{"gene":"MTBP","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2000,"finding":"MTBP (MDM2-binding protein) was identified as a novel MDM2-binding protein via yeast two-hybrid screen. MTBP induces G1 arrest that is suppressed by MDM2, establishing MTBP as a target of MDM2-mediated growth inhibition.","method":"Yeast two-hybrid screen, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification plus functional G1 arrest assay, single lab, two methods","pmids":["10906133"],"is_preprint":false},{"year":2005,"finding":"MTBP promotes MDM2-mediated ubiquitination and proteasomal degradation of p53 in an MDM2 RING finger-dependent manner, and also stabilizes MDM2. siRNA knockdown of endogenous MTBP increases p53 levels and activity, demonstrating MTBP significantly contributes to MDM2-dependent p53 homeostasis. Following UV (but not gamma-irradiation), MTBP is destabilized as part of the stress response.","method":"siRNA knockdown, ubiquitination assays, MDM2 RING finger mutants, Western blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay combined with mutagenesis (RING finger mutants) and siRNA knockdown, single lab but multiple orthogonal methods","pmids":["15632057"],"is_preprint":false},{"year":2007,"finding":"Homozygous deletion of Mtbp in mice causes early embryonic lethality that is not rescued by p53 loss, indicating an essential p53-independent developmental function. Mtbp haploinsufficiency in p53+/- background significantly increases metastatic tumors in vivo, and Mtbp loss increases invasion/migration in osteosarcoma cells, while MTBP overexpression inhibits invasiveness.","method":"Knockout mouse model, in vivo tumor studies, in vitro migration/invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse model with in vivo tumor/metastasis data plus in vitro functional assays, replicated with rescue experiments","pmids":["17906694"],"is_preprint":false},{"year":2011,"finding":"MTBP protein is rapidly degraded during mitosis. A portion of MTBP localizes at kinetochores during prometaphase. MTBP overexpression delays mitotic progression and induces abnormal chromosome segregation, while MTBP downmodulation causes abbreviated metaphase, insufficient mitotic arrest, aneuploidy, and cell death. MTBP is required for accumulation of Mad1 and Mad2 (but not BubR1) at kinetochores during prometaphase, and MTBP degradation is required for mitotic checkpoint silencing.","method":"Immunofluorescence, live-cell imaging, siRNA knockdown, overexpression, flow cytometry","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence with functional consequences established by both knockdown and overexpression, multiple orthogonal readouts, single lab","pmids":["21274008"],"is_preprint":false},{"year":2012,"finding":"MTBP interacts endogenously with alpha-actinin-4 (ACTN4), identified by Co-IP and mass spectrometry. MTBP overexpression inhibits ACTN4-mediated cell migration and filopodia formation. MTBP also inhibits ACTN4-mediated F-actin bundling. Nuclear localization of MTBP is dispensable for inhibiting ACTN4-mediated migration, indicating cytoplasmic MTBP mediates this function.","method":"Co-immunoprecipitation, mass spectrometry, overexpression/knockdown, migration assays, F-actin bundling assay, immunofluorescence","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus MS identification, functional rescue experiments, F-actin bundling biochemical assay, multiple orthogonal methods in single lab","pmids":["22370640"],"is_preprint":false},{"year":2014,"finding":"MTBP binds to MYC transcriptional cofactors TIP48 and TIP49, and indirectly associates with MYC in a complex at MYC-bound promoters. MTBP increases MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. TIP48/TIP49 associations as well as MYC are implicated in MTBP's function in cellular transformation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, transcriptional assays, transformation assays, in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP showing co-occupancy at promoters, Co-IP for binding partners, functional transformation and tumor assays, multiple orthogonal methods, single lab","pmids":["24786788"],"is_preprint":false},{"year":2015,"finding":"MTBP overexpression in HCC cells decreases E-cadherin expression through MDM2 ubiquitination-mediated degradation of E-cadherin, promoting epithelial-to-mesenchymal transition and invasion.","method":"Western blotting, siRNA knockdown, overexpression, migration/invasion assays, in vivo metastasis model","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic claim based primarily on expression changes and functional assays without direct biochemical reconstitution of MDM2-mediated E-cadherin ubiquitination","pmids":["26280083"],"is_preprint":false},{"year":2017,"finding":"MTBP contains a C-terminal domain (CTM domain) homologous to budding yeast Sld7 that binds efficiently to double-stranded DNA and G-quadruplex (G4) DNA. Depletion of MTBP from Xenopus egg extracts (which also removes Treslin) abolishes DNA replication; replication is rescued only by recombinant Treslin-MTBP complex, not by either protein alone. CTM domain mutants are defective in chromatin localization, fail to support Cdc45 loading, and cause severe S-phase defects in human cells.","method":"Xenopus egg extract depletion/add-back, DNA-binding assays, site-directed mutagenesis, chromatin fractionation, flow cytometry","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Xenopus extracts, DNA-binding in vitro assay, domain mutagenesis, validated in human cells with multiple orthogonal readouts","pmids":["28877985"],"is_preprint":false},{"year":2018,"finding":"MTBP inhibits nuclear translocation of phosphorylated Erk1/2 (p-Erk) by binding to importin-7/RanBP7 (IPO7), an importin that shuttles p-Erk into the nucleus, thereby suppressing Elk-1 phosphorylation and transcriptional activity of Elk-1 target genes. This identifies a mechanism by which MTBP suppresses HCC metastasis via the Erk1/2-Elk-1 signaling pathway.","method":"Luciferase reporter signal array, Co-IP, phosphorylation assays, mRNA expression analysis, immunofluorescence, clinical tissue analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating MTBP-IPO7 interaction combined with functional signaling assays and clinical correlation, single lab, multiple methods","pmids":["29765550"],"is_preprint":false},{"year":2020,"finding":"The MTBP subunit of the Treslin-MTBP complex binds at least 30,000 sites in the human genome, predominantly in regions of open chromatin containing transcriptional regulatory elements (promoters, enhancers, super-enhancers). Many binding sites encompass nucleosome-free DNA sequences (e.g., G-quadruplex DNA or AP-1 motif) and nucleosomes bearing H3K4me2 marks, indicating Treslin-MTBP associates coordinately with multiple genomic signals to promote replication initiation.","method":"ChIP-seq, genome-wide mapping, chromatin accessibility analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq in human cells with functional genomic context, single lab","pmids":["32966791"],"is_preprint":false},{"year":2021,"finding":"MTBP is phosphorylated at CDK consensus sites by cell cycle CDKs and Cdk8/19-cyclin C; phospho-mimetic CDK site mutants promote origin firing in human cells while non-phosphorylatable mutants do not. MTBP is also phosphorylated at DNA damage checkpoint kinase consensus sites; phospho-mimetic mutations at these sites inhibit origin firing capability. A non-phospho MTBP mutant induces genome-wide increase of origin firing in unperturbed cells, establishing MTBP as a regulatory platform for metazoan origin firing.","method":"Phospho-mimetic and non-phosphorylatable mutant expression, origin firing assays in human cells, DNA damage response assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutant analysis of phosphorylation sites with origin firing readout, single lab, multiple mutant constructs","pmids":["33608586"],"is_preprint":false},{"year":2021,"finding":"MTBP forms an elongated tetramer with Treslin in Xenopus egg extract, containing two molecules of each protein. Treslin-MTBP is rate-limiting for replication initiation. DDK activity both increases and strengthens the interaction of Treslin-MTBP with licensed chromatin. DDK activity cooperates with CDK activity to drive the interaction of Treslin-MTBP with TopBP1, a key regulated step in pre-initiation complex formation.","method":"Xenopus egg extract immunodepletion/add-back, biochemical fractionation, complex analysis, kinase inhibitor experiments","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reconstitution in Xenopus extracts, complex stoichiometry analysis, kinase dependency experiments, multiple orthogonal biochemical methods in single lab","pmids":["34699733"],"is_preprint":false},{"year":2022,"finding":"The TRESLIN-MTBP complex acts transiently at pre-replication complexes (preRCs) to initiate origin firing and is released after CDC45 recruitment. This dynamic behavior implements a monitoring system detecting the rate of origin firing to prevent premature entry into G2. TRESLIN-MTBP prevents premature S/G2 transition independently of ATR/CHK1 kinases, sensing the natural decline in origin firing in late S phase.","method":"Cell synchronization, flow cytometry, protein depletion/add-back, ChIP, kinase inhibitor experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (depletion, kinase inhibition, chromatin recruitment assays) establishing TRESLIN-MTBP's checkpoint-independent role in S/G2 transition, single lab","pmids":["36049481"],"is_preprint":false},{"year":2022,"finding":"MTBP functions as a co-activator of transcription factor ETS-1, enhancing its transcriptional activity and promoting recruitment of ETS-1 to the mmp1 promoter, thereby promoting HCC cell proliferation.","method":"Luciferase reporter assays, qPCR, chromatin immunoprecipitation, overexpression/knockdown, xenograft models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP showing MTBP-enhanced ETS-1 promoter recruitment, functional luciferase and proliferation assays, single lab with multiple methods","pmids":["36106099"],"is_preprint":false},{"year":2025,"finding":"MTBP is a limiting firing factor for replication initiation whose loading onto phosphorylated MCM2-7 double hexamer (MCM-DH) is controlled by opposing phosphorylation events: Dbf4-dependent kinase (DDK) promotes and RIF1-Protein Phosphatase 1 opposes TRESLIN-MTBP loading, ultimately determining initiation zones (IZs) and replication timing (RT).","method":"Genome-wide mapping of firing factors, auxin-inducible degron (AID) system, kinase/phosphatase manipulation, chromatin fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genomic and biochemical methods, inducible degradation system, kinase/phosphatase functional experiments, single lab","pmids":["41331242"],"is_preprint":false},{"year":2025,"finding":"MTBP is dependent on TRESLIN for proper chromatin association during G1, but not during S phase, indicating two separate modes of chromatin binding. TRESLIN and MTBP binding to chromatin during G1 does not require licensed origins (loaded MCMs), diverging from yeast Sld3-Sld7 mechanism.","method":"CUT&RUN genomic binding assay, Geminin overexpression to inhibit licensing, G1 synchronization, siRNA knockdown","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&RUN with cell cycle synchronization and licensing inhibition experiments, single lab, multiple conditions","pmids":["40624716"],"is_preprint":false},{"year":2025,"finding":"CDK activity controls TRESLIN and MTBP abundance and chromatin recruitment to promote dormant origin activation. WEE1 inhibition (increased CDK activity) blocks PCNA-dependent degradation of TRESLIN and enhances chromatin loading of both TRESLIN and MTBP, leading to elevated helicase recruitment. This effect depends on both TRESLIN and MTBP, and a conserved TRESLIN sequence mediates CDK-sensitive degradation.","method":"WEE1 inhibition, CDK inhibition, PCNA degradation assays, chromatin fractionation, siRNA knockdown, DNA synthesis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint, multiple biochemical methods but not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.06.10.657920"],"is_preprint":true},{"year":2025,"finding":"MTBP allosterically activates Cdk8/19-CycC kinase activity in vitro by repositioning the T-loop of the kinase independently of T-loop phosphorylation, acting as a targeting and activation factor distinct from Med12. MTBP targets Cdk8/19-CycC to Med12-independent cellular roles (including replication origin firing), while Med12 targets it to the Mediator complex for transcription control. Both MTBP and Med12 are mutually exclusive allosteric activators of Cdk8/19-CycC.","method":"In vitro kinase assays, structural analysis, mutagenesis, protein interaction studies","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase reconstitution with structural basis described, but preprint only, single lab","pmids":["bio_10.1101_2025.06.16.659917"],"is_preprint":true}],"current_model":"MTBP is a multifunctional protein that: (1) serves as an essential component of the Treslin-MTBP complex (the metazoan ortholog of yeast Sld3-Sld7) required for CDC45 loading and replication origin firing, with its CTM domain binding DNA and chromatin and its activity regulated by CDK and checkpoint kinase phosphorylation; (2) promotes MDM2-mediated ubiquitination and degradation of p53 while stabilizing MDM2, thereby contributing to p53 homeostasis; (3) suppresses cell migration and metastasis by binding and inhibiting alpha-actinin-4 (ACTN4) and by blocking nuclear import of phospho-Erk1/2 via interaction with importin-7/IPO7; (4) functions as a transcriptional co-activator for MYC and ETS-1 at target gene promoters; and (5) plays a role in mitotic checkpoint regulation by recruiting Mad1/Mad2 to kinetochores, with its degradation required for checkpoint silencing."},"narrative":{"mechanistic_narrative":"MTBP is a multifunctional regulator that operates at the intersection of DNA replication initiation, p53 homeostasis, and cell migration control. Its best-characterized role is as the essential metazoan partner of TRESLIN, with which it forms an elongated tetramer (two copies of each protein) that is rate-limiting for replication origin firing; depletion of MTBP abolishes DNA replication in Xenopus egg extracts and can only be rescued by the reconstituted TRESLIN-MTBP complex [PMID:28877985, PMID:34699733]. A C-terminal Sld7-homologous CTM domain binds double-stranded and G-quadruplex DNA and is required for chromatin localization and CDC45 loading [PMID:28877985], and genome-wide the complex associates with tens of thousands of open-chromatin regulatory elements bearing G4 motifs, AP-1 sites, and H3K4me2 nucleosomes [PMID:32966791]. MTBP loading onto phosphorylated MCM2-7 double hexamers is governed by opposing phosphorylation: CDK and DDK promote, while RIF1-PP1 opposes, thereby setting initiation zones and replication timing [PMID:41331242], and direct CDK phosphorylation of MTBP at activating versus checkpoint-kinase sites tunes origin firing capacity in either direction [PMID:33608586]. By acting transiently at pre-replication complexes and being released after CDC45 recruitment, TRESLIN-MTBP also implements a checkpoint-independent monitoring system that prevents premature S/G2 transition [PMID:36049481]. Independently, MTBP promotes MDM2-mediated ubiquitination and degradation of p53 while stabilizing MDM2, contributing to p53 homeostasis [PMID:15632057], and it has an essential p53-independent developmental function, as Mtbp-null mice die early in embryogenesis irrespective of p53 status [PMID:17906694]. MTBP suppresses cell migration and metastasis by binding and inhibiting the actin-bundling protein ACTN4 [PMID:22370640] and by sequestering importin-7/IPO7 to block nuclear import of phospho-Erk1/2 [PMID:29765550]. It additionally serves as a transcriptional co-activator, associating with MYC cofactors TIP48/TIP49 at MYC-bound promoters to drive transformation [PMID:24786788] and enhancing ETS-1 recruitment to target promoters [PMID:36106099]. A distinct mitotic role involves transient kinetochore localization and recruitment of Mad1/Mad2 during prometaphase, with MTBP degradation required for checkpoint silencing [PMID:21274008].","teleology":[{"year":2000,"claim":"Established MTBP as a physical and functional partner of MDM2, defining its first molecular context as a growth-regulatory factor.","evidence":"Yeast two-hybrid screen and cell cycle analysis identifying MTBP and MDM2-suppressible G1 arrest","pmids":["10906133"],"confidence":"Medium","gaps":["Mechanism of MTBP-induced G1 arrest not defined","Binding interface with MDM2 not mapped"]},{"year":2005,"claim":"Resolved how MTBP feeds into the p53 pathway, showing it potentiates MDM2 ligase function rather than merely binding it.","evidence":"siRNA knockdown, in vitro ubiquitination assays, and MDM2 RING finger mutants with Western blotting","pmids":["15632057"],"confidence":"High","gaps":["Whether MTBP is a direct ubiquitination substrate or only a cofactor","Structural basis of MDM2 stabilization unresolved"]},{"year":2007,"claim":"Demonstrated MTBP has an essential developmental role separable from p53 and a haploinsufficient tumor-suppressive/anti-metastatic function in vivo.","evidence":"Mtbp knockout and haploinsufficient mouse models with in vivo tumor/metastasis and in vitro invasion assays","pmids":["17906694"],"confidence":"High","gaps":["Molecular identity of the essential embryonic function not defined","Mechanism linking MTBP loss to increased metastasis not yet established"]},{"year":2011,"claim":"Identified a mitotic checkpoint role, showing MTBP is needed for Mad1/Mad2 kinetochore recruitment and that its timed degradation permits checkpoint silencing.","evidence":"Immunofluorescence, live-cell imaging, siRNA knockdown and overexpression with flow cytometry","pmids":["21274008"],"confidence":"High","gaps":["Direct binding partners at the kinetochore not identified","Relationship between mitotic and replication functions unclear"]},{"year":2012,"claim":"Provided a biochemical mechanism for MTBP's anti-migratory activity through direct inhibition of ACTN4-mediated actin bundling.","evidence":"Reciprocal Co-IP and mass spectrometry, F-actin bundling assays, and migration assays","pmids":["22370640"],"confidence":"High","gaps":["ACTN4-binding region of MTBP not mapped","Regulation of the cytoplasmic MTBP pool not defined"]},{"year":2014,"claim":"Linked MTBP to oncogenic transcription, showing it associates with MYC cofactors TIP48/TIP49 at MYC promoters to amplify MYC-driven transformation.","evidence":"Co-IP, ChIP at MYC-bound promoters, transcriptional and transformation assays, in vivo tumor models","pmids":["24786788"],"confidence":"High","gaps":["Whether MTBP contacts MYC directly or only via TIP48/TIP49 unresolved","Reconciliation with tumor-suppressive functions not addressed"]},{"year":2015,"claim":"Proposed an EMT-promoting mechanism via MDM2-dependent E-cadherin degradation in HCC.","evidence":"Western blotting, knockdown/overexpression, migration/invasion and in vivo metastasis assays","pmids":["26280083"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of MDM2-mediated E-cadherin ubiquitination","Apparent conflict with anti-metastatic findings unaddressed"]},{"year":2017,"claim":"Defined MTBP's core replication function, establishing the DNA-binding CTM domain and the obligate TRESLIN-MTBP complex as essential for CDC45 loading and origin firing.","evidence":"Xenopus egg extract depletion/add-back, DNA-binding assays, CTM domain mutagenesis, and chromatin fractionation in human cells","pmids":["28877985"],"confidence":"High","gaps":["Structure of the CTM-DNA interaction not solved","Sequence determinants of genomic site selection not defined"]},{"year":2018,"claim":"Added a signaling mechanism for metastasis suppression, showing MTBP blocks IPO7-mediated nuclear import of phospho-Erk1/2 to dampen Elk-1 transcription.","evidence":"Co-IP, reporter signal arrays, phosphorylation assays, immunofluorescence, and clinical tissue analysis","pmids":["29765550"],"confidence":"Medium","gaps":["IPO7-binding interface not mapped","Single-lab Co-IP without reconstitution of the import-blocking step"]},{"year":2020,"claim":"Mapped where TRESLIN-MTBP acts genome-wide, revealing preferential association with open-chromatin regulatory elements and specific DNA/nucleosome signals.","evidence":"ChIP-seq and chromatin accessibility analysis in human cells","pmids":["32966791"],"confidence":"Medium","gaps":["Causal link between individual binding signals and firing not dissected","Functional outcome at each site class not measured"]},{"year":2021,"claim":"Established MTBP as a phospho-regulated platform integrating activating CDK signals and inhibitory checkpoint-kinase signals to set origin-firing levels.","evidence":"Phospho-mimetic and non-phosphorylatable mutants with origin firing and DNA damage response assays in human cells","pmids":["33608586"],"confidence":"Medium","gaps":["Identities of all responsible kinases not fully defined","How phospho-states alter chromatin loading mechanistically unresolved"]},{"year":2021,"claim":"Defined the architecture and kinase-dependent activation of the complex, showing TRESLIN-MTBP is a rate-limiting tetramer whose chromatin and TopBP1 engagement is driven by DDK and CDK.","evidence":"Xenopus egg extract depletion/add-back, complex stoichiometry analysis, and kinase inhibitor experiments","pmids":["34699733"],"confidence":"High","gaps":["High-resolution structure of the tetramer not determined","Order of DDK and CDK inputs not fully ordered"]},{"year":2022,"claim":"Revealed a checkpoint-independent surveillance role, showing transient TRESLIN-MTBP action at preRCs monitors origin firing rate to prevent premature S/G2 transition.","evidence":"Cell synchronization, protein depletion/add-back, ChIP, and kinase inhibitor experiments","pmids":["36049481"],"confidence":"High","gaps":["Molecular sensor reading the firing-rate decline not identified","Downstream effector enforcing S/G2 timing unknown"]},{"year":2022,"claim":"Extended the transcriptional co-activator role to ETS-1, showing MTBP enhances ETS-1 promoter recruitment to drive HCC proliferation.","evidence":"Luciferase reporters, qPCR, ChIP, knockdown/overexpression, and xenograft models","pmids":["36106099"],"confidence":"Medium","gaps":["Direct MTBP-ETS-1 contact versus indirect bridging not resolved","Generality beyond the mmp1 promoter untested"]},{"year":2025,"claim":"Placed MTBP loading at the center of replication timing control, showing opposing DDK and RIF1-PP1 phosphorylation events set initiation zones.","evidence":"Genome-wide firing-factor mapping, auxin-inducible degron, and kinase/phosphatase manipulation with chromatin fractionation","pmids":["41331242"],"confidence":"High","gaps":["Direct phosphosites on MCM-DH targeted by this regulation not enumerated","Quantitative threshold determining IZ selection unresolved"]},{"year":2025,"claim":"Distinguished two chromatin-binding modes, showing MTBP requires TRESLIN for G1 association but binds independently in S phase, diverging from the yeast Sld3-Sld7 paradigm.","evidence":"CUT&RUN with G1 synchronization, Geminin-mediated licensing inhibition, and siRNA knockdown","pmids":["40624716"],"confidence":"Medium","gaps":["Determinants of licensing-independent G1 binding unknown","Functional purpose of pre-licensing chromatin association unclear"]},{"year":2025,"claim":"Identified a kinase-activating function, showing MTBP allosterically activates and targets Cdk8/19-CycC to Med12-independent roles including origin firing.","evidence":"In vitro kinase assays, structural analysis, and mutagenesis (preprint)","pmids":["bio_10.1101_2025.06.16.659917"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","In vivo contribution of MTBP-Cdk8/19 to origin firing not established"]},{"year":null,"claim":"How MTBP's distinct functions in replication initiation, p53/MDM2 control, migration suppression, transcriptional co-activation, and mitotic checkpoint signaling are coordinated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting nuclear replication roles with cytoplasmic anti-migratory roles","Whether distinct functions reflect separable protein pools or domains not determined","Reconciliation of tumor-suppressive versus oncogenic activities unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7,13]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[7,9,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[7,11,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1]}],"complexes":["TRESLIN-MTBP complex"],"partners":["TRESLIN","MDM2","ACTN4","IPO7","TIP48","TIP49","TOPBP1","CDK8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DY7","full_name":"Mdm2-binding protein","aliases":[],"length_aa":904,"mass_kda":102.2,"function":"Inhibits cell migration in vitro and suppresses the invasive behavior of tumor cells (By similarity). May play a role in MDM2-dependent p53/TP53 homeostasis in unstressed cells. Inhibits autoubiquitination of MDM2, thereby enhancing MDM2 stability. This promotes MDM2-mediated ubiquitination of p53/TP53 and its subsequent degradation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96DY7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MTBP","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MTBP","total_profiled":1310},"omim":[{"mim_id":"613298","title":"TOPBP1-INTERACTING CHECKPOINT AND REPLICATION REGULATOR; TICRR","url":"https://www.omim.org/entry/613298"},{"mim_id":"605927","title":"MDM2-BINDING PROTEIN; MDM2BP","url":"https://www.omim.org/entry/605927"},{"mim_id":"173870","title":"POLY(ADP-RIBOSE) POLYMERASE 1; PARP1","url":"https://www.omim.org/entry/173870"},{"mim_id":"164785","title":"MDM2 PROTOONCOGENE; MDM2","url":"https://www.omim.org/entry/164785"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTBP"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96DY7","domains":[{"cath_id":"3.40.50","chopping":"3-15_40-128_138-232","consensus_level":"medium","plddt":74.0568,"start":3,"end":232},{"cath_id":"2.40.290","chopping":"239-269_294-433","consensus_level":"medium","plddt":77.9601,"start":239,"end":433},{"cath_id":"-","chopping":"631-662","consensus_level":"medium","plddt":66.6597,"start":631,"end":662},{"cath_id":"-","chopping":"828-903","consensus_level":"high","plddt":88.5417,"start":828,"end":903}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DY7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DY7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DY7-F1-predicted_aligned_error_v6.png","plddt_mean":63.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTBP","jax_strain_url":"https://www.jax.org/strain/search?query=MTBP"},"sequence":{"accession":"Q96DY7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DY7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DY7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DY7"}},"corpus_meta":[{"pmid":"10906133","id":"PMC_10906133","title":"A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10906133","citation_count":90,"is_preprint":false},{"pmid":"15632057","id":"PMC_15632057","title":"Regulation of p53 and MDM2 activity by MTBP.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15632057","citation_count":62,"is_preprint":false},{"pmid":"22370640","id":"PMC_22370640","title":"MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22370640","citation_count":47,"is_preprint":false},{"pmid":"28877985","id":"PMC_28877985","title":"MTBP, the partner of Treslin, contains a novel DNA-binding domain that is essential for proper initiation of DNA replication.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28877985","citation_count":39,"is_preprint":false},{"pmid":"24786788","id":"PMC_24786788","title":"Oncogenic protein MTBP interacts with MYC to promote tumorigenesis.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24786788","citation_count":38,"is_preprint":false},{"pmid":"24866769","id":"PMC_24866769","title":"MTBP is overexpressed in triple-negative breast cancer and contributes to its growth and survival.","date":"2014","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/24866769","citation_count":34,"is_preprint":false},{"pmid":"17906694","id":"PMC_17906694","title":"Mtbp haploinsufficiency in mice increases tumor metastasis.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17906694","citation_count":27,"is_preprint":false},{"pmid":"34699733","id":"PMC_34699733","title":"The role of DDK and Treslin-MTBP in coordinating replication licensing and pre-initiation complex formation.","date":"2021","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/34699733","citation_count":23,"is_preprint":false},{"pmid":"21274008","id":"PMC_21274008","title":"MTBP plays a crucial role in mitotic progression and chromosome segregation.","date":"2011","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/21274008","citation_count":22,"is_preprint":false},{"pmid":"21692053","id":"PMC_21692053","title":"Loss of MTBP expression is associated with reduced survival in a biomarker-defined subset of patients with squamous cell carcinoma of the head and neck.","date":"2011","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21692053","citation_count":22,"is_preprint":false},{"pmid":"32966791","id":"PMC_32966791","title":"Binding of the Treslin-MTBP Complex to Specific Regions of the Human Genome Promotes the Initiation of DNA Replication.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32966791","citation_count":22,"is_preprint":false},{"pmid":"25759210","id":"PMC_25759210","title":"MTBP inhibits migration and metastasis of hepatocellular carcinoma.","date":"2015","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/25759210","citation_count":20,"is_preprint":false},{"pmid":"33809929","id":"PMC_33809929","title":"Long Non-Coding RNA CRYBG3 Promotes Lung Cancer Metastasis via Activating the eEF1A1/MDM2/MTBP Axis.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33809929","citation_count":20,"is_preprint":false},{"pmid":"31534534","id":"PMC_31534534","title":"MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31534534","citation_count":19,"is_preprint":false},{"pmid":"36049481","id":"PMC_36049481","title":"The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition.","date":"2022","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/36049481","citation_count":19,"is_preprint":false},{"pmid":"29765550","id":"PMC_29765550","title":"MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29765550","citation_count":19,"is_preprint":false},{"pmid":"35741402","id":"PMC_35741402","title":"MTBP and MYC: A Dynamic Duo in Proliferation, Cancer, and Aging.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35741402","citation_count":14,"is_preprint":false},{"pmid":"33608586","id":"PMC_33608586","title":"MTBP phosphorylation controls DNA replication origin firing.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33608586","citation_count":14,"is_preprint":false},{"pmid":"26280083","id":"PMC_26280083","title":"MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin.","date":"2015","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26280083","citation_count":14,"is_preprint":false},{"pmid":"30349307","id":"PMC_30349307","title":"MTBP promotes migration and invasion by regulation of ZEB2-mediated epithelial-mesenchymal transition in lung cancer cells.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30349307","citation_count":14,"is_preprint":false},{"pmid":"23059707","id":"PMC_23059707","title":"The enhancement of stability of p53 in MTBP induced p53-MDM2 regulatory network.","date":"2012","source":"Bio Systems","url":"https://pubmed.ncbi.nlm.nih.gov/23059707","citation_count":12,"is_preprint":false},{"pmid":"36106099","id":"PMC_36106099","title":"MTBP enhances the activation of transcription factor ETS-1 and promotes the proliferation of hepatocellular carcinoma cells.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36106099","citation_count":9,"is_preprint":false},{"pmid":"27803394","id":"PMC_27803394","title":"Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice.","date":"2016","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/27803394","citation_count":9,"is_preprint":false},{"pmid":"14614800","id":"PMC_14614800","title":"Telomere-binding TRF2/MTBP localization during mouse spermatogenesis and cell cycle of the mouse cells L929.","date":"2003","source":"Journal of anti-aging medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14614800","citation_count":8,"is_preprint":false},{"pmid":"34262658","id":"PMC_34262658","title":"MTBP promoted the proliferation, migration and invasion of colon cancer cells by activating the expression of ZEB2.","date":"2021","source":"Animal cells and systems","url":"https://pubmed.ncbi.nlm.nih.gov/34262658","citation_count":8,"is_preprint":false},{"pmid":"14987434","id":"PMC_14987434","title":"A telomere-binding protein (TRF2/MTBP) from mouse nuclear matrix with motives of an intermediate filament-type rod domain.","date":"2003","source":"Journal of anti-aging medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14987434","citation_count":8,"is_preprint":false},{"pmid":"28472921","id":"PMC_28472921","title":"Whole genome sequencing identifies missense mutation in MTBP in Shar-Pei affected with Autoinflammatory Disease (SPAID).","date":"2017","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28472921","citation_count":8,"is_preprint":false},{"pmid":"16859480","id":"PMC_16859480","title":"Telomere and TRF2/MTBP localization in respect to satellite DNA during the cell cycle of mouse cell line L929.","date":"2006","source":"Rejuvenation research","url":"https://pubmed.ncbi.nlm.nih.gov/16859480","citation_count":8,"is_preprint":false},{"pmid":"40624716","id":"PMC_40624716","title":"Cell cycle-dependent TICRR/TRESLIN and MTBP chromatin binding mechanisms and patterns.","date":"2025","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/40624716","citation_count":6,"is_preprint":false},{"pmid":"41331242","id":"PMC_41331242","title":"Regulated TRESLIN-MTBP loading governs initiation zones and replication timing in human DNA replication.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41331242","citation_count":5,"is_preprint":false},{"pmid":"35741348","id":"PMC_35741348","title":"The Role of MTBP as a Replication Origin Firing Factor.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/35741348","citation_count":5,"is_preprint":false},{"pmid":"38009308","id":"PMC_38009308","title":"C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple-negative breast cancer.","date":"2023","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38009308","citation_count":5,"is_preprint":false},{"pmid":"38370757","id":"PMC_38370757","title":"Cell Cycle-Dependent TICRR/TRESLIN and MTBP Chromatin Binding Mechanisms and Patterns.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38370757","citation_count":4,"is_preprint":false},{"pmid":"30692060","id":"PMC_30692060","title":"[MTBP regulates migration and invasion of prostate cancer cells in vitro].","date":"2019","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/30692060","citation_count":4,"is_preprint":false},{"pmid":"38378131","id":"PMC_38378131","title":"Circular RNA Circ_0000119 promotes gastric cancer progression via circ_0000119/miR-502-5p/MTBP axis.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38378131","citation_count":3,"is_preprint":false},{"pmid":"30170409","id":"PMC_30170409","title":"Hyper expression of MTBP may be an adverse signal for the survival of some malignant tumors: A data-based analysis and clinical observation.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30170409","citation_count":3,"is_preprint":false},{"pmid":"17353134","id":"PMC_17353134","title":"Dynamics of satellite binding protein CENP-B and telomere binding protein TRF2/MTBP in the nuclei of mouse spermatogenic line.","date":"2007","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/17353134","citation_count":2,"is_preprint":false},{"pmid":"40680629","id":"PMC_40680629","title":"Unveiling the enigmatic role of MTBP in pan-cancer: A bioinformatics perspective.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40680629","citation_count":1,"is_preprint":false},{"pmid":"41046925","id":"PMC_41046925","title":"The study of MDM2 binding protein (MTBP) in response to apoptosis in Litopenaeus vannamei under ammonia and nitrite nitrogen stress.","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41046925","citation_count":1,"is_preprint":false},{"pmid":"37760565","id":"PMC_37760565","title":"Characterization of an Mtbp Hypomorphic Allele in a Diethylnitrosamine-Induced Liver Carcinogenesis Model.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37760565","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.16.659917","title":"MTBP allosterically activates Cdk8-CycC kinase activity","date":"2025-06-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.16.659917","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.10.657920","title":"Dynamic regulation of origin firing factors links CDK activity to dormant origin activation","date":"2025-06-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.10.657920","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21983,"output_tokens":4802,"usd":0.068989,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12964,"output_tokens":5203,"usd":0.097448,"stage2_stop_reason":"end_turn"},"total_usd":0.166437,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"MTBP (MDM2-binding protein) was identified as a novel MDM2-binding protein via yeast two-hybrid screen. MTBP induces G1 arrest that is suppressed by MDM2, establishing MTBP as a target of MDM2-mediated growth inhibition.\",\n      \"method\": \"Yeast two-hybrid screen, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification plus functional G1 arrest assay, single lab, two methods\",\n      \"pmids\": [\"10906133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MTBP promotes MDM2-mediated ubiquitination and proteasomal degradation of p53 in an MDM2 RING finger-dependent manner, and also stabilizes MDM2. siRNA knockdown of endogenous MTBP increases p53 levels and activity, demonstrating MTBP significantly contributes to MDM2-dependent p53 homeostasis. Following UV (but not gamma-irradiation), MTBP is destabilized as part of the stress response.\",\n      \"method\": \"siRNA knockdown, ubiquitination assays, MDM2 RING finger mutants, Western blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay combined with mutagenesis (RING finger mutants) and siRNA knockdown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15632057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homozygous deletion of Mtbp in mice causes early embryonic lethality that is not rescued by p53 loss, indicating an essential p53-independent developmental function. Mtbp haploinsufficiency in p53+/- background significantly increases metastatic tumors in vivo, and Mtbp loss increases invasion/migration in osteosarcoma cells, while MTBP overexpression inhibits invasiveness.\",\n      \"method\": \"Knockout mouse model, in vivo tumor studies, in vitro migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse model with in vivo tumor/metastasis data plus in vitro functional assays, replicated with rescue experiments\",\n      \"pmids\": [\"17906694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MTBP protein is rapidly degraded during mitosis. A portion of MTBP localizes at kinetochores during prometaphase. MTBP overexpression delays mitotic progression and induces abnormal chromosome segregation, while MTBP downmodulation causes abbreviated metaphase, insufficient mitotic arrest, aneuploidy, and cell death. MTBP is required for accumulation of Mad1 and Mad2 (but not BubR1) at kinetochores during prometaphase, and MTBP degradation is required for mitotic checkpoint silencing.\",\n      \"method\": \"Immunofluorescence, live-cell imaging, siRNA knockdown, overexpression, flow cytometry\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence with functional consequences established by both knockdown and overexpression, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"21274008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MTBP interacts endogenously with alpha-actinin-4 (ACTN4), identified by Co-IP and mass spectrometry. MTBP overexpression inhibits ACTN4-mediated cell migration and filopodia formation. MTBP also inhibits ACTN4-mediated F-actin bundling. Nuclear localization of MTBP is dispensable for inhibiting ACTN4-mediated migration, indicating cytoplasmic MTBP mediates this function.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, overexpression/knockdown, migration assays, F-actin bundling assay, immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus MS identification, functional rescue experiments, F-actin bundling biochemical assay, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"22370640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTBP binds to MYC transcriptional cofactors TIP48 and TIP49, and indirectly associates with MYC in a complex at MYC-bound promoters. MTBP increases MYC-mediated transcription, proliferation, neoplastic transformation, and tumor development. TIP48/TIP49 associations as well as MYC are implicated in MTBP's function in cellular transformation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, transcriptional assays, transformation assays, in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing co-occupancy at promoters, Co-IP for binding partners, functional transformation and tumor assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24786788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MTBP overexpression in HCC cells decreases E-cadherin expression through MDM2 ubiquitination-mediated degradation of E-cadherin, promoting epithelial-to-mesenchymal transition and invasion.\",\n      \"method\": \"Western blotting, siRNA knockdown, overexpression, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic claim based primarily on expression changes and functional assays without direct biochemical reconstitution of MDM2-mediated E-cadherin ubiquitination\",\n      \"pmids\": [\"26280083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MTBP contains a C-terminal domain (CTM domain) homologous to budding yeast Sld7 that binds efficiently to double-stranded DNA and G-quadruplex (G4) DNA. Depletion of MTBP from Xenopus egg extracts (which also removes Treslin) abolishes DNA replication; replication is rescued only by recombinant Treslin-MTBP complex, not by either protein alone. CTM domain mutants are defective in chromatin localization, fail to support Cdc45 loading, and cause severe S-phase defects in human cells.\",\n      \"method\": \"Xenopus egg extract depletion/add-back, DNA-binding assays, site-directed mutagenesis, chromatin fractionation, flow cytometry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Xenopus extracts, DNA-binding in vitro assay, domain mutagenesis, validated in human cells with multiple orthogonal readouts\",\n      \"pmids\": [\"28877985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MTBP inhibits nuclear translocation of phosphorylated Erk1/2 (p-Erk) by binding to importin-7/RanBP7 (IPO7), an importin that shuttles p-Erk into the nucleus, thereby suppressing Elk-1 phosphorylation and transcriptional activity of Elk-1 target genes. This identifies a mechanism by which MTBP suppresses HCC metastasis via the Erk1/2-Elk-1 signaling pathway.\",\n      \"method\": \"Luciferase reporter signal array, Co-IP, phosphorylation assays, mRNA expression analysis, immunofluorescence, clinical tissue analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating MTBP-IPO7 interaction combined with functional signaling assays and clinical correlation, single lab, multiple methods\",\n      \"pmids\": [\"29765550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The MTBP subunit of the Treslin-MTBP complex binds at least 30,000 sites in the human genome, predominantly in regions of open chromatin containing transcriptional regulatory elements (promoters, enhancers, super-enhancers). Many binding sites encompass nucleosome-free DNA sequences (e.g., G-quadruplex DNA or AP-1 motif) and nucleosomes bearing H3K4me2 marks, indicating Treslin-MTBP associates coordinately with multiple genomic signals to promote replication initiation.\",\n      \"method\": \"ChIP-seq, genome-wide mapping, chromatin accessibility analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq in human cells with functional genomic context, single lab\",\n      \"pmids\": [\"32966791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MTBP is phosphorylated at CDK consensus sites by cell cycle CDKs and Cdk8/19-cyclin C; phospho-mimetic CDK site mutants promote origin firing in human cells while non-phosphorylatable mutants do not. MTBP is also phosphorylated at DNA damage checkpoint kinase consensus sites; phospho-mimetic mutations at these sites inhibit origin firing capability. A non-phospho MTBP mutant induces genome-wide increase of origin firing in unperturbed cells, establishing MTBP as a regulatory platform for metazoan origin firing.\",\n      \"method\": \"Phospho-mimetic and non-phosphorylatable mutant expression, origin firing assays in human cells, DNA damage response assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutant analysis of phosphorylation sites with origin firing readout, single lab, multiple mutant constructs\",\n      \"pmids\": [\"33608586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MTBP forms an elongated tetramer with Treslin in Xenopus egg extract, containing two molecules of each protein. Treslin-MTBP is rate-limiting for replication initiation. DDK activity both increases and strengthens the interaction of Treslin-MTBP with licensed chromatin. DDK activity cooperates with CDK activity to drive the interaction of Treslin-MTBP with TopBP1, a key regulated step in pre-initiation complex formation.\",\n      \"method\": \"Xenopus egg extract immunodepletion/add-back, biochemical fractionation, complex analysis, kinase inhibitor experiments\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution in Xenopus extracts, complex stoichiometry analysis, kinase dependency experiments, multiple orthogonal biochemical methods in single lab\",\n      \"pmids\": [\"34699733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The TRESLIN-MTBP complex acts transiently at pre-replication complexes (preRCs) to initiate origin firing and is released after CDC45 recruitment. This dynamic behavior implements a monitoring system detecting the rate of origin firing to prevent premature entry into G2. TRESLIN-MTBP prevents premature S/G2 transition independently of ATR/CHK1 kinases, sensing the natural decline in origin firing in late S phase.\",\n      \"method\": \"Cell synchronization, flow cytometry, protein depletion/add-back, ChIP, kinase inhibitor experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (depletion, kinase inhibition, chromatin recruitment assays) establishing TRESLIN-MTBP's checkpoint-independent role in S/G2 transition, single lab\",\n      \"pmids\": [\"36049481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MTBP functions as a co-activator of transcription factor ETS-1, enhancing its transcriptional activity and promoting recruitment of ETS-1 to the mmp1 promoter, thereby promoting HCC cell proliferation.\",\n      \"method\": \"Luciferase reporter assays, qPCR, chromatin immunoprecipitation, overexpression/knockdown, xenograft models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP showing MTBP-enhanced ETS-1 promoter recruitment, functional luciferase and proliferation assays, single lab with multiple methods\",\n      \"pmids\": [\"36106099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTBP is a limiting firing factor for replication initiation whose loading onto phosphorylated MCM2-7 double hexamer (MCM-DH) is controlled by opposing phosphorylation events: Dbf4-dependent kinase (DDK) promotes and RIF1-Protein Phosphatase 1 opposes TRESLIN-MTBP loading, ultimately determining initiation zones (IZs) and replication timing (RT).\",\n      \"method\": \"Genome-wide mapping of firing factors, auxin-inducible degron (AID) system, kinase/phosphatase manipulation, chromatin fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genomic and biochemical methods, inducible degradation system, kinase/phosphatase functional experiments, single lab\",\n      \"pmids\": [\"41331242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTBP is dependent on TRESLIN for proper chromatin association during G1, but not during S phase, indicating two separate modes of chromatin binding. TRESLIN and MTBP binding to chromatin during G1 does not require licensed origins (loaded MCMs), diverging from yeast Sld3-Sld7 mechanism.\",\n      \"method\": \"CUT&RUN genomic binding assay, Geminin overexpression to inhibit licensing, G1 synchronization, siRNA knockdown\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&RUN with cell cycle synchronization and licensing inhibition experiments, single lab, multiple conditions\",\n      \"pmids\": [\"40624716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDK activity controls TRESLIN and MTBP abundance and chromatin recruitment to promote dormant origin activation. WEE1 inhibition (increased CDK activity) blocks PCNA-dependent degradation of TRESLIN and enhances chromatin loading of both TRESLIN and MTBP, leading to elevated helicase recruitment. This effect depends on both TRESLIN and MTBP, and a conserved TRESLIN sequence mediates CDK-sensitive degradation.\",\n      \"method\": \"WEE1 inhibition, CDK inhibition, PCNA degradation assays, chromatin fractionation, siRNA knockdown, DNA synthesis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, multiple biochemical methods but not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.10.657920\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTBP allosterically activates Cdk8/19-CycC kinase activity in vitro by repositioning the T-loop of the kinase independently of T-loop phosphorylation, acting as a targeting and activation factor distinct from Med12. MTBP targets Cdk8/19-CycC to Med12-independent cellular roles (including replication origin firing), while Med12 targets it to the Mediator complex for transcription control. Both MTBP and Med12 are mutually exclusive allosteric activators of Cdk8/19-CycC.\",\n      \"method\": \"In vitro kinase assays, structural analysis, mutagenesis, protein interaction studies\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase reconstitution with structural basis described, but preprint only, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659917\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MTBP is a multifunctional protein that: (1) serves as an essential component of the Treslin-MTBP complex (the metazoan ortholog of yeast Sld3-Sld7) required for CDC45 loading and replication origin firing, with its CTM domain binding DNA and chromatin and its activity regulated by CDK and checkpoint kinase phosphorylation; (2) promotes MDM2-mediated ubiquitination and degradation of p53 while stabilizing MDM2, thereby contributing to p53 homeostasis; (3) suppresses cell migration and metastasis by binding and inhibiting alpha-actinin-4 (ACTN4) and by blocking nuclear import of phospho-Erk1/2 via interaction with importin-7/IPO7; (4) functions as a transcriptional co-activator for MYC and ETS-1 at target gene promoters; and (5) plays a role in mitotic checkpoint regulation by recruiting Mad1/Mad2 to kinetochores, with its degradation required for checkpoint silencing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTBP is a multifunctional regulator that operates at the intersection of DNA replication initiation, p53 homeostasis, and cell migration control. Its best-characterized role is as the essential metazoan partner of TRESLIN, with which it forms an elongated tetramer (two copies of each protein) that is rate-limiting for replication origin firing; depletion of MTBP abolishes DNA replication in Xenopus egg extracts and can only be rescued by the reconstituted TRESLIN-MTBP complex [#7, #11]. A C-terminal Sld7-homologous CTM domain binds double-stranded and G-quadruplex DNA and is required for chromatin localization and CDC45 loading [#7], and genome-wide the complex associates with tens of thousands of open-chromatin regulatory elements bearing G4 motifs, AP-1 sites, and H3K4me2 nucleosomes [#9]. MTBP loading onto phosphorylated MCM2-7 double hexamers is governed by opposing phosphorylation: CDK and DDK promote, while RIF1-PP1 opposes, thereby setting initiation zones and replication timing [#14], and direct CDK phosphorylation of MTBP at activating versus checkpoint-kinase sites tunes origin firing capacity in either direction [#10]. By acting transiently at pre-replication complexes and being released after CDC45 recruitment, TRESLIN-MTBP also implements a checkpoint-independent monitoring system that prevents premature S/G2 transition [#12]. Independently, MTBP promotes MDM2-mediated ubiquitination and degradation of p53 while stabilizing MDM2, contributing to p53 homeostasis [#1], and it has an essential p53-independent developmental function, as Mtbp-null mice die early in embryogenesis irrespective of p53 status [#2]. MTBP suppresses cell migration and metastasis by binding and inhibiting the actin-bundling protein ACTN4 [#4] and by sequestering importin-7/IPO7 to block nuclear import of phospho-Erk1/2 [#8]. It additionally serves as a transcriptional co-activator, associating with MYC cofactors TIP48/TIP49 at MYC-bound promoters to drive transformation [#5] and enhancing ETS-1 recruitment to target promoters [#13]. A distinct mitotic role involves transient kinetochore localization and recruitment of Mad1/Mad2 during prometaphase, with MTBP degradation required for checkpoint silencing [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established MTBP as a physical and functional partner of MDM2, defining its first molecular context as a growth-regulatory factor.\",\n      \"evidence\": \"Yeast two-hybrid screen and cell cycle analysis identifying MTBP and MDM2-suppressible G1 arrest\",\n      \"pmids\": [\"10906133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MTBP-induced G1 arrest not defined\", \"Binding interface with MDM2 not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how MTBP feeds into the p53 pathway, showing it potentiates MDM2 ligase function rather than merely binding it.\",\n      \"evidence\": \"siRNA knockdown, in vitro ubiquitination assays, and MDM2 RING finger mutants with Western blotting\",\n      \"pmids\": [\"15632057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MTBP is a direct ubiquitination substrate or only a cofactor\", \"Structural basis of MDM2 stabilization unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated MTBP has an essential developmental role separable from p53 and a haploinsufficient tumor-suppressive/anti-metastatic function in vivo.\",\n      \"evidence\": \"Mtbp knockout and haploinsufficient mouse models with in vivo tumor/metastasis and in vitro invasion assays\",\n      \"pmids\": [\"17906694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the essential embryonic function not defined\", \"Mechanism linking MTBP loss to increased metastasis not yet established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a mitotic checkpoint role, showing MTBP is needed for Mad1/Mad2 kinetochore recruitment and that its timed degradation permits checkpoint silencing.\",\n      \"evidence\": \"Immunofluorescence, live-cell imaging, siRNA knockdown and overexpression with flow cytometry\",\n      \"pmids\": [\"21274008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partners at the kinetochore not identified\", \"Relationship between mitotic and replication functions unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided a biochemical mechanism for MTBP's anti-migratory activity through direct inhibition of ACTN4-mediated actin bundling.\",\n      \"evidence\": \"Reciprocal Co-IP and mass spectrometry, F-actin bundling assays, and migration assays\",\n      \"pmids\": [\"22370640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ACTN4-binding region of MTBP not mapped\", \"Regulation of the cytoplasmic MTBP pool not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked MTBP to oncogenic transcription, showing it associates with MYC cofactors TIP48/TIP49 at MYC promoters to amplify MYC-driven transformation.\",\n      \"evidence\": \"Co-IP, ChIP at MYC-bound promoters, transcriptional and transformation assays, in vivo tumor models\",\n      \"pmids\": [\"24786788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MTBP contacts MYC directly or only via TIP48/TIP49 unresolved\", \"Reconciliation with tumor-suppressive functions not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Proposed an EMT-promoting mechanism via MDM2-dependent E-cadherin degradation in HCC.\",\n      \"evidence\": \"Western blotting, knockdown/overexpression, migration/invasion and in vivo metastasis assays\",\n      \"pmids\": [\"26280083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of MDM2-mediated E-cadherin ubiquitination\", \"Apparent conflict with anti-metastatic findings unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined MTBP's core replication function, establishing the DNA-binding CTM domain and the obligate TRESLIN-MTBP complex as essential for CDC45 loading and origin firing.\",\n      \"evidence\": \"Xenopus egg extract depletion/add-back, DNA-binding assays, CTM domain mutagenesis, and chromatin fractionation in human cells\",\n      \"pmids\": [\"28877985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the CTM-DNA interaction not solved\", \"Sequence determinants of genomic site selection not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Added a signaling mechanism for metastasis suppression, showing MTBP blocks IPO7-mediated nuclear import of phospho-Erk1/2 to dampen Elk-1 transcription.\",\n      \"evidence\": \"Co-IP, reporter signal arrays, phosphorylation assays, immunofluorescence, and clinical tissue analysis\",\n      \"pmids\": [\"29765550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IPO7-binding interface not mapped\", \"Single-lab Co-IP without reconstitution of the import-blocking step\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped where TRESLIN-MTBP acts genome-wide, revealing preferential association with open-chromatin regulatory elements and specific DNA/nucleosome signals.\",\n      \"evidence\": \"ChIP-seq and chromatin accessibility analysis in human cells\",\n      \"pmids\": [\"32966791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between individual binding signals and firing not dissected\", \"Functional outcome at each site class not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established MTBP as a phospho-regulated platform integrating activating CDK signals and inhibitory checkpoint-kinase signals to set origin-firing levels.\",\n      \"evidence\": \"Phospho-mimetic and non-phosphorylatable mutants with origin firing and DNA damage response assays in human cells\",\n      \"pmids\": [\"33608586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identities of all responsible kinases not fully defined\", \"How phospho-states alter chromatin loading mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the architecture and kinase-dependent activation of the complex, showing TRESLIN-MTBP is a rate-limiting tetramer whose chromatin and TopBP1 engagement is driven by DDK and CDK.\",\n      \"evidence\": \"Xenopus egg extract depletion/add-back, complex stoichiometry analysis, and kinase inhibitor experiments\",\n      \"pmids\": [\"34699733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the tetramer not determined\", \"Order of DDK and CDK inputs not fully ordered\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a checkpoint-independent surveillance role, showing transient TRESLIN-MTBP action at preRCs monitors origin firing rate to prevent premature S/G2 transition.\",\n      \"evidence\": \"Cell synchronization, protein depletion/add-back, ChIP, and kinase inhibitor experiments\",\n      \"pmids\": [\"36049481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor reading the firing-rate decline not identified\", \"Downstream effector enforcing S/G2 timing unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the transcriptional co-activator role to ETS-1, showing MTBP enhances ETS-1 promoter recruitment to drive HCC proliferation.\",\n      \"evidence\": \"Luciferase reporters, qPCR, ChIP, knockdown/overexpression, and xenograft models\",\n      \"pmids\": [\"36106099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MTBP-ETS-1 contact versus indirect bridging not resolved\", \"Generality beyond the mmp1 promoter untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed MTBP loading at the center of replication timing control, showing opposing DDK and RIF1-PP1 phosphorylation events set initiation zones.\",\n      \"evidence\": \"Genome-wide firing-factor mapping, auxin-inducible degron, and kinase/phosphatase manipulation with chromatin fractionation\",\n      \"pmids\": [\"41331242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphosites on MCM-DH targeted by this regulation not enumerated\", \"Quantitative threshold determining IZ selection unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished two chromatin-binding modes, showing MTBP requires TRESLIN for G1 association but binds independently in S phase, diverging from the yeast Sld3-Sld7 paradigm.\",\n      \"evidence\": \"CUT&RUN with G1 synchronization, Geminin-mediated licensing inhibition, and siRNA knockdown\",\n      \"pmids\": [\"40624716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of licensing-independent G1 binding unknown\", \"Functional purpose of pre-licensing chromatin association unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a kinase-activating function, showing MTBP allosterically activates and targets Cdk8/19-CycC to Med12-independent roles including origin firing.\",\n      \"evidence\": \"In vitro kinase assays, structural analysis, and mutagenesis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"In vivo contribution of MTBP-Cdk8/19 to origin firing not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTBP's distinct functions in replication initiation, p53/MDM2 control, migration suppression, transcriptional co-activation, and mitotic checkpoint signaling are coordinated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting nuclear replication roles with cytoplasmic anti-migratory roles\", \"Whether distinct functions reflect separable protein pools or domains not determined\", \"Reconciliation of tumor-suppressive versus oncogenic activities unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [7, 9, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [7, 11, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"TRESLIN-MTBP complex\"\n    ],\n    \"partners\": [\n      \"TRESLIN\",\n      \"MDM2\",\n      \"ACTN4\",\n      \"IPO7\",\n      \"TIP48\",\n      \"TIP49\",\n      \"TopBP1\",\n      \"CDK8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}