{"gene":"MTA1","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2002,"finding":"A naturally occurring short isoform of MTA1 (MTA1s) contains a unique 33-amino-acid sequence with an ER-binding motif (LRILL). MTA1s localizes in the cytoplasm, sequesters ERα in the cytoplasm via this LRILL motif, and enhances non-genomic ER responses. Deletion of the LRILL motif abolishes MTA1s co-repressor function and its interaction with ERα, and restores nuclear localization of ERα. HER2 dysregulation in breast cancer cells enhances MTA1s expression and cytoplasmic ERα sequestration.","method":"Domain deletion mutagenesis, subcellular fractionation/immunofluorescence, Co-IP, ectopic expression in breast cancer cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific motif, functional rescue, reciprocal interaction assays, multiple orthogonal methods in a single rigorous study","pmids":["12167865"],"is_preprint":false},{"year":2002,"finding":"MTA1 represses MMP-9 (92-kDa type IV collagenase) expression by binding to the distal MMP-9 promoter region and recruiting HDAC2, leading to diminished histone H3/H4 acetylation. MTA1 also recruits the nucleosome-remodeling Mi2 activity to the proximal promoter region. Trichostatin A only partially relieves MTA1-mediated repression, indicating both HDAC-dependent and HDAC-independent (Mi2-dependent) mechanisms.","method":"Chromatin immunoprecipitation (ChIP), Co-IP, DNase I hypersensitivity assay, forced expression, TSA treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP plus Co-IP plus functional rescue with multiple mechanistic components in one study","pmids":["12431981"],"is_preprint":false},{"year":2003,"finding":"MTA1 interacts with MICoA (MTA1-interacting coactivator), identified by yeast two-hybrid screening. MICoA binds to the C-terminal region of MTA1 via an LSRLL nuclear receptor interaction motif, and the interaction was confirmed in vitro and in vivo. MTA1 represses MICoA-stimulated ERα transactivation and interferes with MICoA's association with ER-target gene promoter chromatin.","method":"Yeast two-hybrid, in vitro binding, Co-IP, chromatin immunoprecipitation, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid, in vitro and in vivo binding, ChIP, reporter assay; multiple orthogonal methods","pmids":["12639951"],"is_preprint":false},{"year":2003,"finding":"MTA1 interacts with MAT1, an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK). MTA1 binds the N-terminal RING finger domain of MAT1 via two MTA1 domains (C-terminal GATA domain and N-terminal bromo-domain). MTA1 inhibits CAK-stimulated ERα transactivation and inhibits CAK-mediated phosphorylation of ERα, partly through HDAC recruitment.","method":"Yeast two-hybrid, Co-IP (in vitro and in vivo), reporter assay, kinase assay, TSA treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid, in vitro and in vivo Co-IP, kinase assay, reporter assay; multiple orthogonal methods","pmids":["12527756"],"is_preprint":false},{"year":2006,"finding":"MTA1 acts as a transcriptional activator of BCAS3, a gene amplified in breast cancers. MTA1 stimulation of BCAS3 transcription requires ERα and an ERE half-site in the BCAS3 locus. MTA1 is acetylated on Lys626, and this acetylation is necessary for productive recruitment of RNA polymerase II complex to the BCAS3 enhancer.","method":"Functional genomic/chromatin screen, ChIP, reporter assay, site-directed mutagenesis of acetylation site, transgenic mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, mutagenesis of acetylation site, reporter assay, in vivo transgenic mouse validation","pmids":["16617102"],"is_preprint":false},{"year":2007,"finding":"MTA1-NuRD complex transcriptionally represses BRCA1 by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter in an ERα-dependent manner, recruiting HDAC. MTA1 overexpression causes centrosome amplification (a BRCA1 repression phenotype), reversible by BRCA1 re-expression.","method":"ChIP, Co-IP, siRNA knockdown, HDAC inhibitor (TSA) treatment, centrosome amplification assay, rescue experiment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP, Co-IP, functional rescue experiment, phenotypic readout; multiple orthogonal methods","pmids":["17922032"],"is_preprint":false},{"year":2007,"finding":"MTA1 acetylated on Lys626 interacts with p300 histone acetyltransferase and is recruited to the Pax5 promoter to stimulate Pax5 transcription, identified as a target driving B-cell lymphomagenesis in MTA1-transgenic mice.","method":"ChIP, Co-IP, gene expression profiling, transgenic mouse model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, Co-IP, validated in vivo in MTA1-TG mouse model, gene profiling","pmids":["17671180"],"is_preprint":false},{"year":2008,"finding":"MTA1 and HDAC1/2 physically associate with HIF-1α in the presence of HBx (hepatitis B virus X protein). MTA1/HDAC complex deacetylates the oxygen-dependent degradation domain of HIF-1α, leading to dissociation of prolyl hydroxylases and VHL from HIF-1α and thereby stabilizing HIF-1α. Knockdown of MTA1 abolishes this HBx-induced HIF-1α stabilization.","method":"Co-IP in vivo, siRNA knockdown, immunoprecipitation, HBx-transgenic mouse","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA knockdown with rescue, in vivo transgenic mouse validation","pmids":["18264140"],"is_preprint":false},{"year":2009,"finding":"MTA1 is an ubiquitinated protein targeted by the RING-finger E3 ligase COP1 for degradation via the ubiquitin-proteasome pathway. Wild-type COP1 but not RING motif mutants promotes MTA1 ubiquitination and degradation. MTA1 in turn destabilizes COP1 by promoting COP1 autoubiquitination, creating a feedback loop. Ionizing radiation disrupts COP1-mediated MTA1 proteolysis, stabilizing MTA1 and promoting DNA double-strand break repair.","method":"Ubiquitination assay, proteasome inhibition, COP1 RING mutant expression, siRNA knockdown, Co-IP, DNA damage (IR) assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitination, domain mutagenesis, Co-IP, loss-of-function experiments with multiple readouts","pmids":["19805145"],"is_preprint":false},{"year":2009,"finding":"MTA1 controls p53 stability by competing with COP1 to bind p53 and/or destabilizing COP1 and Mdm2, thereby inhibiting p53 ubiquitination. MTA1 regulates p53-dependent transcription of p53R2 (required for DNA repair). MTA1 depletion impairs p53-dependent p53R2 transcription and DNA repair, reversible by MTA1 re-introduction.","method":"Co-IP, ubiquitination assay, siRNA knockdown, ChIP, reporter assay, DNA repair assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, ubiquitination assay, ChIP, functional rescue; multiple orthogonal methods","pmids":["19837670"],"is_preprint":false},{"year":2010,"finding":"MTA1 is a p53-independent transcriptional corepressor of p21WAF1. The mechanism involves recruitment of MTA1-HDAC2 complexes onto two selective regions of the p21WAF1 promoter. MTA1 depletion superinduces p21WAF1 even in p53-null cells, increases p21WAF1 binding to PCNA, and decreases nuclear PCNA accumulation after ionizing radiation. MTA1 expression in p53-null cells inhibits p21WAF1 promoter activity and increases DNA DSB repair.","method":"ChIP, siRNA knockdown in p53-null cells, reporter assay, Co-IP, gamma-H2AX focus assay, PCNA interaction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP, p53-null genetic system, multiple functional readouts, reporter assay","pmids":["20071335"],"is_preprint":false},{"year":2010,"finding":"UV radiation stabilizes MTA1 in an ATR-dependent manner and increases MTA1 binding to ATR. MTA1 depletion compromises ATR-mediated Chk1 activation by down-regulating Chk1 and its adaptor Claspin, and decreases gamma-H2AX induction and focus formation after UV treatment. MTA1 deficiency causes defective G2-M checkpoint and increased cellular sensitivity to UV-induced DNA damage.","method":"siRNA knockdown, Co-IP (MTA1-ATR), Western blot, gamma-H2AX focus assay, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating MTA1-ATR binding, loss-of-function with defined checkpoint phenotype, multiple readouts","pmids":["20427275"],"is_preprint":false},{"year":2010,"finding":"MTA1 is required for expression of MyD88 in LPS-stimulated macrophages and for MyD88-dependent NF-κB signaling. LPS stimulation promotes enhanced recruitment of MTA1, RNA Pol II, and p65RelA to NF-κB consensus sites in the MyD88 promoter. MTA1 depletion substantially reduces expression of NF-κB target genes (IL-1β, MIP2, TNF-α).","method":"ChIP, siRNA knockdown, NF-κB inhibitor (parthenolide) treatment, reporter assay, cytokine expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP of MTA1 at MyD88 promoter, siRNA with specific NF-κB pathway readouts, pharmacological inhibitor","pmids":["20702415"],"is_preprint":false},{"year":2010,"finding":"MTA1 is an obligatory coregulator of transglutaminase 2 (TG2) expression in LPS-stimulated macrophages. MTA1 depletion impairs basal and LPS-induced TG2 expression. MTA1, p65RelA, and RNA Pol II are recruited to NF-κB consensus sites in the TG2 promoter during LPS stimulation.","method":"ChIP, siRNA knockdown, gene expression analysis, NF-κB inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP at TG2 promoter, siRNA knockdown with specific transcriptional readouts, pharmacological validation","pmids":["21156794"],"is_preprint":false},{"year":2011,"finding":"MTA1 is SUMOylated by SUMO2/3 in vivo at Lys509 within a SUMO consensus site. PIAS proteins enhance SUMOylation of MTA1, while SENP1 and SENP2 act as deSUMOylation enzymes. MTA1 contains a functional SUMO-interacting motif (SIM) at its C terminus required for efficient SUMOylation. SUMO conjugation on Lys509 together with SIM synergistically regulates MTA1 co-repressor activity on pS2 transcription, likely by recruiting HDAC2 to the pS2 promoter. MTA1 also upregulates SUMO2 expression by interacting with RNA Pol II and SP1 at the SUMO2 promoter.","method":"In vivo SUMOylation assay, site-directed mutagenesis (K509), Co-IP, reporter assay, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vivo SUMOylation, mutagenesis of specific lysine residue, ChIP, reporter assay; multiple orthogonal methods","pmids":["21965678"],"is_preprint":false},{"year":2012,"finding":"p53 mediates transcriptional repression of the MTA1 gene through two p53-response elements (p53REs) in the MTA1 promoter. This repression requires poly(ADP-ribosyl)ation of p53 by PARP-1 (identified in the repressor complex by proteomics). p53 and HDAC1/2 are recruited to the MTA1 promoter after 5-FU treatment, with decreased H3K9 acetylation. Repression occurs only in p53 wild-type cells.","method":"ChIP, reporter assay, siRNA, proteomics/pull-down of promoter-bound complex, PARP-1 inhibition","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP, promoter proteomics, p53 WT vs null cells, poly(ADP-ribosyl)ation assay; multiple orthogonal methods","pmids":["22286760"],"is_preprint":false},{"year":2012,"finding":"MTA1 transcriptionally represses SMAD7 (an inhibitory SMAD and negative regulator of TGF-β signaling) in breast cancer cell lines. MTA1 is recruited to the SMAD7 promoter. MTA1 knockdown increases SMAD7 expression (reversed by HDAC inhibitor), and decreases levels of active SMAD2 and SMAD3.","method":"ChIP, shRNA knockdown, HDAC inhibitor treatment, Western blot","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP showing MTA1 promoter binding, siRNA with functional readout; single lab, limited orthogonal validation","pmids":["22841502"],"is_preprint":false},{"year":2013,"finding":"MTA1 acts as a mandatory modifier of breast-to-lung metastasis (without affecting primary tumor formation) in a spontaneous mouse model. The mechanism involves MTA1-dependent stimulation of STAT3 transcription through formation of an MTA1/STAT3/Pol II coactivator complex, and consequent expression of STAT3 target genes including Twist1.","method":"Genetic depletion of MTA1 in spontaneous mouse breast cancer model, Co-IP (MTA1/STAT3/Pol II complex), gene expression analysis, ChIP","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model, Co-IP of complex, ChIP; multiple methods with in vivo validation","pmids":["23580571"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of RbAp48-MTA1 subcomplex was determined. RbAp48 recognizes MTA1 using the same surface it uses to bind histone H4, showing that NuRD assembly modulates RbAp46/48 interactions with histones. The MTA proteins act as scaffolds for NuRD complex assembly, and the RbAp48-MTA1 interaction is essential for in vivo integration of RbAp46/48 into the NuRD complex.","method":"Crystal structure determination, in vitro binding assay, in vivo NuRD complex assembly assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional validation of in vivo complex assembly; orthogonal structural and biochemical methods","pmids":["24920672"],"is_preprint":false},{"year":2014,"finding":"MTA1 localizes to the nucleus, cytoplasm, and nuclear envelope. Nuclear envelope localization depends on TPR (translocated promoter region). Cytoplasmic MTA1 associates with microtubules. Nuclear but not cytoplasmic MTA1 is associated with cancer differentiation: MTA1 overexpression inhibits differentiation and promotes proliferation in HCT116 cells, while MTA1 knockdown results in cell differentiation and death.","method":"Multiple immunofluorescence/localization approaches, siRNA knockdown, OE, differentiation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — subcellular fractionation/imaging with functional consequence, domain-dependent localization assays; single lab","pmids":["24970816"],"is_preprint":false},{"year":2014,"finding":"MTA1 is a higher-order chromatin structure organizer that decondenses interphase chromatin and mitotic chromosomes. MTA1 interacts dynamically with nucleosomes during the cell cycle. MTA1-induced chromatin decondensation is independent of Mi-2 chromatin remodeling activity. MTA1 causes reduced histone H1-chromatin interaction in vivo, and this dynamic MTA1-chromatin interaction contributes to periodic H1-chromatin interaction modulating chromatin/chromosome transitions.","method":"Live-cell imaging, FRAP, chromatin fractionation, siRNA/OE experiments, chromosome structure analysis","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct chromatin interaction assays, live imaging; single lab with functional consequence for chromatin structure","pmids":["25205035"],"is_preprint":false},{"year":2016,"finding":"MTA1 can bind two molecules of RBBP4 (RbAp48). Negative stain electron microscopy and chemical crosslinking data provide a low-resolution model of an MTA1-(RBBP4)2 subcomplex within NuRD.","method":"In vitro binding/pull-down, negative stain EM, chemical crosslinking mass spectrometry","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted subcomplex, structural EM, chemical crosslinking; single lab but multiple orthogonal structural methods","pmids":["27144666"],"is_preprint":false},{"year":2017,"finding":"MTA1 directly induces miR-22 (Epi-miR) expression in prostate cancer cells. MiR-22 directly targets the 3'-UTR of E-cadherin, reducing its expression. MTA1 overexpression promotes invasiveness and migration via this MTA1/miR-22/E-cadherin axis.","method":"siRNA/OE loss- and gain-of-function, luciferase 3'-UTR reporter assay, ChIP for MTA1 at miR-22 locus","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — luciferase 3'-UTR reporter, ChIP, loss/gain-of-function; single lab","pmids":["28231399"],"is_preprint":false},{"year":2017,"finding":"MTA1 promotes transcription of ErbB2 by binding with HDAC2 and acting at the ErbB2 promoter in hepatocellular carcinoma cells. The EMT-promoting effect caused by MTA1 largely depends on ErbB2; reducing ErbB2 activity attenuates MTA1-induced EMT both in vitro and in vivo.","method":"ChIP (MTA1 and HDAC2 at ErbB2 promoter), siRNA/OE, Co-IP, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP, Co-IP, in vivo validation; single lab","pmids":["28288133"],"is_preprint":false},{"year":2018,"finding":"PWWP2A interacts with an MTA1-specific subcomplex of NuRD (M1HR) consisting solely of MTA1, HDAC1, and RBBP4/7 (excluding CHD, GATAD2, and MBD proteins). PWWP2A depletion leads to increased acetylation of H3K27 and H2A.Z, suggesting PWWP2A directs M1HR to H2A.Z-containing chromatin to promote deacetylation.","method":"Affinity purification/MS, Co-IP, ChIP-seq, siRNA knockdown with histone acetylation readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — AP-MS identification of subcomplex, ChIP-seq, loss-of-function with histone modification readout; multiple orthogonal methods","pmids":["30327463"],"is_preprint":false},{"year":2019,"finding":"MTA1 regulates LDHA expression by interacting with c-Myc and recruiting the MTA1-c-Myc complex to the LDHA promoter. LDHA knockdown in MTA1-stably expressing MCF7 cells reduces cell migration, linking MTA1-LDHA axis to breast cancer motility.","method":"ChIP (MTA1 and c-Myc at LDHA promoter), Co-IP, siRNA, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — ChIP, Co-IP, single lab; limited orthogonal validation","pmids":["31570164"],"is_preprint":false},{"year":2019,"finding":"VEGF induces tyrosine phosphorylation of endogenous MTA1 mediated through VEGFR2 and p38-MAP kinase. Extracellular recombinant MTA1 protein binds to cell membranes (distinct from nuclear MTA1), activates ERK and JNK pathways, and induces angiogenesis comparable to or exceeding VEGF. MTA1 upregulates VEGF and Flt-1 gene expression via their promoters.","method":"Recombinant MTA1 protein treatment, immunofluorescence for cell membrane binding, phosphorylation assays, luciferase reporter (VEGF/Flt-1 promoters), in vivo angiogenesis models (cornea, CAM, xenograft)","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple in vitro and in vivo angiogenesis assays, reporter assays; single lab with several methods","pmids":["24265228"],"is_preprint":false},{"year":2019,"finding":"MTA1 is transferred between breast cancer cells via exosomes and can be delivered to vascular endothelial cells. Exosome-transferred MTA1 regulates hypoxic response (co-repressor function) and estrogen receptor signaling (co-activator function) in recipient cells. MTA1 knockout reduces cell proliferation and attenuates hypoxic response, rescued by addition of MTA1-containing exosomes.","method":"Antibody array, CRISPR/Cas9 MTA1 knockout, tdTomato-MTA1 ectopic expression and exosome tracking by fluorescence microscopy, reporter assays, exosome transfer experiments","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — CRISPR KO, exosome tracking with fluorescent tag, reporter assays; single lab","pmids":["30782165"],"is_preprint":false},{"year":2019,"finding":"TGF-β induces MTA1 expression, and MTA1 acts upstream of SOX4 in the TGF-β pathway. The TGF-β-MTA1-SOX4-EZH2 signaling axis drives EMT in multiple cancer cell lines. MTA1 overexpression activates SOX4, which in turn activates EZH2; epistasis experiments show MTA1 is upstream of SOX4 and that SOX4 is required for MTA1-driven EMT.","method":"Epistasis/pathway dissection by siRNA and OE, gene expression profiling, shRNA, in vitro EMT assays in multiple cell lines, TCGA analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — genetic epistasis by siRNA in multiple cell lines, gene expression profiling; single lab","pmids":["31811272"],"is_preprint":false},{"year":2020,"finding":"MTA1 broadly interacts with RNA-binding proteins (RBPs) and directly binds abundant transcripts (preferentially at splicing-responsible motifs) as shown by fCLIP-seq. MTA1 regulates mRNA levels and alternative splicing of mitosis regulators including ATRX and MYBL2. MTA1 deletion causes defective mitotic arrest, aberrant chromosome segregation, and chromosomal instability (CIN), contributing to tumorigenesis.","method":"fCLIP-seq, RNA-seq, siRNA/KO, chromosome segregation and CIN assays, alternative splicing analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel fCLIP-seq method directly mapping MTA1-RNA binding, functional KO with CIN phenotype; multiple orthogonal methods","pmids":["32901005"],"is_preprint":false},{"year":2021,"finding":"O-GlcNAc modification of MTA1 at serine residues S237/S241/S246 (identified by quantitative proteomics) promotes MTA1 interaction with chromatin and enhances its association with the NuRD complex. O-GlcNAc-modified MTA1 shows altered genome-wide chromatin binding patterns (ChIP-seq) and changes expression of target genes involved in genotoxic adaptation in adriamycin-resistant breast cancer cells.","method":"Quantitative proteomics (mass spectrometry of O-GlcNAc sites), ChIP-seq, transcriptome analysis, OGT inhibition/OE","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry-identified modification sites, ChIP-seq; single lab","pmids":["34019948"],"is_preprint":false},{"year":2022,"finding":"RUNX2 recruits the MTA1/NuRD complex and the CUL4B-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex that catalyzes both histone deacetylation and ubiquitylation. Genome-wide analysis identified PPARα and SOD2 as targets of the RUNX2/NuRD(MTA1)/CRL4B complex. This complex promotes breast cancer proliferation, invasion, bone metastasis, and cancer stemness.","method":"Co-IP, ChIP-seq, genome-wide target analysis, in vitro and in vivo functional assays (proliferation, invasion, bone metastasis xenograft)","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of multi-protein complex, ChIP-seq, in vivo xenograft bone metastasis model; multiple orthogonal methods","pmids":["35534547"],"is_preprint":false},{"year":2022,"finding":"RNA-binding protein RALY cooperates with splicing factor SF3B3 to regulate MTA1 alternative splicing, switching from the MTA1-S isoform to MTA1-L. MTA1-S (short isoform) normally inhibits cell proliferation by reducing transcription of cholesterol synthesis genes; the RALY/SF3B3-driven splicing switch reduces MTA1-S levels and thereby relieves inhibition of cholesterol synthesis, promoting hepatocellular carcinoma proliferation.","method":"RNA splicing assays, siRNA/OE of RALY and SF3B3, gene expression analysis, cholesterol synthesis pathway analysis, cell proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — splicing assays, loss- and gain-of-function, pathway readouts; single lab","pmids":["35490918"],"is_preprint":false},{"year":2001,"finding":"Nuclear localization of mouse Mta1 depends on the presence of at least one nuclear localization signal (NLS) and one SH3 binding site (proline-rich Src homology 3 ligand) in the C-terminal region. These SH3 ligands facilitate interaction with the adaptor protein Grb2 and the Src-family tyrosine kinase Fyn. GFP-Mta1 localizes exclusively in the nucleus while GFP-Mta3 is present in both nucleus and cytoplasm.","method":"GFP-tagged deletion construct expression, fluorescence microscopy, Co-IP (Grb2/Fyn interaction)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — deletion constructs with localization readout, Co-IP; single lab, mouse ortholog","pmids":["11483358"],"is_preprint":false},{"year":2010,"finding":"MTA1 induces AMPK activation (associated with increased AMP:ATP ratio and decreased mitochondrial electron transport complex components) and subsequent autophagy flux, contributing to tamoxifen resistance in breast cancer cells. ATG7 knockdown or autophagy inhibition (hydroxychloroquine) restores tamoxifen sensitivity in MTA1-overexpressing and tamoxifen-resistant cells.","method":"Stable MTA1 overexpression cell line, siRNA (ATG7), autophagy flux assay, in vitro and in vivo growth assays, AMPK activation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — stable OE with multiple functional readouts, genetic (ATG7 KD) and pharmacological validation; single lab","pmids":["29130361"],"is_preprint":false}],"current_model":"MTA1 is a multifunctional chromatin modifier that serves as the scaffold subunit of the NuRD (nucleosome remodeling and deacetylase) complex, where it recruits HDAC1/2 via its ELM2-SANT domain and interacts with RbAp46/48 (RBBP4/7) to assemble enzymatic activities; it acts as a transcriptional co-repressor of ERα, BRCA1, p21WAF1, and SMAD7 through HDAC-dependent and -independent (Mi2/chromatin remodeling) mechanisms, and as a co-activator of BCAS3, Pax5, STAT3, and LDHA through acetylation of Lys626, interaction with p300 and c-Myc, and RNA Pol II recruitment; its stability is regulated by COP1-mediated ubiquitin-proteasome degradation and by SUMO2/3 conjugation on Lys509 and by O-GlcNAc modification; it participates in DNA damage response via ATR-Claspin-Chk1 and p53-p53R2 pathways, modulates alternative splicing of mitosis regulators to maintain chromosomal stability, and is transferred between cells via exosomes to regulate hypoxia and estrogen signaling in the tumor microenvironment."},"narrative":{"mechanistic_narrative":"MTA1 is the scaffold subunit of the NuRD (nucleosome remodeling and deacetylase) complex and a multifunctional chromatin-associated coregulator that controls transcription, genome stability, and tumor progression [PMID:24920672, PMID:32901005]. As a NuRD scaffold it binds RbAp46/48 (RBBP4/7) — using the same RbAp48 surface that engages histone H4, and accommodating two RBBP4 molecules — to integrate these subunits into the complex, and it can assemble a minimal MTA1-HDAC1-RBBP4/7 subcomplex (M1HR) recruited to H2A.Z chromatin by PWWP2A [PMID:24920672, PMID:27144666, PMID:30327463]. Through this machinery MTA1 acts predominantly as an HDAC-dependent transcriptional corepressor, binding target promoters and recruiting HDAC1/2 to deacetylate histones; it represses MMP-9 (also via HDAC-independent Mi2/remodeling activity), BRCA1, p21WAF1, and SMAD7, and antagonizes estrogen receptor signaling by sequestering coactivators such as MICoA and inhibiting CAK-mediated ERα phosphorylation [PMID:12431981, PMID:17922032, PMID:20071335, PMID:22841502, PMID:12639951, PMID:12527756]. MTA1 also functions as a context-dependent transcriptional activator: acetylation on Lys626 enables p300 binding and RNA Pol II recruitment to drive BCAS3 and Pax5, and it forms coactivator complexes with STAT3, c-Myc, and NF-κB/p65RelA to induce STAT3 targets, LDHA, and inflammatory genes [PMID:16617102, PMID:17671180, PMID:23580571, PMID:31570164, PMID:20702415]. A cytoplasmic short isoform (MTA1s) bearing an LRILL motif sequesters ERα in the cytoplasm to enhance non-genomic estrogen signaling [PMID:12167865]. MTA1 supports genome integrity by stabilizing HIF-1α through deacetylation, controlling p53 stability and p53R2-dependent repair, coupling to ATR-Claspin-Chk1 checkpoint signaling, and regulating alternative splicing of mitosis regulators to prevent chromosomal instability [PMID:18264140, PMID:19837670, PMID:20427275, PMID:32901005]. Its abundance and activity are tuned by COP1-mediated ubiquitin-proteasome degradation (disrupted by ionizing radiation), p53-PARP1-driven transcriptional repression, SUMO2/3 conjugation at Lys509, and O-GlcNAcylation, the latter enhancing chromatin and NuRD association [PMID:19805145, PMID:22286760, PMID:21965678, PMID:34019948].","teleology":[{"year":2001,"claim":"Established the determinants of MTA1 subcellular targeting, showing nuclear localization is encoded by C-terminal signals while distinct ligand motifs link it to cytoplasmic signaling adaptors.","evidence":"GFP-tagged deletion constructs and Co-IP in mouse Mta1, mapping NLS and SH3 ligand sites and Grb2/Fyn binding","pmids":["11483358"],"confidence":"Medium","gaps":["Human MTA1 not directly tested","Functional consequence of Grb2/Fyn binding for transcription unresolved"]},{"year":2002,"claim":"Defined a non-genomic mode of MTA1 action: a cytoplasmic short isoform directly sequesters ERα to redirect estrogen signaling, answering how MTA1 overexpression dysregulates hormone responses downstream of HER2.","evidence":"Motif-deletion mutagenesis, fractionation/IF, and Co-IP of MTA1s-ERα in breast cancer cells","pmids":["12167865"],"confidence":"High","gaps":["Relative abundance of MTA1s vs full-length in tumors not quantified","Does not address nuclear NuRD functions"]},{"year":2002,"claim":"Showed MTA1 represses a metastasis-relevant gene through dual chromatin mechanisms, establishing that its corepressor activity is only partly HDAC-dependent.","evidence":"ChIP, Co-IP, DNase I hypersensitivity, and TSA treatment at the MMP-9 promoter","pmids":["12431981"],"confidence":"High","gaps":["Precise contribution of Mi2 remodeling vs HDAC not quantified","In vivo relevance to invasion not tested here"]},{"year":2003,"claim":"Identified the mechanistic basis of MTA1 antagonism of estrogen signaling — direct interception of coactivator (MICoA) and the ERα-activating kinase (CAK/MAT1).","evidence":"Yeast two-hybrid, in vitro/in vivo binding, kinase and reporter assays","pmids":["12639951","12527756"],"confidence":"High","gaps":["Endogenous stoichiometry of competing complexes unknown","Generalizability beyond ER targets untested"]},{"year":2006,"claim":"Reversed the corepressor-only view by showing acetylation of MTA1 at Lys626 licenses it to recruit RNA Pol II and activate transcription, defining a PTM switch for coactivator function.","evidence":"ChIP, acetylation-site mutagenesis, reporter assay, and transgenic mouse at the BCAS3 locus","pmids":["16617102"],"confidence":"High","gaps":["Acetyltransferase responsible not fully defined here","How acetylation alters complex composition unresolved"]},{"year":2007,"claim":"Extended the coactivator/corepressor duality to oncogenic targets, linking acetylated MTA1-p300 to Pax5 activation and MTA1-NuRD to BRCA1 repression with a genome-instability phenotype.","evidence":"ChIP, Co-IP, transgenic mouse, and centrosome amplification rescue assays","pmids":["17671180","17922032"],"confidence":"High","gaps":["Determinants selecting activation vs repression at a given promoter unclear","BRCA1 repression in non-breast contexts untested"]},{"year":2008,"claim":"Connected MTA1 to hypoxic signaling, showing the MTA1/HDAC complex deacetylates HIF-1α to block its VHL-mediated degradation.","evidence":"Reciprocal Co-IP, siRNA knockdown, and HBx-transgenic mouse","pmids":["18264140"],"confidence":"High","gaps":["HBx-independent HIF-1α regulation not fully resolved","Specific HIF-1α lysines deacetylated not mapped"]},{"year":2009,"claim":"Placed MTA1 within the ubiquitin-proteasome and p53 networks, defining a COP1-MTA1 degradation/feedback loop and MTA1's stabilization of p53 to drive DNA-repair gene expression.","evidence":"Ubiquitination assays, COP1 RING mutants, Co-IP, ChIP, and DNA repair assays","pmids":["19805145","19837670"],"confidence":"High","gaps":["Quantitative balance of MTA1's p53-stabilizing vs corepressor roles unclear","In vivo physiological setting of the COP1 loop not established"]},{"year":2010,"claim":"Established MTA1 as a checkpoint and repair effector — repressing p21WAF1 independently of p53 and acting downstream of ATR to sustain Chk1/Claspin and the G2-M checkpoint.","evidence":"ChIP and siRNA in p53-null cells, Co-IP of MTA1-ATR, γH2AX focus and cell-cycle assays","pmids":["20071335","20427275"],"confidence":"High","gaps":["Direct enzymatic role of MTA1 in repair vs scaffolding unresolved","Mechanism of UV-induced MTA1 stabilization beyond ATR unclear"]},{"year":2010,"claim":"Revealed an immune/inflammatory function, showing MTA1 is required as a coactivator at NF-κB-driven promoters (MyD88, TG2) in LPS-stimulated macrophages.","evidence":"ChIP, siRNA, NF-κB inhibitor treatment, and cytokine/target gene readouts","pmids":["20702415","21156794"],"confidence":"High","gaps":["Mechanism of MTA1 switching to coactivation at NF-κB sites unclear","In vivo inflammatory phenotype not established here"]},{"year":2011,"claim":"Defined SUMOylation as a regulatory layer, mapping SUMO2/3 conjugation at Lys509 and a C-terminal SIM that together tune corepressor activity.","evidence":"In vivo SUMOylation assays, K509 mutagenesis, PIAS/SENP manipulation, ChIP, reporter assays","pmids":["21965678"],"confidence":"High","gaps":["Signals controlling MTA1 SUMOylation dynamics unknown","Genome-wide impact of SUMO state not mapped"]},{"year":2012,"claim":"Closed a regulatory circuit by showing p53 transcriptionally represses MTA1 via PARP-1-dependent poly(ADP-ribosyl)ation, and demonstrated MTA1-NuRD repression of SMAD7 in TGF-β signaling.","evidence":"ChIP, promoter proteomics, p53 WT/null comparison, PARP-1 inhibition; ChIP/shRNA at SMAD7","pmids":["22286760","22841502"],"confidence":"Medium","gaps":["SMAD7 finding limited to single-lab ChIP/knockdown","Conditions favoring p53 repression of MTA1 in vivo unclear"]},{"year":2013,"claim":"Identified MTA1 as a selective metastasis modifier acting through an MTA1/STAT3/Pol II coactivator complex to induce Twist1, dissociating metastatic from primary-tumor functions.","evidence":"Genetic MTA1 depletion in a spontaneous mouse breast cancer model, Co-IP, ChIP","pmids":["23580571"],"confidence":"High","gaps":["Determinants of MTA1-STAT3 complex assembly unclear","Relative contribution of STAT3 vs other axes to metastasis not quantified"]},{"year":2014,"claim":"Provided the structural and architectural basis for NuRD assembly, showing MTA1 scaffolds RbAp46/48 by occluding the histone-H4-binding surface and binds two RBBP4 molecules.","evidence":"Crystal structure of RbAp48-MTA1, in vitro binding, in vivo assembly assays; negative-stain EM and crosslinking MS","pmids":["24920672","27144666"],"confidence":"High","gaps":["Full NuRD architecture not resolved at high resolution","How scaffold occupancy gates histone engagement in vivo untested"]},{"year":2014,"claim":"Broadened MTA1's role beyond NuRD to direct chromatin organization, showing it decondenses chromatin independently of Mi-2 and modulates H1-chromatin interaction, plus a domain-dependent multi-compartment localization.","evidence":"Live-cell imaging, FRAP, chromatin fractionation; IF/fractionation with differentiation assays","pmids":["25205035","24970816"],"confidence":"Medium","gaps":["Single-lab findings without orthogonal confirmation","Molecular basis of MTA1-driven decondensation unresolved"]},{"year":2017,"claim":"Mechanistically linked MTA1 to EMT and invasion via target programs — inducing miR-22 to repress E-cadherin and activating ErbB2 transcription with HDAC2.","evidence":"3'-UTR luciferase reporter, ChIP, Co-IP, loss/gain-of-function, in vivo tumor model","pmids":["28231399","28288133"],"confidence":"Medium","gaps":["Single-lab studies with limited orthogonal validation","Whether these axes operate together in the same tumors unclear"]},{"year":2018,"claim":"Defined a targeting mechanism for a minimal MTA1 subcomplex, showing PWWP2A directs M1HR (MTA1-HDAC1-RBBP4/7) to H2A.Z chromatin for deacetylation.","evidence":"AP-MS, Co-IP, ChIP-seq, and siRNA with histone acetylation readout","pmids":["30327463"],"confidence":"High","gaps":["Relationship between M1HR and canonical NuRD in cells unclear","Genome-wide functional outcome of M1HR loss not fully mapped"]},{"year":2019,"claim":"Expanded MTA1 into metabolic and extracellular/paracrine roles — c-Myc-dependent LDHA activation, autophagy/AMPK-driven tamoxifen resistance, VEGFR2-mediated phosphorylation with extracellular pro-angiogenic activity, and exosomal intercellular transfer.","evidence":"ChIP/Co-IP at LDHA; autophagy flux and ATG7 knockdown; recombinant MTA1 angiogenesis assays; CRISPR KO and exosome tracking with reporters","pmids":["31570164","29130361","24265228","30782165"],"confidence":"Medium","gaps":["Each axis from a single lab with limited replication","Physiological levels of extracellular/exosomal MTA1 not established"]},{"year":2020,"claim":"Discovered an RNA-level function, showing MTA1 directly binds transcripts and regulates alternative splicing of mitosis regulators, with loss causing chromosomal instability.","evidence":"fCLIP-seq, RNA-seq, siRNA/KO, and chromosome segregation/CIN assays","pmids":["32901005"],"confidence":"High","gaps":["Direct RNA-binding domain of MTA1 not defined","Relationship between RNA-binding and chromatin functions unresolved"]},{"year":2021,"claim":"Added O-GlcNAcylation as a chromatin-targeting PTM, mapping S237/S241/S246 modification that enhances MTA1 chromatin and NuRD association and reprograms target genes in drug-resistant cells.","evidence":"Quantitative MS site mapping, ChIP-seq, transcriptomics, and OGT manipulation","pmids":["34019948"],"confidence":"Medium","gaps":["Single-lab study","Signaling controlling MTA1 O-GlcNAcylation unclear"]},{"year":2022,"claim":"Revealed higher-order repressive complex assembly and isoform-level control, showing RUNX2 recruits MTA1/NuRD with CRL4B to couple deacetylation and ubiquitylation, and that RALY/SF3B3-driven MTA1 splicing controls proliferation.","evidence":"Co-IP, ChIP-seq, genome-wide target analysis, bone metastasis xenografts; splicing assays with RALY/SF3B3 manipulation and pathway readouts","pmids":["35534547","35490918"],"confidence":"Medium","gaps":["Generality of RUNX2/NuRD/CRL4B complex beyond breast cancer unclear","Isoform-switch mechanism single-lab"]},{"year":null,"claim":"How MTA1's competing corepressor versus coactivator states, RNA-binding versus chromatin functions, and the array of PTMs (acetylation, SUMO, O-GlcNAc) are integrated to specify a given target at a given locus remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to activator/repressor choice","Direct RNA-binding determinants undefined","High-resolution architecture of full NuRD lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,5,10,12,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,5,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[29]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[18,21,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19,33,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,19]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[19]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[20]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[18,24,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,4,5,10,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,9,10,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,12,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,14,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,17,31]}],"complexes":["NuRD complex","M1HR (MTA1-HDAC1-RBBP4/7) subcomplex"],"partners":["HDAC1","HDAC2","RBBP4","RBBP7","STAT3","MYC","ATR","COP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13330","full_name":"Metastasis-associated protein MTA1","aliases":[],"length_aa":715,"mass_kda":80.8,"function":"Transcriptional coregulator which can act as both a transcriptional corepressor and coactivator (PubMed:16617102, PubMed:17671180, PubMed:17922032, PubMed:21965678, PubMed:24413532). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). In the NuRD complex, regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA (PubMed:17671180). In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A (PubMed:17922032, PubMed:24413532). Acts as a transcriptional coactivator of BCAS3, and SUMO2, independent of the NuRD complex (PubMed:16617102, PubMed:17671180, PubMed:21965678). Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3 (By similarity). Regulates p53-dependent and -independent DNA repair processes following genotoxic stress (PubMed:19837670). Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair (PubMed:19837670). Plays a role in the regulation of the circadian clock and is essential for the generation and maintenance of circadian rhythms under constant light and for normal entrainment of behavior to light-dark (LD) cycles (By similarity). Positively regulates the CLOCK-BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1 (By similarity). Regulates deacetylation of BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression (By similarity). With TFCP2L1, promotes establishment and maintenance of pluripotency in embryonic stem cells (ESCs) and inhibits endoderm differentiation (By similarity) Binds to ESR1 and sequesters it in the cytoplasm and enhances its non-genomic responses","subcellular_location":"Nucleus; Nucleus envelope; Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q13330/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTA1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":10.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"H1F0","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"KPNA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MTA1","total_profiled":1310},"omim":[{"mim_id":"615786","title":"NACC FAMILY, MEMBER 2, BEN AND BTB/POZ DOMAINS-CONTAINING; NACC2","url":"https://www.omim.org/entry/615786"},{"mim_id":"614161","title":"PR DOMAIN-CONTAINING PROTEIN 5; PRDM5","url":"https://www.omim.org/entry/614161"},{"mim_id":"613716","title":"MICRO RNA 661; MIR661","url":"https://www.omim.org/entry/613716"},{"mim_id":"613484","title":"SPEN FAMILY TRANSCRIPTIONAL REPRESSOR; SPEN","url":"https://www.omim.org/entry/613484"},{"mim_id":"609050","title":"METASTASIS-ASSOCIATED GENE 3; MTA3","url":"https://www.omim.org/entry/609050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTA1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13330","domains":[{"cath_id":"2.30.30.490","chopping":"6-68_89-163","consensus_level":"high","plddt":90.0209,"start":6,"end":163},{"cath_id":"4.10.1240.50","chopping":"199-283","consensus_level":"medium","plddt":92.3807,"start":199,"end":283},{"cath_id":"1.10.10.60","chopping":"288-354","consensus_level":"medium","plddt":94.6237,"start":288,"end":354},{"cath_id":"3.30.50","chopping":"364-381_393-437","consensus_level":"medium","plddt":82.0444,"start":364,"end":437},{"cath_id":"-","chopping":"478-520","consensus_level":"high","plddt":83.4263,"start":478,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13330","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13330-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13330-F1-predicted_aligned_error_v6.png","plddt_mean":72.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTA1","jax_strain_url":"https://www.jax.org/strain/search?query=MTA1"},"sequence":{"accession":"Q13330","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13330.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13330/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13330"}},"corpus_meta":[{"pmid":"12167865","id":"PMC_12167865","title":"A 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MTA1s localizes in the cytoplasm, sequesters ERα in the cytoplasm via this LRILL motif, and enhances non-genomic ER responses. Deletion of the LRILL motif abolishes MTA1s co-repressor function and its interaction with ERα, and restores nuclear localization of ERα. HER2 dysregulation in breast cancer cells enhances MTA1s expression and cytoplasmic ERα sequestration.\",\n      \"method\": \"Domain deletion mutagenesis, subcellular fractionation/immunofluorescence, Co-IP, ectopic expression in breast cancer cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific motif, functional rescue, reciprocal interaction assays, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12167865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MTA1 represses MMP-9 (92-kDa type IV collagenase) expression by binding to the distal MMP-9 promoter region and recruiting HDAC2, leading to diminished histone H3/H4 acetylation. MTA1 also recruits the nucleosome-remodeling Mi2 activity to the proximal promoter region. Trichostatin A only partially relieves MTA1-mediated repression, indicating both HDAC-dependent and HDAC-independent (Mi2-dependent) mechanisms.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), Co-IP, DNase I hypersensitivity assay, forced expression, TSA treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP plus Co-IP plus functional rescue with multiple mechanistic components in one study\",\n      \"pmids\": [\"12431981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTA1 interacts with MICoA (MTA1-interacting coactivator), identified by yeast two-hybrid screening. MICoA binds to the C-terminal region of MTA1 via an LSRLL nuclear receptor interaction motif, and the interaction was confirmed in vitro and in vivo. MTA1 represses MICoA-stimulated ERα transactivation and interferes with MICoA's association with ER-target gene promoter chromatin.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, Co-IP, chromatin immunoprecipitation, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid, in vitro and in vivo binding, ChIP, reporter assay; multiple orthogonal methods\",\n      \"pmids\": [\"12639951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTA1 interacts with MAT1, an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK). MTA1 binds the N-terminal RING finger domain of MAT1 via two MTA1 domains (C-terminal GATA domain and N-terminal bromo-domain). MTA1 inhibits CAK-stimulated ERα transactivation and inhibits CAK-mediated phosphorylation of ERα, partly through HDAC recruitment.\",\n      \"method\": \"Yeast two-hybrid, Co-IP (in vitro and in vivo), reporter assay, kinase assay, TSA treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid, in vitro and in vivo Co-IP, kinase assay, reporter assay; multiple orthogonal methods\",\n      \"pmids\": [\"12527756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MTA1 acts as a transcriptional activator of BCAS3, a gene amplified in breast cancers. MTA1 stimulation of BCAS3 transcription requires ERα and an ERE half-site in the BCAS3 locus. MTA1 is acetylated on Lys626, and this acetylation is necessary for productive recruitment of RNA polymerase II complex to the BCAS3 enhancer.\",\n      \"method\": \"Functional genomic/chromatin screen, ChIP, reporter assay, site-directed mutagenesis of acetylation site, transgenic mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, mutagenesis of acetylation site, reporter assay, in vivo transgenic mouse validation\",\n      \"pmids\": [\"16617102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MTA1-NuRD complex transcriptionally represses BRCA1 by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter in an ERα-dependent manner, recruiting HDAC. MTA1 overexpression causes centrosome amplification (a BRCA1 repression phenotype), reversible by BRCA1 re-expression.\",\n      \"method\": \"ChIP, Co-IP, siRNA knockdown, HDAC inhibitor (TSA) treatment, centrosome amplification assay, rescue experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP, Co-IP, functional rescue experiment, phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"17922032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MTA1 acetylated on Lys626 interacts with p300 histone acetyltransferase and is recruited to the Pax5 promoter to stimulate Pax5 transcription, identified as a target driving B-cell lymphomagenesis in MTA1-transgenic mice.\",\n      \"method\": \"ChIP, Co-IP, gene expression profiling, transgenic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, Co-IP, validated in vivo in MTA1-TG mouse model, gene profiling\",\n      \"pmids\": [\"17671180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MTA1 and HDAC1/2 physically associate with HIF-1α in the presence of HBx (hepatitis B virus X protein). MTA1/HDAC complex deacetylates the oxygen-dependent degradation domain of HIF-1α, leading to dissociation of prolyl hydroxylases and VHL from HIF-1α and thereby stabilizing HIF-1α. Knockdown of MTA1 abolishes this HBx-induced HIF-1α stabilization.\",\n      \"method\": \"Co-IP in vivo, siRNA knockdown, immunoprecipitation, HBx-transgenic mouse\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA knockdown with rescue, in vivo transgenic mouse validation\",\n      \"pmids\": [\"18264140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MTA1 is an ubiquitinated protein targeted by the RING-finger E3 ligase COP1 for degradation via the ubiquitin-proteasome pathway. Wild-type COP1 but not RING motif mutants promotes MTA1 ubiquitination and degradation. MTA1 in turn destabilizes COP1 by promoting COP1 autoubiquitination, creating a feedback loop. Ionizing radiation disrupts COP1-mediated MTA1 proteolysis, stabilizing MTA1 and promoting DNA double-strand break repair.\",\n      \"method\": \"Ubiquitination assay, proteasome inhibition, COP1 RING mutant expression, siRNA knockdown, Co-IP, DNA damage (IR) assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitination, domain mutagenesis, Co-IP, loss-of-function experiments with multiple readouts\",\n      \"pmids\": [\"19805145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MTA1 controls p53 stability by competing with COP1 to bind p53 and/or destabilizing COP1 and Mdm2, thereby inhibiting p53 ubiquitination. MTA1 regulates p53-dependent transcription of p53R2 (required for DNA repair). MTA1 depletion impairs p53-dependent p53R2 transcription and DNA repair, reversible by MTA1 re-introduction.\",\n      \"method\": \"Co-IP, ubiquitination assay, siRNA knockdown, ChIP, reporter assay, DNA repair assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, ubiquitination assay, ChIP, functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"19837670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTA1 is a p53-independent transcriptional corepressor of p21WAF1. The mechanism involves recruitment of MTA1-HDAC2 complexes onto two selective regions of the p21WAF1 promoter. MTA1 depletion superinduces p21WAF1 even in p53-null cells, increases p21WAF1 binding to PCNA, and decreases nuclear PCNA accumulation after ionizing radiation. MTA1 expression in p53-null cells inhibits p21WAF1 promoter activity and increases DNA DSB repair.\",\n      \"method\": \"ChIP, siRNA knockdown in p53-null cells, reporter assay, Co-IP, gamma-H2AX focus assay, PCNA interaction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP, p53-null genetic system, multiple functional readouts, reporter assay\",\n      \"pmids\": [\"20071335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UV radiation stabilizes MTA1 in an ATR-dependent manner and increases MTA1 binding to ATR. MTA1 depletion compromises ATR-mediated Chk1 activation by down-regulating Chk1 and its adaptor Claspin, and decreases gamma-H2AX induction and focus formation after UV treatment. MTA1 deficiency causes defective G2-M checkpoint and increased cellular sensitivity to UV-induced DNA damage.\",\n      \"method\": \"siRNA knockdown, Co-IP (MTA1-ATR), Western blot, gamma-H2AX focus assay, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating MTA1-ATR binding, loss-of-function with defined checkpoint phenotype, multiple readouts\",\n      \"pmids\": [\"20427275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTA1 is required for expression of MyD88 in LPS-stimulated macrophages and for MyD88-dependent NF-κB signaling. LPS stimulation promotes enhanced recruitment of MTA1, RNA Pol II, and p65RelA to NF-κB consensus sites in the MyD88 promoter. MTA1 depletion substantially reduces expression of NF-κB target genes (IL-1β, MIP2, TNF-α).\",\n      \"method\": \"ChIP, siRNA knockdown, NF-κB inhibitor (parthenolide) treatment, reporter assay, cytokine expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of MTA1 at MyD88 promoter, siRNA with specific NF-κB pathway readouts, pharmacological inhibitor\",\n      \"pmids\": [\"20702415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTA1 is an obligatory coregulator of transglutaminase 2 (TG2) expression in LPS-stimulated macrophages. MTA1 depletion impairs basal and LPS-induced TG2 expression. MTA1, p65RelA, and RNA Pol II are recruited to NF-κB consensus sites in the TG2 promoter during LPS stimulation.\",\n      \"method\": \"ChIP, siRNA knockdown, gene expression analysis, NF-κB inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at TG2 promoter, siRNA knockdown with specific transcriptional readouts, pharmacological validation\",\n      \"pmids\": [\"21156794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MTA1 is SUMOylated by SUMO2/3 in vivo at Lys509 within a SUMO consensus site. PIAS proteins enhance SUMOylation of MTA1, while SENP1 and SENP2 act as deSUMOylation enzymes. MTA1 contains a functional SUMO-interacting motif (SIM) at its C terminus required for efficient SUMOylation. SUMO conjugation on Lys509 together with SIM synergistically regulates MTA1 co-repressor activity on pS2 transcription, likely by recruiting HDAC2 to the pS2 promoter. MTA1 also upregulates SUMO2 expression by interacting with RNA Pol II and SP1 at the SUMO2 promoter.\",\n      \"method\": \"In vivo SUMOylation assay, site-directed mutagenesis (K509), Co-IP, reporter assay, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vivo SUMOylation, mutagenesis of specific lysine residue, ChIP, reporter assay; multiple orthogonal methods\",\n      \"pmids\": [\"21965678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p53 mediates transcriptional repression of the MTA1 gene through two p53-response elements (p53REs) in the MTA1 promoter. This repression requires poly(ADP-ribosyl)ation of p53 by PARP-1 (identified in the repressor complex by proteomics). p53 and HDAC1/2 are recruited to the MTA1 promoter after 5-FU treatment, with decreased H3K9 acetylation. Repression occurs only in p53 wild-type cells.\",\n      \"method\": \"ChIP, reporter assay, siRNA, proteomics/pull-down of promoter-bound complex, PARP-1 inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP, promoter proteomics, p53 WT vs null cells, poly(ADP-ribosyl)ation assay; multiple orthogonal methods\",\n      \"pmids\": [\"22286760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MTA1 transcriptionally represses SMAD7 (an inhibitory SMAD and negative regulator of TGF-β signaling) in breast cancer cell lines. MTA1 is recruited to the SMAD7 promoter. MTA1 knockdown increases SMAD7 expression (reversed by HDAC inhibitor), and decreases levels of active SMAD2 and SMAD3.\",\n      \"method\": \"ChIP, shRNA knockdown, HDAC inhibitor treatment, Western blot\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP showing MTA1 promoter binding, siRNA with functional readout; single lab, limited orthogonal validation\",\n      \"pmids\": [\"22841502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MTA1 acts as a mandatory modifier of breast-to-lung metastasis (without affecting primary tumor formation) in a spontaneous mouse model. The mechanism involves MTA1-dependent stimulation of STAT3 transcription through formation of an MTA1/STAT3/Pol II coactivator complex, and consequent expression of STAT3 target genes including Twist1.\",\n      \"method\": \"Genetic depletion of MTA1 in spontaneous mouse breast cancer model, Co-IP (MTA1/STAT3/Pol II complex), gene expression analysis, ChIP\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model, Co-IP of complex, ChIP; multiple methods with in vivo validation\",\n      \"pmids\": [\"23580571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of RbAp48-MTA1 subcomplex was determined. RbAp48 recognizes MTA1 using the same surface it uses to bind histone H4, showing that NuRD assembly modulates RbAp46/48 interactions with histones. The MTA proteins act as scaffolds for NuRD complex assembly, and the RbAp48-MTA1 interaction is essential for in vivo integration of RbAp46/48 into the NuRD complex.\",\n      \"method\": \"Crystal structure determination, in vitro binding assay, in vivo NuRD complex assembly assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional validation of in vivo complex assembly; orthogonal structural and biochemical methods\",\n      \"pmids\": [\"24920672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTA1 localizes to the nucleus, cytoplasm, and nuclear envelope. Nuclear envelope localization depends on TPR (translocated promoter region). Cytoplasmic MTA1 associates with microtubules. Nuclear but not cytoplasmic MTA1 is associated with cancer differentiation: MTA1 overexpression inhibits differentiation and promotes proliferation in HCT116 cells, while MTA1 knockdown results in cell differentiation and death.\",\n      \"method\": \"Multiple immunofluorescence/localization approaches, siRNA knockdown, OE, differentiation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — subcellular fractionation/imaging with functional consequence, domain-dependent localization assays; single lab\",\n      \"pmids\": [\"24970816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MTA1 is a higher-order chromatin structure organizer that decondenses interphase chromatin and mitotic chromosomes. MTA1 interacts dynamically with nucleosomes during the cell cycle. MTA1-induced chromatin decondensation is independent of Mi-2 chromatin remodeling activity. MTA1 causes reduced histone H1-chromatin interaction in vivo, and this dynamic MTA1-chromatin interaction contributes to periodic H1-chromatin interaction modulating chromatin/chromosome transitions.\",\n      \"method\": \"Live-cell imaging, FRAP, chromatin fractionation, siRNA/OE experiments, chromosome structure analysis\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct chromatin interaction assays, live imaging; single lab with functional consequence for chromatin structure\",\n      \"pmids\": [\"25205035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MTA1 can bind two molecules of RBBP4 (RbAp48). Negative stain electron microscopy and chemical crosslinking data provide a low-resolution model of an MTA1-(RBBP4)2 subcomplex within NuRD.\",\n      \"method\": \"In vitro binding/pull-down, negative stain EM, chemical crosslinking mass spectrometry\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted subcomplex, structural EM, chemical crosslinking; single lab but multiple orthogonal structural methods\",\n      \"pmids\": [\"27144666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MTA1 directly induces miR-22 (Epi-miR) expression in prostate cancer cells. MiR-22 directly targets the 3'-UTR of E-cadherin, reducing its expression. MTA1 overexpression promotes invasiveness and migration via this MTA1/miR-22/E-cadherin axis.\",\n      \"method\": \"siRNA/OE loss- and gain-of-function, luciferase 3'-UTR reporter assay, ChIP for MTA1 at miR-22 locus\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — luciferase 3'-UTR reporter, ChIP, loss/gain-of-function; single lab\",\n      \"pmids\": [\"28231399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MTA1 promotes transcription of ErbB2 by binding with HDAC2 and acting at the ErbB2 promoter in hepatocellular carcinoma cells. The EMT-promoting effect caused by MTA1 largely depends on ErbB2; reducing ErbB2 activity attenuates MTA1-induced EMT both in vitro and in vivo.\",\n      \"method\": \"ChIP (MTA1 and HDAC2 at ErbB2 promoter), siRNA/OE, Co-IP, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP, Co-IP, in vivo validation; single lab\",\n      \"pmids\": [\"28288133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PWWP2A interacts with an MTA1-specific subcomplex of NuRD (M1HR) consisting solely of MTA1, HDAC1, and RBBP4/7 (excluding CHD, GATAD2, and MBD proteins). PWWP2A depletion leads to increased acetylation of H3K27 and H2A.Z, suggesting PWWP2A directs M1HR to H2A.Z-containing chromatin to promote deacetylation.\",\n      \"method\": \"Affinity purification/MS, Co-IP, ChIP-seq, siRNA knockdown with histone acetylation readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS identification of subcomplex, ChIP-seq, loss-of-function with histone modification readout; multiple orthogonal methods\",\n      \"pmids\": [\"30327463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTA1 regulates LDHA expression by interacting with c-Myc and recruiting the MTA1-c-Myc complex to the LDHA promoter. LDHA knockdown in MTA1-stably expressing MCF7 cells reduces cell migration, linking MTA1-LDHA axis to breast cancer motility.\",\n      \"method\": \"ChIP (MTA1 and c-Myc at LDHA promoter), Co-IP, siRNA, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — ChIP, Co-IP, single lab; limited orthogonal validation\",\n      \"pmids\": [\"31570164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VEGF induces tyrosine phosphorylation of endogenous MTA1 mediated through VEGFR2 and p38-MAP kinase. Extracellular recombinant MTA1 protein binds to cell membranes (distinct from nuclear MTA1), activates ERK and JNK pathways, and induces angiogenesis comparable to or exceeding VEGF. MTA1 upregulates VEGF and Flt-1 gene expression via their promoters.\",\n      \"method\": \"Recombinant MTA1 protein treatment, immunofluorescence for cell membrane binding, phosphorylation assays, luciferase reporter (VEGF/Flt-1 promoters), in vivo angiogenesis models (cornea, CAM, xenograft)\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple in vitro and in vivo angiogenesis assays, reporter assays; single lab with several methods\",\n      \"pmids\": [\"24265228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MTA1 is transferred between breast cancer cells via exosomes and can be delivered to vascular endothelial cells. Exosome-transferred MTA1 regulates hypoxic response (co-repressor function) and estrogen receptor signaling (co-activator function) in recipient cells. MTA1 knockout reduces cell proliferation and attenuates hypoxic response, rescued by addition of MTA1-containing exosomes.\",\n      \"method\": \"Antibody array, CRISPR/Cas9 MTA1 knockout, tdTomato-MTA1 ectopic expression and exosome tracking by fluorescence microscopy, reporter assays, exosome transfer experiments\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — CRISPR KO, exosome tracking with fluorescent tag, reporter assays; single lab\",\n      \"pmids\": [\"30782165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGF-β induces MTA1 expression, and MTA1 acts upstream of SOX4 in the TGF-β pathway. The TGF-β-MTA1-SOX4-EZH2 signaling axis drives EMT in multiple cancer cell lines. MTA1 overexpression activates SOX4, which in turn activates EZH2; epistasis experiments show MTA1 is upstream of SOX4 and that SOX4 is required for MTA1-driven EMT.\",\n      \"method\": \"Epistasis/pathway dissection by siRNA and OE, gene expression profiling, shRNA, in vitro EMT assays in multiple cell lines, TCGA analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — genetic epistasis by siRNA in multiple cell lines, gene expression profiling; single lab\",\n      \"pmids\": [\"31811272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MTA1 broadly interacts with RNA-binding proteins (RBPs) and directly binds abundant transcripts (preferentially at splicing-responsible motifs) as shown by fCLIP-seq. MTA1 regulates mRNA levels and alternative splicing of mitosis regulators including ATRX and MYBL2. MTA1 deletion causes defective mitotic arrest, aberrant chromosome segregation, and chromosomal instability (CIN), contributing to tumorigenesis.\",\n      \"method\": \"fCLIP-seq, RNA-seq, siRNA/KO, chromosome segregation and CIN assays, alternative splicing analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel fCLIP-seq method directly mapping MTA1-RNA binding, functional KO with CIN phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"32901005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"O-GlcNAc modification of MTA1 at serine residues S237/S241/S246 (identified by quantitative proteomics) promotes MTA1 interaction with chromatin and enhances its association with the NuRD complex. O-GlcNAc-modified MTA1 shows altered genome-wide chromatin binding patterns (ChIP-seq) and changes expression of target genes involved in genotoxic adaptation in adriamycin-resistant breast cancer cells.\",\n      \"method\": \"Quantitative proteomics (mass spectrometry of O-GlcNAc sites), ChIP-seq, transcriptome analysis, OGT inhibition/OE\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry-identified modification sites, ChIP-seq; single lab\",\n      \"pmids\": [\"34019948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUNX2 recruits the MTA1/NuRD complex and the CUL4B-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex that catalyzes both histone deacetylation and ubiquitylation. Genome-wide analysis identified PPARα and SOD2 as targets of the RUNX2/NuRD(MTA1)/CRL4B complex. This complex promotes breast cancer proliferation, invasion, bone metastasis, and cancer stemness.\",\n      \"method\": \"Co-IP, ChIP-seq, genome-wide target analysis, in vitro and in vivo functional assays (proliferation, invasion, bone metastasis xenograft)\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multi-protein complex, ChIP-seq, in vivo xenograft bone metastasis model; multiple orthogonal methods\",\n      \"pmids\": [\"35534547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNA-binding protein RALY cooperates with splicing factor SF3B3 to regulate MTA1 alternative splicing, switching from the MTA1-S isoform to MTA1-L. MTA1-S (short isoform) normally inhibits cell proliferation by reducing transcription of cholesterol synthesis genes; the RALY/SF3B3-driven splicing switch reduces MTA1-S levels and thereby relieves inhibition of cholesterol synthesis, promoting hepatocellular carcinoma proliferation.\",\n      \"method\": \"RNA splicing assays, siRNA/OE of RALY and SF3B3, gene expression analysis, cholesterol synthesis pathway analysis, cell proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — splicing assays, loss- and gain-of-function, pathway readouts; single lab\",\n      \"pmids\": [\"35490918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Nuclear localization of mouse Mta1 depends on the presence of at least one nuclear localization signal (NLS) and one SH3 binding site (proline-rich Src homology 3 ligand) in the C-terminal region. These SH3 ligands facilitate interaction with the adaptor protein Grb2 and the Src-family tyrosine kinase Fyn. GFP-Mta1 localizes exclusively in the nucleus while GFP-Mta3 is present in both nucleus and cytoplasm.\",\n      \"method\": \"GFP-tagged deletion construct expression, fluorescence microscopy, Co-IP (Grb2/Fyn interaction)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — deletion constructs with localization readout, Co-IP; single lab, mouse ortholog\",\n      \"pmids\": [\"11483358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MTA1 induces AMPK activation (associated with increased AMP:ATP ratio and decreased mitochondrial electron transport complex components) and subsequent autophagy flux, contributing to tamoxifen resistance in breast cancer cells. ATG7 knockdown or autophagy inhibition (hydroxychloroquine) restores tamoxifen sensitivity in MTA1-overexpressing and tamoxifen-resistant cells.\",\n      \"method\": \"Stable MTA1 overexpression cell line, siRNA (ATG7), autophagy flux assay, in vitro and in vivo growth assays, AMPK activation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — stable OE with multiple functional readouts, genetic (ATG7 KD) and pharmacological validation; single lab\",\n      \"pmids\": [\"29130361\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTA1 is a multifunctional chromatin modifier that serves as the scaffold subunit of the NuRD (nucleosome remodeling and deacetylase) complex, where it recruits HDAC1/2 via its ELM2-SANT domain and interacts with RbAp46/48 (RBBP4/7) to assemble enzymatic activities; it acts as a transcriptional co-repressor of ERα, BRCA1, p21WAF1, and SMAD7 through HDAC-dependent and -independent (Mi2/chromatin remodeling) mechanisms, and as a co-activator of BCAS3, Pax5, STAT3, and LDHA through acetylation of Lys626, interaction with p300 and c-Myc, and RNA Pol II recruitment; its stability is regulated by COP1-mediated ubiquitin-proteasome degradation and by SUMO2/3 conjugation on Lys509 and by O-GlcNAc modification; it participates in DNA damage response via ATR-Claspin-Chk1 and p53-p53R2 pathways, modulates alternative splicing of mitosis regulators to maintain chromosomal stability, and is transferred between cells via exosomes to regulate hypoxia and estrogen signaling in the tumor microenvironment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTA1 is the scaffold subunit of the NuRD (nucleosome remodeling and deacetylase) complex and a multifunctional chromatin-associated coregulator that controls transcription, genome stability, and tumor progression [#18, #29]. As a NuRD scaffold it binds RbAp46/48 (RBBP4/7) — using the same RbAp48 surface that engages histone H4, and accommodating two RBBP4 molecules — to integrate these subunits into the complex, and it can assemble a minimal MTA1-HDAC1-RBBP4/7 subcomplex (M1HR) recruited to H2A.Z chromatin by PWWP2A [#18, #21, #24]. Through this machinery MTA1 acts predominantly as an HDAC-dependent transcriptional corepressor, binding target promoters and recruiting HDAC1/2 to deacetylate histones; it represses MMP-9 (also via HDAC-independent Mi2/remodeling activity), BRCA1, p21WAF1, and SMAD7, and antagonizes estrogen receptor signaling by sequestering coactivators such as MICoA and inhibiting CAK-mediated ERα phosphorylation [#1, #5, #10, #16, #2, #3]. MTA1 also functions as a context-dependent transcriptional activator: acetylation on Lys626 enables p300 binding and RNA Pol II recruitment to drive BCAS3 and Pax5, and it forms coactivator complexes with STAT3, c-Myc, and NF-κB/p65RelA to induce STAT3 targets, LDHA, and inflammatory genes [#4, #6, #17, #25, #12]. A cytoplasmic short isoform (MTA1s) bearing an LRILL motif sequesters ERα in the cytoplasm to enhance non-genomic estrogen signaling [#0]. MTA1 supports genome integrity by stabilizing HIF-1α through deacetylation, controlling p53 stability and p53R2-dependent repair, coupling to ATR-Claspin-Chk1 checkpoint signaling, and regulating alternative splicing of mitosis regulators to prevent chromosomal instability [#7, #9, #11, #29]. Its abundance and activity are tuned by COP1-mediated ubiquitin-proteasome degradation (disrupted by ionizing radiation), p53-PARP1-driven transcriptional repression, SUMO2/3 conjugation at Lys509, and O-GlcNAcylation, the latter enhancing chromatin and NuRD association [#8, #15, #14, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the determinants of MTA1 subcellular targeting, showing nuclear localization is encoded by C-terminal signals while distinct ligand motifs link it to cytoplasmic signaling adaptors.\",\n      \"evidence\": \"GFP-tagged deletion constructs and Co-IP in mouse Mta1, mapping NLS and SH3 ligand sites and Grb2/Fyn binding\",\n      \"pmids\": [\"11483358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human MTA1 not directly tested\", \"Functional consequence of Grb2/Fyn binding for transcription unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined a non-genomic mode of MTA1 action: a cytoplasmic short isoform directly sequesters ERα to redirect estrogen signaling, answering how MTA1 overexpression dysregulates hormone responses downstream of HER2.\",\n      \"evidence\": \"Motif-deletion mutagenesis, fractionation/IF, and Co-IP of MTA1s-ERα in breast cancer cells\",\n      \"pmids\": [\"12167865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative abundance of MTA1s vs full-length in tumors not quantified\", \"Does not address nuclear NuRD functions\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed MTA1 represses a metastasis-relevant gene through dual chromatin mechanisms, establishing that its corepressor activity is only partly HDAC-dependent.\",\n      \"evidence\": \"ChIP, Co-IP, DNase I hypersensitivity, and TSA treatment at the MMP-9 promoter\",\n      \"pmids\": [\"12431981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise contribution of Mi2 remodeling vs HDAC not quantified\", \"In vivo relevance to invasion not tested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the mechanistic basis of MTA1 antagonism of estrogen signaling — direct interception of coactivator (MICoA) and the ERα-activating kinase (CAK/MAT1).\",\n      \"evidence\": \"Yeast two-hybrid, in vitro/in vivo binding, kinase and reporter assays\",\n      \"pmids\": [\"12639951\", \"12527756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stoichiometry of competing complexes unknown\", \"Generalizability beyond ER targets untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reversed the corepressor-only view by showing acetylation of MTA1 at Lys626 licenses it to recruit RNA Pol II and activate transcription, defining a PTM switch for coactivator function.\",\n      \"evidence\": \"ChIP, acetylation-site mutagenesis, reporter assay, and transgenic mouse at the BCAS3 locus\",\n      \"pmids\": [\"16617102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible not fully defined here\", \"How acetylation alters complex composition unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended the coactivator/corepressor duality to oncogenic targets, linking acetylated MTA1-p300 to Pax5 activation and MTA1-NuRD to BRCA1 repression with a genome-instability phenotype.\",\n      \"evidence\": \"ChIP, Co-IP, transgenic mouse, and centrosome amplification rescue assays\",\n      \"pmids\": [\"17671180\", \"17922032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting activation vs repression at a given promoter unclear\", \"BRCA1 repression in non-breast contexts untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected MTA1 to hypoxic signaling, showing the MTA1/HDAC complex deacetylates HIF-1α to block its VHL-mediated degradation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, and HBx-transgenic mouse\",\n      \"pmids\": [\"18264140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HBx-independent HIF-1α regulation not fully resolved\", \"Specific HIF-1α lysines deacetylated not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed MTA1 within the ubiquitin-proteasome and p53 networks, defining a COP1-MTA1 degradation/feedback loop and MTA1's stabilization of p53 to drive DNA-repair gene expression.\",\n      \"evidence\": \"Ubiquitination assays, COP1 RING mutants, Co-IP, ChIP, and DNA repair assays\",\n      \"pmids\": [\"19805145\", \"19837670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance of MTA1's p53-stabilizing vs corepressor roles unclear\", \"In vivo physiological setting of the COP1 loop not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established MTA1 as a checkpoint and repair effector — repressing p21WAF1 independently of p53 and acting downstream of ATR to sustain Chk1/Claspin and the G2-M checkpoint.\",\n      \"evidence\": \"ChIP and siRNA in p53-null cells, Co-IP of MTA1-ATR, γH2AX focus and cell-cycle assays\",\n      \"pmids\": [\"20071335\", \"20427275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic role of MTA1 in repair vs scaffolding unresolved\", \"Mechanism of UV-induced MTA1 stabilization beyond ATR unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an immune/inflammatory function, showing MTA1 is required as a coactivator at NF-κB-driven promoters (MyD88, TG2) in LPS-stimulated macrophages.\",\n      \"evidence\": \"ChIP, siRNA, NF-κB inhibitor treatment, and cytokine/target gene readouts\",\n      \"pmids\": [\"20702415\", \"21156794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MTA1 switching to coactivation at NF-κB sites unclear\", \"In vivo inflammatory phenotype not established here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined SUMOylation as a regulatory layer, mapping SUMO2/3 conjugation at Lys509 and a C-terminal SIM that together tune corepressor activity.\",\n      \"evidence\": \"In vivo SUMOylation assays, K509 mutagenesis, PIAS/SENP manipulation, ChIP, reporter assays\",\n      \"pmids\": [\"21965678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling MTA1 SUMOylation dynamics unknown\", \"Genome-wide impact of SUMO state not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Closed a regulatory circuit by showing p53 transcriptionally represses MTA1 via PARP-1-dependent poly(ADP-ribosyl)ation, and demonstrated MTA1-NuRD repression of SMAD7 in TGF-β signaling.\",\n      \"evidence\": \"ChIP, promoter proteomics, p53 WT/null comparison, PARP-1 inhibition; ChIP/shRNA at SMAD7\",\n      \"pmids\": [\"22286760\", \"22841502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SMAD7 finding limited to single-lab ChIP/knockdown\", \"Conditions favoring p53 repression of MTA1 in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified MTA1 as a selective metastasis modifier acting through an MTA1/STAT3/Pol II coactivator complex to induce Twist1, dissociating metastatic from primary-tumor functions.\",\n      \"evidence\": \"Genetic MTA1 depletion in a spontaneous mouse breast cancer model, Co-IP, ChIP\",\n      \"pmids\": [\"23580571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of MTA1-STAT3 complex assembly unclear\", \"Relative contribution of STAT3 vs other axes to metastasis not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the structural and architectural basis for NuRD assembly, showing MTA1 scaffolds RbAp46/48 by occluding the histone-H4-binding surface and binds two RBBP4 molecules.\",\n      \"evidence\": \"Crystal structure of RbAp48-MTA1, in vitro binding, in vivo assembly assays; negative-stain EM and crosslinking MS\",\n      \"pmids\": [\"24920672\", \"27144666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full NuRD architecture not resolved at high resolution\", \"How scaffold occupancy gates histone engagement in vivo untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened MTA1's role beyond NuRD to direct chromatin organization, showing it decondenses chromatin independently of Mi-2 and modulates H1-chromatin interaction, plus a domain-dependent multi-compartment localization.\",\n      \"evidence\": \"Live-cell imaging, FRAP, chromatin fractionation; IF/fractionation with differentiation assays\",\n      \"pmids\": [\"25205035\", \"24970816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without orthogonal confirmation\", \"Molecular basis of MTA1-driven decondensation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mechanistically linked MTA1 to EMT and invasion via target programs — inducing miR-22 to repress E-cadherin and activating ErbB2 transcription with HDAC2.\",\n      \"evidence\": \"3'-UTR luciferase reporter, ChIP, Co-IP, loss/gain-of-function, in vivo tumor model\",\n      \"pmids\": [\"28231399\", \"28288133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies with limited orthogonal validation\", \"Whether these axes operate together in the same tumors unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a targeting mechanism for a minimal MTA1 subcomplex, showing PWWP2A directs M1HR (MTA1-HDAC1-RBBP4/7) to H2A.Z chromatin for deacetylation.\",\n      \"evidence\": \"AP-MS, Co-IP, ChIP-seq, and siRNA with histone acetylation readout\",\n      \"pmids\": [\"30327463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between M1HR and canonical NuRD in cells unclear\", \"Genome-wide functional outcome of M1HR loss not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded MTA1 into metabolic and extracellular/paracrine roles — c-Myc-dependent LDHA activation, autophagy/AMPK-driven tamoxifen resistance, VEGFR2-mediated phosphorylation with extracellular pro-angiogenic activity, and exosomal intercellular transfer.\",\n      \"evidence\": \"ChIP/Co-IP at LDHA; autophagy flux and ATG7 knockdown; recombinant MTA1 angiogenesis assays; CRISPR KO and exosome tracking with reporters\",\n      \"pmids\": [\"31570164\", \"29130361\", \"24265228\", \"30782165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each axis from a single lab with limited replication\", \"Physiological levels of extracellular/exosomal MTA1 not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovered an RNA-level function, showing MTA1 directly binds transcripts and regulates alternative splicing of mitosis regulators, with loss causing chromosomal instability.\",\n      \"evidence\": \"fCLIP-seq, RNA-seq, siRNA/KO, and chromosome segregation/CIN assays\",\n      \"pmids\": [\"32901005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding domain of MTA1 not defined\", \"Relationship between RNA-binding and chromatin functions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added O-GlcNAcylation as a chromatin-targeting PTM, mapping S237/S241/S246 modification that enhances MTA1 chromatin and NuRD association and reprograms target genes in drug-resistant cells.\",\n      \"evidence\": \"Quantitative MS site mapping, ChIP-seq, transcriptomics, and OGT manipulation\",\n      \"pmids\": [\"34019948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Signaling controlling MTA1 O-GlcNAcylation unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed higher-order repressive complex assembly and isoform-level control, showing RUNX2 recruits MTA1/NuRD with CRL4B to couple deacetylation and ubiquitylation, and that RALY/SF3B3-driven MTA1 splicing controls proliferation.\",\n      \"evidence\": \"Co-IP, ChIP-seq, genome-wide target analysis, bone metastasis xenografts; splicing assays with RALY/SF3B3 manipulation and pathway readouts\",\n      \"pmids\": [\"35534547\", \"35490918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of RUNX2/NuRD/CRL4B complex beyond breast cancer unclear\", \"Isoform-switch mechanism single-lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTA1's competing corepressor versus coactivator states, RNA-binding versus chromatin functions, and the array of PTMs (acetylation, SUMO, O-GlcNAc) are integrated to specify a given target at a given locus remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to activator/repressor choice\", \"Direct RNA-binding determinants undefined\", \"High-resolution architecture of full NuRD lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 5, 10, 12, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 5, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [18, 21, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19, 33, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [18, 24, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 4, 5, 10, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 12, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 14, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 17, 31]}\n    ],\n    \"complexes\": [\"NuRD complex\", \"M1HR (MTA1-HDAC1-RBBP4/7) subcomplex\"],\n    \"partners\": [\"HDAC1\", \"HDAC2\", \"RBBP4\", \"RBBP7\", \"STAT3\", \"MYC\", \"ATR\", \"COP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}