping, Aurora inhibitor/knockdown, and RNAi mitotic phenotyping","pmids":["20177074"],"confidence":"High","gaps":["Downstream effector of S1303 phosphorylation unknown","Link between mitotic and nucleolar functions unresolved"]},{"year":2011,"claim":"Defined the core stress-sensing mechanism: nucleolar RNA tethers MYBBP1A, and its loss triggers translocation that promotes p53–p300 interaction and acetylation.","evidence":"RNAi (including RPL5/RPL11), localization imaging, p53-p300 co-IP, and p53 acetylation immunoblots","pmids":["21297583"],"confidence":"High","gaps":["RNA species mediating tethering not molecularly defined","How translocation rate is sensed not quantified"]},{"year":2012,"claim":"Demonstrated MYBBP1A regulates rRNA synthesis itself, repressing Pol I transcription and being required for pre-rRNA processing, and maintains rDNA silencing via HDAC1/2.","evidence":"Pol I co-IP and ChIP, Pol I reporter assays, rRNA precursor analysis, bisulfite/methylation analysis with knockdown","pmids":["22645127","22686419"],"confidence":"High","gaps":["How repressive versus processing roles are partitioned unclear","Recruitment to active versus silent rDNA not fully mapped"]},{"year":2012,"claim":"Established the organismal and tumor-suppressor importance of MYBBP1A through embryonic lethality, mitotic defects, and increased Ras-transformation susceptibility upon loss.","evidence":"Conditional knockout, siRNA with cell-cycle and expression profiling, mitotic imaging, and transformation assays","pmids":["23056166"],"confidence":"High","gaps":["Essential function driving embryonic lethality not pinpointed","Whether tumor suppression is p53-dependent not isolated"]},{"year":2013,"claim":"Provided the structural logic for p53 activation: MYBBP1A self-assembles and binds the p53 C-terminus to template tetramer formation required for acetylation and death.","evidence":"In vitro binding, deletion mapping, size-exclusion tetramer analysis, and actinomycin D cell-death assays","pmids":["24375404"],"confidence":"High","gaps":["No high-resolution structure of the platform","Stoichiometry of self-assembly not defined"]},{"year":2013,"claim":"Extended the chromatin/p53 axis through interactions with Sirt7 (inhibiting H3K18 deacetylation) and p53 under anoikis, where MYBBP1A loss promotes tumorigenesis.","evidence":"Co-IP, deletion mapping, deacetylation assays, and anoikis/colony/xenograft assays in p53-WT breast cancer cells","pmids":["24134843","23388179"],"confidence":"Medium","gaps":["Sirt7 interaction lacks in vivo functional follow-up","Anoikis effect not mechanistically tied to a specific p53 target set"]},{"year":2015,"claim":"Distinguished two nucleolar stress modes, showing graded rRNA transcription loss (not processing inhibition) drives MYBBP1A translocation, p53 acetylation, and apoptosis versus G1 arrest.","evidence":"RNAi against transcription versus processing factors with paired localization, acetylation, p21/BAX, and flow-cytometry readouts","pmids":["26044764"],"confidence":"High","gaps":["Threshold of nucleolar RNA loss that flips the switch not quantified","Generality across cell types not established"]},{"year":2019,"claim":"Linked MYBBP1A to renal cancer metabolism and stemness through dual repression of PGC-1α and c-MYB and to hepatocellular IGF/AKT signaling via DNMT1-dependent IGFBP5 silencing.","evidence":"siRNA knockdown with metabolic, sphere, and xenograft assays; co-IP, ChIP, and bisulfite sequencing for DNMT1/IGFBP5","pmids":["31066170","30781655","31109829"],"confidence":"Medium","gaps":["Context-dependence on c-MYB levels not generalized","DNMT1 recruitment mechanism to IGFBP5 not defined"]},{"year":2024,"claim":"Added post-transcriptional and lncRNA layers of control: NAT10 ac4C modification stabilizes MYBBP1A mRNA to drive p53/SLC7A11-dependent ferroptosis, and GAS5 lncRNA stabilizes p53 by binding MYBBP1A.","evidence":"ac4C assay, stability immunoblots, co-IP, RNA-IP, ferroptosis/reporter assays, and in vivo cardiac I/R and tumor models","pmids":["38583415","38762546"],"confidence":"Medium","gaps":["ac4C site on MYBBP1A mRNA not mapped","GAS5 binding region on MYBBP1A undefined"]},{"year":null,"claim":"How the diverse co-repressor activities, mitotic phosphorylation, and nucleolar stress-sensing are integrated into a single regulatory program remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the MYBBP1A p53-tethering platform","Molecular identity of the nucleolar RNA tether unknown","Whether mitotic and nucleolar functions share a common regulatory logic untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,5,10,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11,19]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,4,7,16]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,5,10,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,16,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,13]}],"complexes":["RNA Polymerase I transcription complex","MYBBP1A-ribosomal subunit large complex"],"partners":["TP53","EP300","PPARGC1A","RELA","CRY1","PREP1","SIRT7","DNMT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BQG0","full_name":"Myb-binding protein 1A","aliases":[],"length_aa":1328,"mass_kda":148.9,"function":"May activate or repress transcription via interactions with sequence specific DNA-binding proteins (By similarity). Repression may be mediated at least in part by histone deacetylase activity (HDAC activity) (By similarity). Acts as a corepressor and in concert with CRY1, represses the transcription of the core circadian clock component PER2 (By similarity). Preferentially binds to dimethylated histone H3 'Lys-9' (H3K9me2) on the PER2 promoter (By similarity). 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Stemness.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31968688","citation_count":29,"is_preprint":false},{"pmid":"26044764","id":"PMC_26044764","title":"Gradual reduction in rRNA transcription triggers p53 acetylation and apoptosis via MYBBP1A.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26044764","citation_count":29,"is_preprint":false},{"pmid":"23388179","id":"PMC_23388179","title":"MYBBP1A suppresses breast cancer tumorigenesis by enhancing the p53 dependent anoikis.","date":"2013","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23388179","citation_count":28,"is_preprint":false},{"pmid":"24134843","id":"PMC_24134843","title":"Inhibition of H3K18 deacetylation of Sirt7 by Myb-binding protein 1a (Mybbp1a).","date":"2013","source":"Biochemical and biophysical research 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cleavage of the cell surface protein p160 is required for detachment of the fertilization envelope in the sea urchin.","date":"2004","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15242800","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49994,"output_tokens":6270,"usd":0.122016,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15050,"output_tokens":5072,"usd":0.101025,"stage2_stop_reason":"end_turn"},"total_usd":0.223041,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MYBBP1A (p160 Myb-binding protein) was cloned and found to localize predominantly in the nucleolus by immunofluorescence. The p67 N-terminal fragment (generated by proteolytic cleavage in some cell types) but not full-length p160 can inhibit transactivation by c-Myb, indicating that the Myb-binding site lies within the N-terminal 580 residues and the Jun-binding site is C-terminal to that region.\",\n      \"method\": \"Molecular cloning, immunofluorescence localization, transactivation assays, proteolytic cleavage characterization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cloning and functional characterization with multiple orthogonal methods (immunofluorescence, binding specificity assays, transactivation reporter assays) in the foundational paper\",\n      \"pmids\": [\"9447996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MYBBP1A (p160MBP) was identified as a direct repressor of PGC-1alpha. MYBBP1A binds PGC-1alpha and suppresses its transcriptional activity, reducing mitochondrial respiration and electron transport gene expression in myoblasts. p38 MAPK phosphorylation of PGC-1alpha disrupts the MYBBP1A–PGC-1alpha interaction, providing a mechanism for p38-mediated activation of PGC-1alpha.\",\n      \"method\": \"Co-immunoprecipitation, adenoviral overexpression in myoblasts, mitochondrial respiration assay, reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional overexpression with phenotypic readout (respiration), and p38 phosphorylation mechanistic link, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"14744933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MYBBP1A acts as a co-repressor of NF-κB by directly binding the transcription activation domain of RelA/p65. MYBBP1A repressed NF-κB-dependent transcription from chromatinized templates in vitro at a step before pre-initiation complex formation without affecting RelA/p65 nuclear translocation or DNA binding. MYBBP1A competed with the histone acetyltransferase p300 for interaction with the RelA/p65 transactivation domain.\",\n      \"method\": \"Co-immunoprecipitation, in vitro transcription from chromatinized templates, reporter assays, competition binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro chromatin transcription assay plus co-IP competition assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17196614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MYBBP1A (p160) interacts with the homeodomain transcription factor Prep1 and competes with Pbx1 for Prep1 binding in vitro. The N-terminal p67 fragment of p160 binds the HR1 domain of Prep1 at residues LFPLL (L63/L66). MYBBP1A inhibits Prep1-dependent HoxB2 expression. Actinomycin D-induced translocation of p160 from the nucleolus to the nucleoplasm promotes endogenous co-localization and co-immunoprecipitation with Prep1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro competition binding, reporter assays, immunofluorescence co-localization, mutagenesis of Prep1 binding motif\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis, and functional reporter assays in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17875935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MYBBP1A (Mybbp1a) is present in two distinct complexes in cells: a smaller complex containing the processed p67/p140 fragments (lacking nucleolar localization sequences) and a larger complex containing intact p160 associated with ribosomal subunits. Treatment with actinomycin D, cisplatin, or UV (all inhibitors of ribosome biogenesis) induced proteolytic processing of p160 into p140 and p67 and caused translocation of Mybbp1a from the nucleolus to the nucleoplasm. Both complexes contain nucleophosmin and nucleolin; nucleostemin is only in the large complex.\",\n      \"method\": \"Biochemical purification of complexes, mass spectrometry, immunofluorescence, western blot of processed forms\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex purification with mass spectrometry identification plus cellular localization experiments, single lab multiple methods\",\n      \"pmids\": [\"18173745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MYBBP1A functions as a co-repressor on the Period2 (Per2) circadian clock gene promoter by interacting with mouse CRY1 (mCRY1). Chromatin immunoprecipitation showed endogenous Mybbp1a binding to the Per2 promoter temporally coinciding with mCRY1 binding and correlated with down-regulation of Per2 expression and dimethylation of histone H3 Lys9.\",\n      \"method\": \"Affinity purification of mCRY1 complexes, co-immunoprecipitation, reporter assays, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRY1 complex purification, ChIP on endogenous promoter, functional reporter assay, single lab with multiple methods\",\n      \"pmids\": [\"19129230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MYBBP1A is a substrate of Aurora B kinase; serine 1303 was identified as the major phosphorylation site by mass spectrometry. MYBBP1A is phosphorylated at S1303 in nocodazole-arrested mitotic cells and dephosphorylated upon Aurora B silencing or treatment with the Aurora kinase inhibitor Danusertib. Depletion of MYBBP1A by RNAi causes mitotic progression delay and spindle assembly defects.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry identification of phosphosite, RNAi knockdown with mitotic phenotype, inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with MS phosphosite identification, confirmed in cells with inhibitor and knockdown, single lab multiple methods\",\n      \"pmids\": [\"20177074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MYBBP1A is tethered to the nucleolus through nucleolar RNA. Upon nucleolar stress (suppression of rRNA transcription), nucleolar RNA content decreases, MYBBP1A translocates from the nucleolus to the nucleoplasm, and then facilitates p53–p300 interaction to enhance p53 acetylation and p53 accumulation. Depletion of RPL5 or RPL11 blocked rRNA export, maintained nucleolar RNA levels, and thereby prevented MYBBP1A translocation and p53 activation.\",\n      \"method\": \"RNAi knockdown, immunofluorescence tracking of MYBBP1A localization, co-immunoprecipitation of p53-p300 complex, western blot of p53 acetylation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockdown conditions, localization imaging, and co-IP with functional p53 acetylation readout replicated across perturbations\",\n      \"pmids\": [\"21297583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Quantitative proteomics identified MYBBP1A (p160 Myb-binding protein) as a novel substrate/target of the VHL ubiquitin ligase complex, suggesting VHL regulates MYBBP1A protein levels.\",\n      \"method\": \"Quantitative proteomics (SILAC-based ubiquitin ligase substrate identification)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomics screen, no functional validation of ubiquitination mechanism described in abstract\",\n      \"pmids\": [\"21386990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MYBBP1A is essential for early mouse embryonic development (required prior to blastocyst formation). In HeLa cells, MYBBP1A down-regulation promotes apoptosis, causes G2/M arrest or anomalous mitosis, and affects expression of genes controlling chromosomal segregation. At mitosis, MYBBP1A localizes to a parachromosomal region. In NIH3T3 cells, MYBBP1A down-regulation increases susceptibility to Ras-induced transformation, indicating tumor suppressor activity.\",\n      \"method\": \"Conditional knockout (embryonic lethal phenotype), siRNA knockdown, gene-expression profiling, cell cycle analysis, immunofluorescence at mitosis, transformation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in mouse, multiple cell line KD experiments with defined phenotypic readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23056166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mybbp1a associates with the RNA Polymerase I transcription complex and ribosome biogenesis machinery. Mybbp1a represses rRNA gene transcription (shown by reporter assay decoupling transcription from processing) and reduces RNA Pol I loading on rDNA genes (ChIP). Depletion of Mybbp1a causes accumulation of unprocessed rRNA precursor and growth arrest, indicating a dual role in rRNA transcription repression and pre-rRNA processing.\",\n      \"method\": \"Co-immunoprecipitation with Pol I complex, ChIP for Pol I loading, Pol I reporter assay, siRNA knockdown with rRNA precursor analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, and knockdown with molecular phenotype, single lab multiple orthogonal methods\",\n      \"pmids\": [\"22645127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mybbp1a binds to the chromatin around hypermethylated/inactive rDNA gene promoters and maintains rDNA repeats in a silenced state by associating with HDAC1/2. Knockdown of Mybbp1a abrogates local DNA methylation and histone silencing marks, displaces UBF and HDACs from the promoter, and elevates rRNA expression.\",\n      \"method\": \"ChIP, siRNA knockdown, bisulfite sequencing/methylation analysis, western blot\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP and methylation analysis with knockdown, single lab single set of experiments\",\n      \"pmids\": [\"22686419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYBBP1A enhances p53 tetramerization and subsequent p300-mediated acetylation in response to nucleolar stress. MYBBP1A has two regions that directly bind lysine residues of the p53 C-terminal regulatory domain. MYBBP1A forms self-assembled complexes that provide a molecular platform for p53 tetramer formation, and tetramerization is required for efficient p53 acetylation and cell death.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, size-exclusion chromatography for tetramer analysis, deletion mapping, cell death assays with actinomycin D\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapping with deletion mutants, in vitro tetramerization assay, and functional cell death readout, single lab multiple methods\",\n      \"pmids\": [\"24375404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYBBP1A binds to Sirt7 in vitro and in vivo (co-IP), and inhibits Sirt7-mediated deacetylation of histone H3K18. The N- and C-terminal regions of Sirt7 and the C-terminal region of Mybbp1a are required for this interaction.\",\n      \"method\": \"Co-immunoprecipitation (in vivo), in vitro binding assay, serial deletion mapping, histone deacetylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding and co-IP with functional deacetylation assay, single lab single study\",\n      \"pmids\": [\"24134843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYBBP1A binds p53 and enhances p53 target gene transcription under anoikis conditions. MYBBP1A knockdown in breast cancer cells with wild-type p53 (MCF-7, ZR-75-1) enhanced tumorigenesis, colony formation, and anoikis resistance.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, colony formation assay, xenograft assay, anoikis assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus multiple functional assays (anoikis, colony formation, xenograft), single lab\",\n      \"pmids\": [\"23388179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ANK (progressive ankylosis protein) interacts with MYBBP1a via its cytoplasmic C-terminal loop. MYBBP1a nuclear levels are regulated by the ANK interaction; loss of ANK/MYBBP1a interaction (in ank/ank chondrocytes) increases nuclear MYBBP1a, decreases NF-κB activity, and reduces catabolic marker expression and cartilage degradation in IL-1β-treated chondrocytes.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, immunohistochemistry/immunoblotting for MYBBP1a nuclear/cytoplasmic distribution, NF-κB reporter assay, transfection with mutant ank constructs\",\n      \"journal\": \"Osteoarthritis and cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, functional rescue with mutant constructs, single lab\",\n      \"pmids\": [\"24747173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gradual reduction in rRNA transcription (not rRNA processing inhibition) triggers MYBBP1A translocation from the nucleolus to the nucleoplasm. MYBBP1A translocation correlates with increased p53 acetylation, p21 and BAX induction, and apoptosis. In contrast, when rRNA processing is inhibited (nucleolar RNA levels maintained), MYBBP1A remains in the nucleolus, p53 accumulates without acetylation, and cells undergo G1 arrest rather than apoptosis.\",\n      \"method\": \"RNAi depletion of rRNA transcription/processing factors, immunofluorescence for MYBBP1A localization, western blot for p53 acetylation and p21/BAX, flow cytometry for cell cycle/apoptosis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic comparison of multiple perturbations with paired localization and functional readouts, mechanistically distinguishes two distinct nucleolar stress responses\",\n      \"pmids\": [\"26044764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYBBP1A directly represses PGC-1α and also represses c-MYB, which in turn regulates PGC-1α mRNA levels. Loss of MYBBP1A simultaneously relieves both modes of repression, causing a metabolic switch from glycolysis to OXPHOS in renal cancer cells. This effect is selective to cells expressing high c-MYB levels.\",\n      \"method\": \"siRNA knockdown, gene expression analysis, metabolic assays (glycolysis vs OXPHOS), xenograft models\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockdown with metabolic phenotype and in vivo xenograft, single lab\",\n      \"pmids\": [\"31066170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYBBP1A loss increases c-MYB transcriptional activity, leading to expansion of the cancer stem cell population in renal carcinoma cells expressing high c-MYB. This increases tumorigenic properties in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, stem cell sphere assay, xenograft, gene expression analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"30781655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYBBP1A forms a complex with DNMT1 (shown by co-IP) and induces aberrant hypermethylation of CpG islands in the IGFBP5 promoter, suppressing IGFBP5 secretion and thereby activating the IGF1/AKT signaling pathway in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, bisulfite sequencing/pyrosequencing for CpG methylation, siRNA knockdown with proliferation/migration readout\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and methylation assays with functional pathway readout, single lab multiple methods\",\n      \"pmids\": [\"31109829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10 induces ac4C modification of Mybbp1a mRNA, increasing Mybbp1a protein stability. Elevated Mybbp1a in turn activates p53 and represses transcription of the anti-ferroptotic gene SLC7A11, promoting cardiomyocyte ferroptosis during ischemia/reperfusion injury. Knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on ferroptosis.\",\n      \"method\": \"ac4C RNA modification assay, western blot for Mybbp1a stability, co-immunoprecipitation, siRNA knockdown, ferroptosis assay, cardiac I/R mouse model with cardiomyocyte-specific NAT10 KO\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C modification assay, co-IP, and in vivo cardiac model with KO, single lab\",\n      \"pmids\": [\"38583415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GAS5 lncRNA stabilizes p53 by directly binding to MYBBP1A and facilitating the MYBBP1A–p53 interaction, enhancing p53-mediated transcription of IRF1 and activating type I interferon signaling (CXCL10, CCL5 production) in NSCLC cells.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, reporter assays, overexpression/knockdown experiments, in vivo tumor models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and RNA-IP with functional downstream readout, single lab\",\n      \"pmids\": [\"38762546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human MYBBP1A cDNA was cloned; the protein was mapped to chromosome 17p13.3 by FISH. The gene physically links with the ALOX15 gene locus.\",\n      \"method\": \"cDNA cloning, fluorescence in situ hybridization (FISH), radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and chromosomal mapping by FISH, standard genomics methods\",\n      \"pmids\": [\"10644447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Prep1-hypomorphic mice, reduced Prep1 causes reduced p160 (MYBBP1A) protein levels in skeletal muscle (Prep1 controls p160 protein stability). This reduction in p160 increases PGC-1α and GLUT4 expression in muscle, enhancing insulin sensitivity and glucose uptake. Overexpression of p160 (but not Pbx1) in L6 muscle cells or in vivo reversed the phenotype, confirming that p160 mediates the Prep1 effect on PGC-1α/GLUT4.\",\n      \"method\": \"Hypomorphic mouse model, in vivo muscle delivery of p160 cDNA, L6 cell overexpression, glucose uptake assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model plus in vivo rescue with p160 cDNA and cell line overexpression, multiple orthogonal approaches\",\n      \"pmids\": [\"18644868\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYBBP1A is a predominantly nucleolar protein that is tethered to the nucleolus via nucleolar RNA; upon nucleolar stress (reduced rRNA transcription), it translocates to the nucleoplasm where it directly binds and promotes p53 tetramerization and p300-mediated p53 acetylation to trigger apoptosis, represses NF-κB by competing with p300 for RelA/p65, represses PGC-1α and c-MYB transcriptional activity, acts as a co-repressor on circadian (Per2) and ribosomal RNA gene promoters in association with HDACs and CRY1, is phosphorylated by Aurora B kinase at S1303 during mitosis (required for proper spindle assembly), and is subject to ac4C modification by NAT10 (regulating its stability), with its nucleolar-to-nucleoplasmic shuttling serving as a stress-sensing switch that links ribosome biogenesis status to p53 activation and cell fate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYBBP1A is a predominantly nucleolar protein that functions as a stress-sensing transcriptional co-repressor coupling ribosome biogenesis status to p53 activation and cell fate [#0, #7]. Within the nucleolus it associates with the RNA Polymerase I transcription complex and ribosome biogenesis machinery, repressing rRNA gene transcription and reducing Pol I loading on rDNA while also being required for pre-rRNA processing [#10], and it maintains silenced rDNA repeats through association with HDAC1/2 and preservation of DNA methylation and histone silencing marks [#11]. MYBBP1A is tethered to the nucleolus by nucleolar RNA; when rRNA transcription falls during nucleolar stress, nucleolar RNA content drops and MYBBP1A translocates to the nucleoplasm [#7], where it acts as a self-assembling platform that directly binds the p53 C-terminal regulatory domain to promote p53 tetramerization and p300-mediated acetylation, driving p21/BAX induction and apoptosis [#7, #12]. The nature of the nucleolar insult determines outcome: graded loss of rRNA transcription drives translocation, p53 acetylation and apoptosis, whereas processing inhibition that preserves nucleolar RNA retains MYBBP1A in the nucleolus and yields p53 accumulation without acetylation and G1 arrest [#16]. Beyond p53, MYBBP1A is a direct repressor of multiple transcription factors: it binds and represses PGC-1\\u03b1 to limit mitochondrial respiration [#1], represses c-MYB transactivation via its N-terminal Myb-binding region [#0, #17], and competes with p300 for the RelA/p65 transactivation domain to repress NF-\\u03baB before pre-initiation complex formation [#2]. It also acts as a co-repressor on the Per2 circadian promoter in concert with CRY1 and H3K9 dimethylation [#5]. Consistent with these growth-restraining activities, MYBBP1A is essential for early mouse embryonic development and behaves as a tumor suppressor whose loss increases susceptibility to Ras-induced transformation [#9]. MYBBP1A is phosphorylated by Aurora B at serine 1303 during mitosis, with its depletion causing spindle assembly defects and mitotic delay [#6], and its protein abundance is regulated post-transcriptionally through NAT10-mediated ac4C modification of its mRNA [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established MYBBP1A as a nucleolar protein with defined transcription-factor-binding architecture, answering where it resides and what it binds.\",\n      \"evidence\": \"Molecular cloning, immunofluorescence, and transactivation assays mapping the N-terminal Myb-binding region\",\n      \"pmids\": [\"9447996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how nucleolar localization relates to function\", \"Physiological role of proteolytic p67 fragment unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified MYBBP1A as a direct repressor of PGC-1\\u03b1, linking it to metabolic/mitochondrial control and to a p38 MAPK regulatory switch.\",\n      \"evidence\": \"Reciprocal co-IP, adenoviral overexpression in myoblasts, mitochondrial respiration and reporter assays\",\n      \"pmids\": [\"14744933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on PGC-1\\u03b1 not mapped\", \"Whether repression occurs at promoter chromatin not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a co-repressor mechanism for NF-\\u03baB, showing MYBBP1A competes with p300 rather than blocking RelA nuclear entry or DNA binding.\",\n      \"evidence\": \"In vitro transcription from chromatinized templates plus co-IP competition assays\",\n      \"pmids\": [\"17196614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous NF-\\u03baB target genes not profiled\", \"Stimulus dependence of repression untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed MYBBP1A extends its co-repressor role to homeodomain factor Prep1 and that actinomycin D-driven nucleoplasmic translocation enables endogenous interaction.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro competition with Pbx1, binding-motif mutagenesis, and reporter assays\",\n      \"pmids\": [\"17875935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence on broader Hox program unclear\", \"Translocation trigger mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved MYBBP1A into distinct full-length and processed complexes and linked ribosome-biogenesis stress to its proteolytic processing and nucleolar-to-nucleoplasmic relocation.\",\n      \"evidence\": \"Biochemical complex purification with mass spectrometry, immunofluorescence, and processing immunoblots under actinomycin D/cisplatin/UV\",\n      \"pmids\": [\"18173745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for processing not identified\", \"Functional difference between complexes not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic mouse model placed MYBBP1A downstream of Prep1 in metabolic control, showing Prep1 controls p160 stability to set PGC-1\\u03b1/GLUT4 levels and insulin sensitivity.\",\n      \"evidence\": \"Prep1-hypomorphic mice with in vivo and L6 cell p160 rescue and glucose uptake assays\",\n      \"pmids\": [\"18644868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Prep1 stabilizes p160 unknown\", \"Tissue specificity of metabolic effect not fully delineated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected MYBBP1A to mitosis by identifying it as an Aurora B substrate at S1303 required for proper spindle assembly.\",\n      \"evidence\": \"In vitro kinase assay with MS phosphosite mapping, Aurora inhibitor/knockdown, and RNAi mitotic phenotyping\",\n      \"pmids\": [\"20177074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector of S1303 phosphorylation unknown\", \"Link between mitotic and nucleolar functions unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the core stress-sensing mechanism: nucleolar RNA tethers MYBBP1A, and its loss triggers translocation that promotes p53\\u2013p300 interaction and acetylation.\",\n      \"evidence\": \"RNAi (including RPL5/RPL11), localization imaging, p53-p300 co-IP, and p53 acetylation immunoblots\",\n      \"pmids\": [\"21297583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA species mediating tethering not molecularly defined\", \"How translocation rate is sensed not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated MYBBP1A regulates rRNA synthesis itself, repressing Pol I transcription and being required for pre-rRNA processing, and maintains rDNA silencing via HDAC1/2.\",\n      \"evidence\": \"Pol I co-IP and ChIP, Pol I reporter assays, rRNA precursor analysis, bisulfite/methylation analysis with knockdown\",\n      \"pmids\": [\"22645127\", \"22686419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How repressive versus processing roles are partitioned unclear\", \"Recruitment to active versus silent rDNA not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the organismal and tumor-suppressor importance of MYBBP1A through embryonic lethality, mitotic defects, and increased Ras-transformation susceptibility upon loss.\",\n      \"evidence\": \"Conditional knockout, siRNA with cell-cycle and expression profiling, mitotic imaging, and transformation assays\",\n      \"pmids\": [\"23056166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Essential function driving embryonic lethality not pinpointed\", \"Whether tumor suppression is p53-dependent not isolated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural logic for p53 activation: MYBBP1A self-assembles and binds the p53 C-terminus to template tetramer formation required for acetylation and death.\",\n      \"evidence\": \"In vitro binding, deletion mapping, size-exclusion tetramer analysis, and actinomycin D cell-death assays\",\n      \"pmids\": [\"24375404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the platform\", \"Stoichiometry of self-assembly not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the chromatin/p53 axis through interactions with Sirt7 (inhibiting H3K18 deacetylation) and p53 under anoikis, where MYBBP1A loss promotes tumorigenesis.\",\n      \"evidence\": \"Co-IP, deletion mapping, deacetylation assays, and anoikis/colony/xenograft assays in p53-WT breast cancer cells\",\n      \"pmids\": [\"24134843\", \"23388179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sirt7 interaction lacks in vivo functional follow-up\", \"Anoikis effect not mechanistically tied to a specific p53 target set\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguished two nucleolar stress modes, showing graded rRNA transcription loss (not processing inhibition) drives MYBBP1A translocation, p53 acetylation, and apoptosis versus G1 arrest.\",\n      \"evidence\": \"RNAi against transcription versus processing factors with paired localization, acetylation, p21/BAX, and flow-cytometry readouts\",\n      \"pmids\": [\"26044764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Threshold of nucleolar RNA loss that flips the switch not quantified\", \"Generality across cell types not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked MYBBP1A to renal cancer metabolism and stemness through dual repression of PGC-1\\u03b1 and c-MYB and to hepatocellular IGF/AKT signaling via DNMT1-dependent IGFBP5 silencing.\",\n      \"evidence\": \"siRNA knockdown with metabolic, sphere, and xenograft assays; co-IP, ChIP, and bisulfite sequencing for DNMT1/IGFBP5\",\n      \"pmids\": [\"31066170\", \"30781655\", \"31109829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence on c-MYB levels not generalized\", \"DNMT1 recruitment mechanism to IGFBP5 not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added post-transcriptional and lncRNA layers of control: NAT10 ac4C modification stabilizes MYBBP1A mRNA to drive p53/SLC7A11-dependent ferroptosis, and GAS5 lncRNA stabilizes p53 by binding MYBBP1A.\",\n      \"evidence\": \"ac4C assay, stability immunoblots, co-IP, RNA-IP, ferroptosis/reporter assays, and in vivo cardiac I/R and tumor models\",\n      \"pmids\": [\"38583415\", \"38762546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ac4C site on MYBBP1A mRNA not mapped\", \"GAS5 binding region on MYBBP1A undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse co-repressor activities, mitotic phosphorylation, and nucleolar stress-sensing are integrated into a single regulatory program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the MYBBP1A p53-tethering platform\", \"Molecular identity of the nucleolar RNA tether unknown\", \"Whether mitotic and nucleolar functions share a common regulatory logic untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 4, 7, 16]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 5, 10, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 16, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [\n      \"RNA Polymerase I transcription complex\",\n      \"MYBBP1A-ribosomal subunit large complex\"\n    ],\n    \"partners\": [\n      \"TP53\",\n      \"EP300\",\n      \"PPARGC1A\",\n      \"RELA\",\n      \"CRY1\",\n      \"PREP1\",\n      \"SIRT7\",\n      \"DNMT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}