{"gene":"ZMYM2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1998,"finding":"ZNF198 (ZMYM2) is fused to the FGFR1 tyrosine-kinase domain in the t(8;13)(p11;q12) translocation; the resulting ZNF198-FGFR1 fusion protein (~87 kDa) localizes predominantly to the cytoplasm and directs synthesis of a polypeptide whose ZNF198 zinc-finger domains are proposed to mediate homodimerization leading to constitutive FGFR1 tyrosine kinase activation.","method":"Molecular cloning, transient expression, subcellular localization by immunofluorescence","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with expression studies and localization, single lab but multiple methods; dimerization mechanism proposed but mechanistic detail is limited in abstract","pmids":["9425908"],"is_preprint":false},{"year":1998,"finding":"The FIM/ZNF198-FGFR1 fusion protein has constitutive tyrosine kinase activity, as demonstrated by in vitro kinase assays on the fusion product generated from the t(8;13) translocation.","method":"In vitro tyrosine kinase assay on immunoprecipitated fusion protein","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay, replicated across multiple labs (PMID 9425908, 9576949, 10480903)","pmids":["9576949"],"is_preprint":false},{"year":1999,"finding":"FIM (ZMYM2) normally has nuclear and nucleolar localization (colocalizing with the upstream binding factor in interphase cells, suggesting a role in rRNA transcription regulation), whereas the FIM-FGFR1 fusion protein is cytoplasmic. Nuclear targeting depends on the C-terminal region of FIM, which is absent in FIM-FGFR1. FIM-FGFR1 has constitutive dimerization capability mediated by FIM N-terminal sequences.","method":"Subcellular fractionation, confocal immunofluorescence, co-immunoprecipitation, deletion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, co-IP, deletion analysis), single lab but comprehensive mechanistic study","pmids":["10480903"],"is_preprint":false},{"year":1999,"finding":"ZNF198-FGFR1 self-associates in vitro (shown by co-immunoprecipitation of differentially tagged constructs) and is a cytoplasmic protein with constitutive transformation activity, inducing IL-3-independent growth of Ba/F3 cells with constitutive tyrosine phosphorylation of STAT1 and STAT5.","method":"In vitro transcription/translation co-immunoprecipitation, Ba/F3 transformation assay, Western blot for phospho-STAT","journal":"Neoplasia","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of differentially tagged constructs plus functional transformation assay, replicated across labs","pmids":["10935490"],"is_preprint":false},{"year":2000,"finding":"The proline-rich region of ZNF198 constitutes a self-association/oligomerization domain; when fused to the intracellular domain of FGFR1, this proline-rich region alone is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3-independent growth.","method":"Ba/F3 transformation assay, domain deletion/swap constructs, biochemical oligomerization assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional domain mapping with deletion constructs, transformation assay, and oligomerization biochemistry; single lab but multiple orthogonal methods","pmids":["10887137"],"is_preprint":false},{"year":2003,"finding":"ZNF198 forms protein complexes with the DNA repair-associated proteins HHR6A/6B (RAD6 homologs) and RAD18, as shown by yeast two-hybrid and co-immunoprecipitation. The ZNF198-FGFR1 fusion protein also binds HHR6 but not RAD18. Cells expressing the fusion kinase show markedly increased sensitivity to UVB irradiation, suggesting dominant-negative interference with DNA repair.","method":"Yeast two-hybrid, co-immunoprecipitation, UVB sensitivity assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, functional UVB sensitivity assay; single lab, two orthogonal methods","pmids":["12776193"],"is_preprint":false},{"year":2003,"finding":"ZNF198-FGFR1 fusion kinase activates STATs 1, 3, and 5 constitutively; STAT5 activation (but not STAT1 or STAT3) is essential for the anti-apoptotic effect of the fusion, for elevated BclXL levels, for cell cycle progression, and for Rad51 upregulation in transformed cells.","method":"Dominant-negative STAT mutant induction, Western blot, cell viability/cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative epistasis experiments with functional readouts; single lab but multiple pathway readouts and rigorous controls","pmids":["14660670"],"is_preprint":false},{"year":2004,"finding":"ZNF198-FGFR1 induces EMS-like myeloproliferative disease and T lymphoma in mice from common multipotential progenitors. Mutation of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying phospholipase C-gamma1 as a downstream effector. The fusion protein thus signals through both the FGFR1 kinase domain and the ZNF198 fusion partner to determine disease phenotype.","method":"Murine bone marrow transplantation model, site-directed mutagenesis (Y766F), disease phenotyping","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with site-directed mutagenesis identifying specific downstream effector, rigorous genetic approach","pmids":["15050920"],"is_preprint":false},{"year":2005,"finding":"ZNF198 mass spectrometry-based immunoprecipitation identified splicing-associated proteins PSF, hnRNP H3, hnRNP A2/B1, and TLS/FUS as interacting partners of ZNF198 in the nucleus. PTB also interacts with ZNF198. In cells expressing ZNF198/FGFR1 fusion, neither PSF nor PTB binds the cytoplasmic fusion protein, consistent with their differential localization.","method":"GFP-tag immunoprecipitation combined with MALDI-TOF mass spectrometry, Western blot confirmation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome with Western blot confirmation; single lab, interaction confirmed by two orthogonal methods","pmids":["15975576"],"is_preprint":false},{"year":2006,"finding":"ZNF198 is covalently modified by SUMO-1 and co-localizes with SUMO-1 and PML at PML nuclear bodies. ZNF198 and sumoylated ZNF198 form a protein complex with PML. Mutation of the SUMO-1 binding site in ZNF198 results in loss of distinct PML bodies and reduced PML levels. In cells expressing ZNF198/FGFR1, which lacks the SUMO-1 binding site, SUMO-1 is mislocalized to the cytoplasm with loss of PML bodies.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, site-directed mutagenesis of SUMO binding site","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, co-IP, imaging, mutagenesis) in single lab establishing SUMO modification and PML body function","pmids":["17027752"],"is_preprint":false},{"year":2007,"finding":"ZNF198-FGFR1 activates both the AKT and MAPK pro-survival signaling pathways, leading to phosphorylation of FOXO3a (T32) and BAD (S112), which are then sequestered by 14-3-3 proteins to prevent apoptosis. Disruption of 14-3-3–ligand interactions by a competitive antagonist R18 induces apoptosis in ZNF198-FGFR1-transformed cells primarily through liberation of FOXO3a.","method":"Western blot phosphorylation analysis, peptide antagonist competition assay, apoptosis assay in Ba/F3 and KG-1a cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-specific Western blots plus functional peptide antagonist; single lab, two orthogonal approaches","pmids":["17389761"],"is_preprint":false},{"year":2008,"finding":"ZNF198 binds preferentially to the intact LSD1-CoREST-HDAC1 (LCH) ternary complex but not its individual subunits. ZNF198- and REST-binding to LCH are mutually exclusive. ZNF198 associates with chromatin independently of LCH. SUMO modification of HDAC1 weakens HDAC1-CoREST interaction but stimulates HDAC1 binding to ZNF198. The LCH-binding and HDAC1-SUMO-binding domains of ZNF198 were mapped to tandem MYM-type zinc finger repeats. ZNF198-like proteins are required for repression of E-cadherin (an LSD1 target) but not REST-responsive genes.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, in vitro sumoylation assay, domain mapping with deletion constructs, gene expression analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (co-IP, ChIP, in vitro SUMO assay, domain mapping) with functional gene expression readouts in single comprehensive study","pmids":["18806873"],"is_preprint":false},{"year":2009,"finding":"ZNF198-FGFR1 fusion kinase specifically phosphorylates SSBP2 and ABL proteins (as well as FLJ14235, CALM, and TRIM4), identified by anti-phosphotyrosine immunoprecipitation and mass spectrometry in HEK293 cells, confirmed by protein-specific immunoprecipitation and Western blotting. Phosphorylation events within the ZNF198 moiety of the chimeric protein were also detected.","method":"Phosphotyrosine immunoprecipitation, mass spectrometry, confirmatory co-immunoprecipitation and Western blot","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification confirmed by orthogonal immunoprecipitation/Western blot; single lab","pmids":["19658100"],"is_preprint":false},{"year":2011,"finding":"ZNF198 protein levels are regulated post-translationally by PLK1: co-immunoprecipitation of the PLK1 polo-box domain with ZNF198 suggests ZNF198 is a PLK1 substrate. Knockdown of ZNF198 by siRNA reduces p53 stability and DNA repair, and rescues HBx-expressing hepatocytes from DNA damage-induced apoptosis, while enhancing HBV replication.","method":"siRNA knockdown, co-immunoprecipitation (Plk1 polo-box domain with ZNF198), Western blot, apoptosis assay","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional siRNA knockdown assays; single lab, interaction evidence is partial (polo-box domain construct, not full co-IP)","pmids":["21480320"],"is_preprint":false},{"year":2014,"finding":"MYM-type zinc fingers of ZNF198 (and ZNF261) are necessary and sufficient for SUMO binding, functioning as SUMO-interacting motifs (SIMs). Individual MYM zinc fingers act as SIMs that interact with the same SUMO-2 surface as the consensus SIM. MYM zinc fingers of ZNF198 are necessary for localization to PML nuclear bodies.","method":"In vitro SUMO binding assays, domain truncation analysis, immunofluorescence microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding assays with domain truncations plus imaging, two proteins studied with convergent results, multiple orthogonal methods","pmids":["25133527"],"is_preprint":false},{"year":2015,"finding":"PLK1 induces proteasomal degradation of ZNF198 through site-specific phosphorylation. PLK1-dependent ubiquitination of ZNF198 is enhanced by the lncRNA HOTAIR, significantly reducing ZNF198 stability. This mechanism leads to destabilization of the LSD1/Co-REST/HDAC1 corepressor complex that ZNF198 normally stabilizes.","method":"Phosphorylation assays, ubiquitination assays, cycloheximide chase (protein stability), co-immunoprecipitation, in vivo mouse model validation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple biochemical assays (phosphorylation, ubiquitination, stability) combined with in vivo model validation; single lab with multiple orthogonal methods","pmids":["25855382"],"is_preprint":false},{"year":2015,"finding":"ZMYM2/ZNF198 is recruited to chromatin via a multi-SUMO interaction mechanism requiring its multiple SUMO-interacting motifs (SIMs), which bind multi-SUMO platforms. This multi-SIM module is required for ZMYM2's function as a transcriptional co-repressor and its chromatin recruitment.","method":"Screen for multi-SUMO binding proteins, SIM mutagenesis, chromatin immunoprecipitation, functional transcriptional repression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic screen combined with mutagenesis, ChIP, and functional transcription assays; single lab but multiple orthogonal methods","pmids":["26283374"],"is_preprint":false},{"year":2020,"finding":"ZMYM2 recruits the LSD1/HDAC corepressor complex to MERVL LTR elements for transcriptional repression. miR-344 (activated by DUX) post-transcriptionally represses ZMYM2 and its partner LSD1, relieving MERVL repression and inducing a 2C-like totipotent state. Zygotic depletion of Zmym2 compromises the totipotency-to-pluripotency transition during early mouse development.","method":"miRNA overexpression/knockdown, ChIP, reporter assays, morpholino knockdown in zygotes, gene expression analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, loss-of-function in vitro and in vivo, reporter assays) establishing pathway position and chromatin mechanism","pmids":["32032525"],"is_preprint":false},{"year":2020,"finding":"ZMYM2 loss-of-function mutations (heterozygous) in humans cause congenital anomalies of the kidney and urinary tract (CAKUT). Protein-protein interaction assays show ZMYM2 interacts with FOXP1 (a transcription factor linked to CAKUT) and with additional epigenetic silencing complexes. Heterozygous Zmym2-deficient mice recapitulate CAKUT features with high penetrance.","method":"Whole-exome sequencing, morpholino knockdown in X. tropicalis, heterozygous mouse knockout, protein-protein interaction assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — converging human genetics, two animal models, and biochemical interaction assays establishing ZMYM2 role in renal development","pmids":["32891193"],"is_preprint":false},{"year":2020,"finding":"ZMYM2 is the most potent growth-restricting chromatin-associated protein in human ESCs, functioning through the LSD1-CoREST (BHC) complex. ZMYM2-null human ESCs show genome-wide promoter H3 hyper-acetylation, overexpression of pluripotency genes, resistance to in vitro differentiation, and failure to produce teratomas in immunodeficient mice.","method":"CRISPR/Cas9 knockout screen in ESCs, ChIP-seq, teratoma assay, gene expression analysis","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen with functional validation using ChIP-seq, in vitro differentiation, and in vivo teratoma assay","pmids":["32559458"],"is_preprint":false},{"year":2020,"finding":"ZMYM2 and ZMYM4 are novel B-MYB binding partners, identified by affinity purification/mass spectrometry and confirmed by co-immunoprecipitation. Knockdown of ZMYM2 strongly impairs G1/S-phase progression in HepG2 cells, suggesting ZMYM2 is required for S-phase entry in these cells.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, cell cycle analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interaction confirmed by co-IP plus functional cell cycle phenotype; single lab","pmids":["32439918"],"is_preprint":false},{"year":2021,"finding":"Avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 through a minimal drug-responsive element contained within the MYM zinc-chelating domain. This domain is universally included in ZMYM2-FGFR1 and ZMYM2-FLT3 fusion oncoproteins, and avadomide induces degradation of these chimeric oncoproteins both in vitro and in vivo.","method":"Ubiquitination assays, proteasome inhibitor rescue, domain mapping, in vitro and in vivo xenograft models","journal":"Blood cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic domain mapping combined with in vitro ubiquitination assays and in vivo validation; multiple orthogonal methods","pmids":["34027417"],"is_preprint":false},{"year":2022,"finding":"ZMYM2 is recruited to DNA double-strand breaks (DSBs) in a PIAS4 (SUMO E3 ligase) and SUMO-binding-dependent manner, where it restricts 53BP1 recruitment to favor BRCA1 loading and homologous recombination (HR). ZMYM2-deficient cells show genome instability, PARP inhibitor and ionizing radiation sensitivity, and reduced HR. Depletion of 53BP1 in ZMYM2-deficient cells rescues BRCA1 recruitment and HR, establishing the epistatic relationship.","method":"CRISPR/KO and siRNA knockdown, live-cell imaging of DSB recruitment, HR/NHEJ reporter assays, epistasis analysis (53BP1 depletion rescue), PARP inhibitor/IR sensitivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, functional repair assays, genetic epistasis) establishing molecular mechanism at DSBs; rigorous controls","pmids":["35253893"],"is_preprint":false},{"year":2022,"finding":"UBE2B and RAD18 form a complex that monoubiquitinates ZMYM2, increasing ZMYM2 protein stability by reducing polyubiquitination and proteasomal degradation. RAD18 knockdown impairs UBE2B-induced ZMYM2 monoubiquitination.","method":"Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, siRNA knockdown, xenograft tumor model","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, and stability assay in single lab; mechanistic detail confirmed by multiple biochemical methods","pmids":["35313791"],"is_preprint":false},{"year":2023,"finding":"ZMYM2 is essential for DNA methylation and silencing of germline gene promoters and active LINE elements in embryonic development. In Zmym2-/- embryos (lethal by E10.5), germline genes and young LINE-1 elements are upregulated and demethylated. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, and its absence causes hypermethylation of H3K4 at target sites, creating a chromatin landscape unfavorable for DNA methylation establishment. A conserved role in LINE element repression was confirmed in ZMYM2-/- human ESCs.","method":"Mouse and human ESC knockout, DNA methylation analysis (bisulfite), ChIP-seq, RNA-seq, H3K4me analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive multi-omics (ChIP-seq, RNA-seq, methylation) with both mouse KO and human ESC KO confirming conserved mechanism; replicated across two species","pmids":["37395395"],"is_preprint":false},{"year":2023,"finding":"ZMYM2 is part of distinct chromatin-bound complexes: the established LSD1-CoREST-HDAC1 complex, and newly identified complexes with ADNP and with TRIM28/KAP1. The ZMYM2-TRIM28 complex forms in a SUMO-dependent manner and is associated with repressive chromatin. ZMYM2-ADNP complexes regulate SINEs, while ZMYM2-TRIM28 complexes regulate LTR retrotransposons within TADs.","method":"Co-immunoprecipitation, ChIP-seq, Hi-C/TAD analysis, SUMO-dependence assays, gene expression analysis after knockdown","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical and genomic methods identifying distinct complex compositions with functional consequences; single lab but comprehensive multi-omics approach","pmids":["37934570"],"is_preprint":false}],"current_model":"ZMYM2 (ZNF198/FIM) is a nuclear zinc-finger transcriptional co-repressor that stabilizes and bridges multiple chromatin-remodeling complexes—primarily LSD1-CoREST-HDAC1, and also ADNP- and TRIM28/KAP1-containing complexes—at retrotransposons and developmentally regulated genes; it is recruited to chromatin via multivalent SUMO binding through its MYM-type zinc fingers, is regulated post-translationally by PLK1-mediated phosphorylation and proteasomal degradation (stabilized by UBE2B/RAD18-mediated monoubiquitination), localizes to PML nuclear bodies in a SUMO-1-dependent manner, and participates in DNA double-strand break repair by restricting 53BP1 to favor BRCA1-mediated homologous recombination; its N-terminal MYM domain is constitutively fused to FGFR1 (or FLT3) in the t(8;13) myeloproliferative syndrome, where the ZNF198 proline-rich self-association domain drives FGFR1 dimerization and constitutive tyrosine kinase activity that signals through PLCγ1, STAT5, AKT, and MAPK to transform hematopoietic progenitors."},"narrative":{"mechanistic_narrative":"ZMYM2 (ZNF198/FIM) is a nuclear MYM-type zinc-finger protein that acts as a SUMO-dependent scaffold for chromatin-modifying corepressor complexes, restraining transposable elements and developmentally regulated genes [PMID:26283374, PMID:32032525, PMID:37934570]. Its tandem MYM zinc fingers function as SUMO-interacting motifs that bind multi-SUMO platforms, and this multi-SIM module is required both for recruitment to chromatin and for transcriptional repression [PMID:25133527, PMID:26283374]. Through these domains ZMYM2 binds the intact LSD1-CoREST-HDAC1 ternary complex (and additionally ADNP- and TRIM28/KAP1-containing complexes assembled in a SUMO-dependent manner), engagements that are mutually exclusive with REST and that direct repression of LSD1 target genes and retrotransposons [PMID:18806873, PMID:37934570]. At the genome level ZMYM2 represses MERVL/LTR elements, SINEs, and young LINE-1 elements and supports DNA methylation and H3K4 demethylation at germline-gene and retroelement promoters, controlling the totipotency-to-pluripotency transition and restraining pluripotency-gene expression in embryonic stem cells [PMID:32032525, PMID:32559458, PMID:37395395]. ZMYM2 also functions in genome maintenance, being recruited to DNA double-strand breaks via PIAS4 and SUMO binding where it restricts 53BP1 to favor BRCA1-mediated homologous recombination [PMID:35253893]. Its abundance is set post-translationally: PLK1-mediated phosphorylation drives ubiquitination and proteasomal degradation (enhanced by the lncRNA HOTAIR), whereas UBE2B/RAD18-mediated monoubiquitination stabilizes the protein [PMID:25855382, PMID:35313791]. Heterozygous ZMYM2 loss-of-function mutations cause congenital anomalies of the kidney and urinary tract in humans [PMID:32891193]. Independently, the ZMYM2 N-terminal region is fused to the FGFR1 tyrosine kinase domain in the t(8;13) myeloproliferative syndrome, where the ZMYM2 proline-rich self-association domain drives FGFR1 dimerization and constitutive kinase activity that signals through STAT5, AKT, MAPK, and PLCγ1 to transform hematopoietic progenitors [PMID:9425908, PMID:10887137, PMID:15050920].","teleology":[{"year":1998,"claim":"Defined the disease context by showing ZMYM2 is fused to the FGFR1 kinase domain in t(8;13) and that this fusion has constitutive tyrosine kinase activity, establishing it as the transforming lesion.","evidence":"Molecular cloning, expression, immunofluorescence localization, and in vitro kinase assay on the fusion protein","pmids":["9425908","9576949"],"confidence":"High","gaps":["Did not define which ZMYM2 sequences mediate dimerization","Normal cellular function of full-length ZMYM2 not yet addressed"]},{"year":1999,"claim":"Distinguished normal from oncogenic ZMYM2 behavior, showing native FIM is nuclear/nucleolar with a C-terminal nuclear-targeting region while the fusion is cytoplasmic and self-associates via N-terminal sequences.","evidence":"Subcellular fractionation, confocal microscopy, co-IP and deletion constructs; reciprocal co-IP transformation assay in Ba/F3 cells","pmids":["10480903","10935490"],"confidence":"High","gaps":["Functional role of nucleolar localization (rRNA transcription) only inferred from colocalization","Did not map the precise self-association element"]},{"year":2000,"claim":"Mapped the oligomerization activity to the ZMYM2 proline-rich region, showing it alone is sufficient to dimerize and activate FGFR1, defining the mechanistic basis of fusion-driven kinase activation.","evidence":"Domain deletion/swap constructs, biochemical oligomerization assay, Ba/F3 transformation","pmids":["10887137"],"confidence":"High","gaps":["Role of the proline-rich domain in normal ZMYM2 function unknown","Structural basis of oligomerization not resolved"]},{"year":2003,"claim":"Connected the fusion to downstream survival signaling and a DNA-repair interactome, identifying HHR6/RAD18 binding and STAT5 as the essential anti-apoptotic effector.","evidence":"Yeast two-hybrid, co-IP, UVB sensitivity assay; dominant-negative STAT epistasis with viability and Rad51 readouts","pmids":["12776193","14660670"],"confidence":"Medium","gaps":["Whether full-length ZMYM2 uses HHR6/RAD18 in normal DNA repair not established here","STAT5 link is specific to the fusion context"]},{"year":2004,"claim":"Established in vivo that both the FGFR1 kinase and the ZMYM2 partner shape disease phenotype, identifying PLCγ1 (FGFR1 Y766) as a required effector for myeloid and lymphoid disease.","evidence":"Murine bone-marrow transplantation model with Y766F site-directed mutagenesis and disease phenotyping","pmids":["15050920"],"confidence":"High","gaps":["Mechanism by which ZMYM2 sequences modulate phenotype not dissected","Did not address normal ZMYM2 hematopoietic function"]},{"year":2005,"claim":"Began defining the normal nuclear interactome, identifying splicing-associated partners (PSF, hnRNP H3, hnRNP A2/B1, TLS/FUS, PTB) that fail to bind the cytoplasmic fusion.","evidence":"GFP-IP MALDI-TOF mass spectrometry with Western blot confirmation","pmids":["15975576"],"confidence":"Medium","gaps":["Functional consequence of splicing-factor interactions unestablished","No reciprocal validation of all interactions"]},{"year":2006,"claim":"Established ZMYM2 as a SUMO-1-modified component of PML nuclear bodies whose SUMO-binding is required for PML body integrity, linking it to SUMO biology.","evidence":"Yeast two-hybrid, co-IP, confocal microscopy, SUMO-binding-site mutagenesis","pmids":["17027752"],"confidence":"High","gaps":["Exact SUMO-binding determinant not yet mapped to MYM fingers","Functional output of PML body localization unresolved"]},{"year":2008,"claim":"Identified the core chromatin function, showing ZMYM2 binds the intact LSD1-CoREST-HDAC1 complex mutually exclusively with REST and represses LSD1 targets, with binding domains in tandem MYM zinc fingers.","evidence":"Co-IP, ChIP, in vitro sumoylation, domain mapping, gene expression analysis","pmids":["18806873"],"confidence":"High","gaps":["Genome-wide target repertoire not yet defined","How SUMO modification gates complex selection only partially characterized"]},{"year":2014,"claim":"Provided the molecular basis of SUMO recognition, demonstrating MYM zinc fingers function directly as SUMO-interacting motifs necessary for PML body targeting.","evidence":"In vitro SUMO-binding assays, domain truncation, immunofluorescence","pmids":["25133527"],"confidence":"High","gaps":["In vivo chromatin SUMO targets not enumerated","Structural detail of MYM-SUMO interface limited"]},{"year":2015,"claim":"Defined recruitment logic and turnover control, showing multi-SIM binding to multi-SUMO platforms drives chromatin recruitment while PLK1 phosphorylation (enhanced by HOTAIR) triggers degradation that destabilizes the corepressor complex.","evidence":"Multi-SUMO binding screen, SIM mutagenesis, ChIP, repression assays; phosphorylation/ubiquitination/CHX-chase assays with in vivo validation","pmids":["26283374","25855382"],"confidence":"High","gaps":["Precise PLK1 phosphosites and E3 ligase not fully defined","How SUMO valency is sensed quantitatively unresolved"]},{"year":2020,"claim":"Established ZMYM2 as a master repressor of transposons and pluripotency in development, restraining MERVL/2C-like state, restricting ESC growth via the BHC/LSD1-CoREST complex, and as a CAKUT disease gene interacting with FOXP1.","evidence":"miRNA and morpholino loss-of-function in zygotes, ChIP, CRISPR KO screen and ChIP-seq/teratoma in ESCs, exome sequencing with mouse/Xenopus models and PPI assays","pmids":["32032525","32559458","32891193"],"confidence":"High","gaps":["Mechanism linking renal phenotype to specific target genes incomplete","Cell-cycle role identified in HepG2 (PMID 32439918) not mechanistically integrated"]},{"year":2022,"claim":"Extended ZMYM2 into genome maintenance and clarified its stability control, showing PIAS4/SUMO-dependent recruitment to DSBs where it restricts 53BP1 to favor BRCA1/HR, and UBE2B/RAD18 monoubiquitination that stabilizes the protein.","evidence":"CRISPR/siRNA, live-cell DSB imaging, HR/NHEJ reporters, 53BP1-depletion epistasis, PARPi/IR sensitivity; co-IP, CHX-chase, ubiquitination assays, xenograft","pmids":["35253893","35313791"],"confidence":"High","gaps":["How the same SUMO-binding module is partitioned between repair and transcription unclear","UBE2B/RAD18 monoubiquitination site not mapped"]},{"year":2023,"claim":"Resolved ZMYM2 into distinct repressive complexes and defined its epigenetic mechanism, showing ADNP- and SUMO-dependent TRIM28/KAP1 complexes that silence SINEs and LTRs within TADs and that ZMYM2 enables DNA methylation by limiting H3K4 methylation at germline and LINE-1 targets.","evidence":"Co-IP, ChIP-seq, Hi-C/TAD analysis, bisulfite methylation and RNA-seq in mouse and human ESC knockouts","pmids":["37934570","37395395"],"confidence":"High","gaps":["Determinants selecting LSD1-CoREST vs ADNP vs TRIM28 complexes per locus unresolved","Order of events linking ZMYM2 binding to de novo methylation not fully ordered"]},{"year":null,"claim":"How a single SUMO-binding scaffold is dynamically allocated among transcriptional repression, DNA-damage repair, PML body organization, and its developmental and renal functions remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of how multivalent SUMO binding selects among partner complexes","Causal chain from ZMYM2 loss to CAKUT not mapped to specific targets","Interplay between PLK1-driven degradation and RAD18-driven stabilization not quantitatively integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,16,19,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,16,22,25]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,16]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[11,22,24]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,17,24,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,16,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,18,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,18]}],"complexes":["LSD1-CoREST-HDAC1 (BHC) complex","ZMYM2-ADNP complex","ZMYM2-TRIM28/KAP1 complex","PML nuclear bodies"],"partners":["LSD1","HDAC1","COREST","TRIM28","ADNP","PML","PIAS4","RAD18"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBW7","full_name":"Zinc finger MYM-type protein 2","aliases":["Fused in myeloproliferative disorders protein","Rearranged in atypical myeloproliferative disorder protein","Zinc finger protein 198"],"length_aa":1377,"mass_kda":154.9,"function":"Involved in the negative regulation of transcription","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBW7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZMYM2","classification":"Not 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cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17321332","citation_count":19,"is_preprint":false},{"pmid":"15975576","id":"PMC_15975576","title":"Mass spectroscopy identifies the splicing-associated proteins, PSF, hnRNP H3, hnRNP A2/B1, and TLS/FUS as interacting partners of the ZNF198 protein associated with rearrangement in myeloproliferative disease.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15975576","citation_count":19,"is_preprint":false},{"pmid":"18034794","id":"PMC_18034794","title":"DNA sequence heterogeneity in Fim tyrosine-integrase recombinase-binding elements and functional motif asymmetries determine the directionality of the fim genetic switch in Escherichia coli K-12.","date":"2007","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18034794","citation_count":19,"is_preprint":false},{"pmid":"23751892","id":"PMC_23751892","title":"A ZMYM2-FGFR1 8p11 myeloproliferative neoplasm with a novel nonsense RUNX1 mutation and tumor lysis upon imatinib treatment.","date":"2013","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23751892","citation_count":18,"is_preprint":false},{"pmid":"27005999","id":"PMC_27005999","title":"Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27005999","citation_count":17,"is_preprint":false},{"pmid":"17307320","id":"PMC_17307320","title":"Evaluation of ADL in patients with Hunter disease using FIM score.","date":"2007","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/17307320","citation_count":17,"is_preprint":false},{"pmid":"19658100","id":"PMC_19658100","title":"Phosphorylation of the SSBP2 and ABL proteins by the ZNF198-FGFR1 fusion kinase seen in atypical myeloproliferative disorders as revealed by phosphopeptide-specific MS.","date":"2009","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/19658100","citation_count":16,"is_preprint":false},{"pmid":"32559458","id":"PMC_32559458","title":"The Chromatin Regulator ZMYM2 Restricts Human Pluripotent Stem Cell Growth and Is Essential for Teratoma Formation.","date":"2020","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32559458","citation_count":15,"is_preprint":false},{"pmid":"32944148","id":"PMC_32944148","title":"Phylogenetic diversity in fim and mfa gene clusters between Porphyromonas gingivalis and Porphyromonas gulae, as a potential cause of host specificity.","date":"2020","source":"Journal of oral microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32944148","citation_count":15,"is_preprint":false},{"pmid":"1684407","id":"PMC_1684407","title":"Expression of Bordetella pertussis fimbrial (fim) genes in Bordetella bronchiseptica: fimX is expressed at a low level and vir-regulated.","date":"1991","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1684407","citation_count":15,"is_preprint":false},{"pmid":"29445547","id":"PMC_29445547","title":"Temporal Regulation of fim Genes in Uropathogenic Escherichia coli during Infection of the Murine Urinary Tract.","date":"2017","source":"Journal of pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29445547","citation_count":15,"is_preprint":false},{"pmid":"15322026","id":"PMC_15322026","title":"A Salmonella fim homologue in Citrobacter freundii mediates invasion in vitro and crossing of the blood-brain barrier in the rat pup model.","date":"2004","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15322026","citation_count":15,"is_preprint":false},{"pmid":"30506766","id":"PMC_30506766","title":"Sectioning and extensively examining the fimbriated end (SEE-FIM) of the fallopian tube in routine practices, is it worth the effort?","date":"2018","source":"The journal of obstetrics and gynaecology research","url":"https://pubmed.ncbi.nlm.nih.gov/30506766","citation_count":14,"is_preprint":false},{"pmid":"6620255","id":"PMC_6620255","title":"Presence of the factor increasing monocytopoiesis (FIM) in rabbit peripheral blood during an acute inflammation.","date":"1983","source":"Journal of the Reticuloendothelial Society","url":"https://pubmed.ncbi.nlm.nih.gov/6620255","citation_count":14,"is_preprint":false},{"pmid":"32439918","id":"PMC_32439918","title":"Characterization of the zinc finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32439918","citation_count":13,"is_preprint":false},{"pmid":"9628019","id":"PMC_9628019","title":"Transcription pattern of a FIM homologue in Impatiens during floral development and reversion.","date":"1998","source":"The Plant journal : for cell and molecular 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stabilization.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35313791","citation_count":11,"is_preprint":false},{"pmid":"32852395","id":"PMC_32852395","title":"Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion.","date":"2021","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32852395","citation_count":11,"is_preprint":false},{"pmid":"32982742","id":"PMC_32982742","title":"Renal and Neurologic Benefit of Levosimendan vs Dobutamine in Patients With Low Cardiac Output Syndrome After Cardiac Surgery: Clinical Trial FIM-BGC-2014-01.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32982742","citation_count":11,"is_preprint":false},{"pmid":"29951317","id":"PMC_29951317","title":"Differential Regulation of Escherichia coli fim Genes following Binding to Mannose Receptors.","date":"2018","source":"Journal of pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29951317","citation_count":10,"is_preprint":false},{"pmid":"23594707","id":"PMC_23594707","title":"B-lymphoblastic leukemia/lymphoma associated with t(8;13)(p11;q12)/ ZMYM2 (ZNF198)-FGFR1 : rare case and review of the literature.","date":"2013","source":"Acta haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/23594707","citation_count":9,"is_preprint":false},{"pmid":"33384692","id":"PMC_33384692","title":"Anti-FIM and Anti-FHA Antibodies Inhibit Bordetella pertussis Growth and Reduce Epithelial Cell Inflammation Through Bacterial Aggregation.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33384692","citation_count":9,"is_preprint":false},{"pmid":"10529207","id":"PMC_10529207","title":"Rapid in vitro conformational changes of the catalytic site of PKC alpha assessed by FIM-1 fluorescence.","date":"1999","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10529207","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46798,"output_tokens":6970,"usd":0.122472,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16002,"output_tokens":5003,"usd":0.102542,"stage2_stop_reason":"end_turn"},"total_usd":0.225014,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"ZNF198 (ZMYM2) is fused to the FGFR1 tyrosine-kinase domain in the t(8;13)(p11;q12) translocation; the resulting ZNF198-FGFR1 fusion protein (~87 kDa) localizes predominantly to the cytoplasm and directs synthesis of a polypeptide whose ZNF198 zinc-finger domains are proposed to mediate homodimerization leading to constitutive FGFR1 tyrosine kinase activation.\",\n      \"method\": \"Molecular cloning, transient expression, subcellular localization by immunofluorescence\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with expression studies and localization, single lab but multiple methods; dimerization mechanism proposed but mechanistic detail is limited in abstract\",\n      \"pmids\": [\"9425908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The FIM/ZNF198-FGFR1 fusion protein has constitutive tyrosine kinase activity, as demonstrated by in vitro kinase assays on the fusion product generated from the t(8;13) translocation.\",\n      \"method\": \"In vitro tyrosine kinase assay on immunoprecipitated fusion protein\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay, replicated across multiple labs (PMID 9425908, 9576949, 10480903)\",\n      \"pmids\": [\"9576949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FIM (ZMYM2) normally has nuclear and nucleolar localization (colocalizing with the upstream binding factor in interphase cells, suggesting a role in rRNA transcription regulation), whereas the FIM-FGFR1 fusion protein is cytoplasmic. Nuclear targeting depends on the C-terminal region of FIM, which is absent in FIM-FGFR1. FIM-FGFR1 has constitutive dimerization capability mediated by FIM N-terminal sequences.\",\n      \"method\": \"Subcellular fractionation, confocal immunofluorescence, co-immunoprecipitation, deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, co-IP, deletion analysis), single lab but comprehensive mechanistic study\",\n      \"pmids\": [\"10480903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ZNF198-FGFR1 self-associates in vitro (shown by co-immunoprecipitation of differentially tagged constructs) and is a cytoplasmic protein with constitutive transformation activity, inducing IL-3-independent growth of Ba/F3 cells with constitutive tyrosine phosphorylation of STAT1 and STAT5.\",\n      \"method\": \"In vitro transcription/translation co-immunoprecipitation, Ba/F3 transformation assay, Western blot for phospho-STAT\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of differentially tagged constructs plus functional transformation assay, replicated across labs\",\n      \"pmids\": [\"10935490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The proline-rich region of ZNF198 constitutes a self-association/oligomerization domain; when fused to the intracellular domain of FGFR1, this proline-rich region alone is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3-independent growth.\",\n      \"method\": \"Ba/F3 transformation assay, domain deletion/swap constructs, biochemical oligomerization assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional domain mapping with deletion constructs, transformation assay, and oligomerization biochemistry; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10887137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ZNF198 forms protein complexes with the DNA repair-associated proteins HHR6A/6B (RAD6 homologs) and RAD18, as shown by yeast two-hybrid and co-immunoprecipitation. The ZNF198-FGFR1 fusion protein also binds HHR6 but not RAD18. Cells expressing the fusion kinase show markedly increased sensitivity to UVB irradiation, suggesting dominant-negative interference with DNA repair.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, UVB sensitivity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, functional UVB sensitivity assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"12776193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ZNF198-FGFR1 fusion kinase activates STATs 1, 3, and 5 constitutively; STAT5 activation (but not STAT1 or STAT3) is essential for the anti-apoptotic effect of the fusion, for elevated BclXL levels, for cell cycle progression, and for Rad51 upregulation in transformed cells.\",\n      \"method\": \"Dominant-negative STAT mutant induction, Western blot, cell viability/cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative epistasis experiments with functional readouts; single lab but multiple pathway readouts and rigorous controls\",\n      \"pmids\": [\"14660670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ZNF198-FGFR1 induces EMS-like myeloproliferative disease and T lymphoma in mice from common multipotential progenitors. Mutation of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying phospholipase C-gamma1 as a downstream effector. The fusion protein thus signals through both the FGFR1 kinase domain and the ZNF198 fusion partner to determine disease phenotype.\",\n      \"method\": \"Murine bone marrow transplantation model, site-directed mutagenesis (Y766F), disease phenotyping\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with site-directed mutagenesis identifying specific downstream effector, rigorous genetic approach\",\n      \"pmids\": [\"15050920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ZNF198 mass spectrometry-based immunoprecipitation identified splicing-associated proteins PSF, hnRNP H3, hnRNP A2/B1, and TLS/FUS as interacting partners of ZNF198 in the nucleus. PTB also interacts with ZNF198. In cells expressing ZNF198/FGFR1 fusion, neither PSF nor PTB binds the cytoplasmic fusion protein, consistent with their differential localization.\",\n      \"method\": \"GFP-tag immunoprecipitation combined with MALDI-TOF mass spectrometry, Western blot confirmation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome with Western blot confirmation; single lab, interaction confirmed by two orthogonal methods\",\n      \"pmids\": [\"15975576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ZNF198 is covalently modified by SUMO-1 and co-localizes with SUMO-1 and PML at PML nuclear bodies. ZNF198 and sumoylated ZNF198 form a protein complex with PML. Mutation of the SUMO-1 binding site in ZNF198 results in loss of distinct PML bodies and reduced PML levels. In cells expressing ZNF198/FGFR1, which lacks the SUMO-1 binding site, SUMO-1 is mislocalized to the cytoplasm with loss of PML bodies.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, site-directed mutagenesis of SUMO binding site\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, co-IP, imaging, mutagenesis) in single lab establishing SUMO modification and PML body function\",\n      \"pmids\": [\"17027752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZNF198-FGFR1 activates both the AKT and MAPK pro-survival signaling pathways, leading to phosphorylation of FOXO3a (T32) and BAD (S112), which are then sequestered by 14-3-3 proteins to prevent apoptosis. Disruption of 14-3-3–ligand interactions by a competitive antagonist R18 induces apoptosis in ZNF198-FGFR1-transformed cells primarily through liberation of FOXO3a.\",\n      \"method\": \"Western blot phosphorylation analysis, peptide antagonist competition assay, apoptosis assay in Ba/F3 and KG-1a cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-specific Western blots plus functional peptide antagonist; single lab, two orthogonal approaches\",\n      \"pmids\": [\"17389761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZNF198 binds preferentially to the intact LSD1-CoREST-HDAC1 (LCH) ternary complex but not its individual subunits. ZNF198- and REST-binding to LCH are mutually exclusive. ZNF198 associates with chromatin independently of LCH. SUMO modification of HDAC1 weakens HDAC1-CoREST interaction but stimulates HDAC1 binding to ZNF198. The LCH-binding and HDAC1-SUMO-binding domains of ZNF198 were mapped to tandem MYM-type zinc finger repeats. ZNF198-like proteins are required for repression of E-cadherin (an LSD1 target) but not REST-responsive genes.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, in vitro sumoylation assay, domain mapping with deletion constructs, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (co-IP, ChIP, in vitro SUMO assay, domain mapping) with functional gene expression readouts in single comprehensive study\",\n      \"pmids\": [\"18806873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ZNF198-FGFR1 fusion kinase specifically phosphorylates SSBP2 and ABL proteins (as well as FLJ14235, CALM, and TRIM4), identified by anti-phosphotyrosine immunoprecipitation and mass spectrometry in HEK293 cells, confirmed by protein-specific immunoprecipitation and Western blotting. Phosphorylation events within the ZNF198 moiety of the chimeric protein were also detected.\",\n      \"method\": \"Phosphotyrosine immunoprecipitation, mass spectrometry, confirmatory co-immunoprecipitation and Western blot\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification confirmed by orthogonal immunoprecipitation/Western blot; single lab\",\n      \"pmids\": [\"19658100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ZNF198 protein levels are regulated post-translationally by PLK1: co-immunoprecipitation of the PLK1 polo-box domain with ZNF198 suggests ZNF198 is a PLK1 substrate. Knockdown of ZNF198 by siRNA reduces p53 stability and DNA repair, and rescues HBx-expressing hepatocytes from DNA damage-induced apoptosis, while enhancing HBV replication.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (Plk1 polo-box domain with ZNF198), Western blot, apoptosis assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional siRNA knockdown assays; single lab, interaction evidence is partial (polo-box domain construct, not full co-IP)\",\n      \"pmids\": [\"21480320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYM-type zinc fingers of ZNF198 (and ZNF261) are necessary and sufficient for SUMO binding, functioning as SUMO-interacting motifs (SIMs). Individual MYM zinc fingers act as SIMs that interact with the same SUMO-2 surface as the consensus SIM. MYM zinc fingers of ZNF198 are necessary for localization to PML nuclear bodies.\",\n      \"method\": \"In vitro SUMO binding assays, domain truncation analysis, immunofluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding assays with domain truncations plus imaging, two proteins studied with convergent results, multiple orthogonal methods\",\n      \"pmids\": [\"25133527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PLK1 induces proteasomal degradation of ZNF198 through site-specific phosphorylation. PLK1-dependent ubiquitination of ZNF198 is enhanced by the lncRNA HOTAIR, significantly reducing ZNF198 stability. This mechanism leads to destabilization of the LSD1/Co-REST/HDAC1 corepressor complex that ZNF198 normally stabilizes.\",\n      \"method\": \"Phosphorylation assays, ubiquitination assays, cycloheximide chase (protein stability), co-immunoprecipitation, in vivo mouse model validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple biochemical assays (phosphorylation, ubiquitination, stability) combined with in vivo model validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25855382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZMYM2/ZNF198 is recruited to chromatin via a multi-SUMO interaction mechanism requiring its multiple SUMO-interacting motifs (SIMs), which bind multi-SUMO platforms. This multi-SIM module is required for ZMYM2's function as a transcriptional co-repressor and its chromatin recruitment.\",\n      \"method\": \"Screen for multi-SUMO binding proteins, SIM mutagenesis, chromatin immunoprecipitation, functional transcriptional repression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic screen combined with mutagenesis, ChIP, and functional transcription assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26283374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYM2 recruits the LSD1/HDAC corepressor complex to MERVL LTR elements for transcriptional repression. miR-344 (activated by DUX) post-transcriptionally represses ZMYM2 and its partner LSD1, relieving MERVL repression and inducing a 2C-like totipotent state. Zygotic depletion of Zmym2 compromises the totipotency-to-pluripotency transition during early mouse development.\",\n      \"method\": \"miRNA overexpression/knockdown, ChIP, reporter assays, morpholino knockdown in zygotes, gene expression analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, loss-of-function in vitro and in vivo, reporter assays) establishing pathway position and chromatin mechanism\",\n      \"pmids\": [\"32032525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYM2 loss-of-function mutations (heterozygous) in humans cause congenital anomalies of the kidney and urinary tract (CAKUT). Protein-protein interaction assays show ZMYM2 interacts with FOXP1 (a transcription factor linked to CAKUT) and with additional epigenetic silencing complexes. Heterozygous Zmym2-deficient mice recapitulate CAKUT features with high penetrance.\",\n      \"method\": \"Whole-exome sequencing, morpholino knockdown in X. tropicalis, heterozygous mouse knockout, protein-protein interaction assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — converging human genetics, two animal models, and biochemical interaction assays establishing ZMYM2 role in renal development\",\n      \"pmids\": [\"32891193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYM2 is the most potent growth-restricting chromatin-associated protein in human ESCs, functioning through the LSD1-CoREST (BHC) complex. ZMYM2-null human ESCs show genome-wide promoter H3 hyper-acetylation, overexpression of pluripotency genes, resistance to in vitro differentiation, and failure to produce teratomas in immunodeficient mice.\",\n      \"method\": \"CRISPR/Cas9 knockout screen in ESCs, ChIP-seq, teratoma assay, gene expression analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen with functional validation using ChIP-seq, in vitro differentiation, and in vivo teratoma assay\",\n      \"pmids\": [\"32559458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZMYM2 and ZMYM4 are novel B-MYB binding partners, identified by affinity purification/mass spectrometry and confirmed by co-immunoprecipitation. Knockdown of ZMYM2 strongly impairs G1/S-phase progression in HepG2 cells, suggesting ZMYM2 is required for S-phase entry in these cells.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction confirmed by co-IP plus functional cell cycle phenotype; single lab\",\n      \"pmids\": [\"32439918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 through a minimal drug-responsive element contained within the MYM zinc-chelating domain. This domain is universally included in ZMYM2-FGFR1 and ZMYM2-FLT3 fusion oncoproteins, and avadomide induces degradation of these chimeric oncoproteins both in vitro and in vivo.\",\n      \"method\": \"Ubiquitination assays, proteasome inhibitor rescue, domain mapping, in vitro and in vivo xenograft models\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic domain mapping combined with in vitro ubiquitination assays and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"34027417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYM2 is recruited to DNA double-strand breaks (DSBs) in a PIAS4 (SUMO E3 ligase) and SUMO-binding-dependent manner, where it restricts 53BP1 recruitment to favor BRCA1 loading and homologous recombination (HR). ZMYM2-deficient cells show genome instability, PARP inhibitor and ionizing radiation sensitivity, and reduced HR. Depletion of 53BP1 in ZMYM2-deficient cells rescues BRCA1 recruitment and HR, establishing the epistatic relationship.\",\n      \"method\": \"CRISPR/KO and siRNA knockdown, live-cell imaging of DSB recruitment, HR/NHEJ reporter assays, epistasis analysis (53BP1 depletion rescue), PARP inhibitor/IR sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, functional repair assays, genetic epistasis) establishing molecular mechanism at DSBs; rigorous controls\",\n      \"pmids\": [\"35253893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UBE2B and RAD18 form a complex that monoubiquitinates ZMYM2, increasing ZMYM2 protein stability by reducing polyubiquitination and proteasomal degradation. RAD18 knockdown impairs UBE2B-induced ZMYM2 monoubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase assay, ubiquitination assay, siRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, and stability assay in single lab; mechanistic detail confirmed by multiple biochemical methods\",\n      \"pmids\": [\"35313791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZMYM2 is essential for DNA methylation and silencing of germline gene promoters and active LINE elements in embryonic development. In Zmym2-/- embryos (lethal by E10.5), germline genes and young LINE-1 elements are upregulated and demethylated. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, and its absence causes hypermethylation of H3K4 at target sites, creating a chromatin landscape unfavorable for DNA methylation establishment. A conserved role in LINE element repression was confirmed in ZMYM2-/- human ESCs.\",\n      \"method\": \"Mouse and human ESC knockout, DNA methylation analysis (bisulfite), ChIP-seq, RNA-seq, H3K4me analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive multi-omics (ChIP-seq, RNA-seq, methylation) with both mouse KO and human ESC KO confirming conserved mechanism; replicated across two species\",\n      \"pmids\": [\"37395395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZMYM2 is part of distinct chromatin-bound complexes: the established LSD1-CoREST-HDAC1 complex, and newly identified complexes with ADNP and with TRIM28/KAP1. The ZMYM2-TRIM28 complex forms in a SUMO-dependent manner and is associated with repressive chromatin. ZMYM2-ADNP complexes regulate SINEs, while ZMYM2-TRIM28 complexes regulate LTR retrotransposons within TADs.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, Hi-C/TAD analysis, SUMO-dependence assays, gene expression analysis after knockdown\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical and genomic methods identifying distinct complex compositions with functional consequences; single lab but comprehensive multi-omics approach\",\n      \"pmids\": [\"37934570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYM2 (ZNF198/FIM) is a nuclear zinc-finger transcriptional co-repressor that stabilizes and bridges multiple chromatin-remodeling complexes—primarily LSD1-CoREST-HDAC1, and also ADNP- and TRIM28/KAP1-containing complexes—at retrotransposons and developmentally regulated genes; it is recruited to chromatin via multivalent SUMO binding through its MYM-type zinc fingers, is regulated post-translationally by PLK1-mediated phosphorylation and proteasomal degradation (stabilized by UBE2B/RAD18-mediated monoubiquitination), localizes to PML nuclear bodies in a SUMO-1-dependent manner, and participates in DNA double-strand break repair by restricting 53BP1 to favor BRCA1-mediated homologous recombination; its N-terminal MYM domain is constitutively fused to FGFR1 (or FLT3) in the t(8;13) myeloproliferative syndrome, where the ZNF198 proline-rich self-association domain drives FGFR1 dimerization and constitutive tyrosine kinase activity that signals through PLCγ1, STAT5, AKT, and MAPK to transform hematopoietic progenitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZMYM2 (ZNF198/FIM) is a nuclear MYM-type zinc-finger protein that acts as a SUMO-dependent scaffold for chromatin-modifying corepressor complexes, restraining transposable elements and developmentally regulated genes [#16, #17, #25]. Its tandem MYM zinc fingers function as SUMO-interacting motifs that bind multi-SUMO platforms, and this multi-SIM module is required both for recruitment to chromatin and for transcriptional repression [#14, #16]. Through these domains ZMYM2 binds the intact LSD1-CoREST-HDAC1 ternary complex (and additionally ADNP- and TRIM28/KAP1-containing complexes assembled in a SUMO-dependent manner), engagements that are mutually exclusive with REST and that direct repression of LSD1 target genes and retrotransposons [#11, #25]. At the genome level ZMYM2 represses MERVL/LTR elements, SINEs, and young LINE-1 elements and supports DNA methylation and H3K4 demethylation at germline-gene and retroelement promoters, controlling the totipotency-to-pluripotency transition and restraining pluripotency-gene expression in embryonic stem cells [#17, #19, #24]. ZMYM2 also functions in genome maintenance, being recruited to DNA double-strand breaks via PIAS4 and SUMO binding where it restricts 53BP1 to favor BRCA1-mediated homologous recombination [#22]. Its abundance is set post-translationally: PLK1-mediated phosphorylation drives ubiquitination and proteasomal degradation (enhanced by the lncRNA HOTAIR), whereas UBE2B/RAD18-mediated monoubiquitination stabilizes the protein [#15, #23]. Heterozygous ZMYM2 loss-of-function mutations cause congenital anomalies of the kidney and urinary tract in humans [#18]. Independently, the ZMYM2 N-terminal region is fused to the FGFR1 tyrosine kinase domain in the t(8;13) myeloproliferative syndrome, where the ZMYM2 proline-rich self-association domain drives FGFR1 dimerization and constitutive kinase activity that signals through STAT5, AKT, MAPK, and PLCγ1 to transform hematopoietic progenitors [#0, #4, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the disease context by showing ZMYM2 is fused to the FGFR1 kinase domain in t(8;13) and that this fusion has constitutive tyrosine kinase activity, establishing it as the transforming lesion.\",\n      \"evidence\": \"Molecular cloning, expression, immunofluorescence localization, and in vitro kinase assay on the fusion protein\",\n      \"pmids\": [\"9425908\", \"9576949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which ZMYM2 sequences mediate dimerization\", \"Normal cellular function of full-length ZMYM2 not yet addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Distinguished normal from oncogenic ZMYM2 behavior, showing native FIM is nuclear/nucleolar with a C-terminal nuclear-targeting region while the fusion is cytoplasmic and self-associates via N-terminal sequences.\",\n      \"evidence\": \"Subcellular fractionation, confocal microscopy, co-IP and deletion constructs; reciprocal co-IP transformation assay in Ba/F3 cells\",\n      \"pmids\": [\"10480903\", \"10935490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of nucleolar localization (rRNA transcription) only inferred from colocalization\", \"Did not map the precise self-association element\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the oligomerization activity to the ZMYM2 proline-rich region, showing it alone is sufficient to dimerize and activate FGFR1, defining the mechanistic basis of fusion-driven kinase activation.\",\n      \"evidence\": \"Domain deletion/swap constructs, biochemical oligomerization assay, Ba/F3 transformation\",\n      \"pmids\": [\"10887137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of the proline-rich domain in normal ZMYM2 function unknown\", \"Structural basis of oligomerization not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected the fusion to downstream survival signaling and a DNA-repair interactome, identifying HHR6/RAD18 binding and STAT5 as the essential anti-apoptotic effector.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, UVB sensitivity assay; dominant-negative STAT epistasis with viability and Rad51 readouts\",\n      \"pmids\": [\"12776193\", \"14660670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether full-length ZMYM2 uses HHR6/RAD18 in normal DNA repair not established here\", \"STAT5 link is specific to the fusion context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established in vivo that both the FGFR1 kinase and the ZMYM2 partner shape disease phenotype, identifying PLCγ1 (FGFR1 Y766) as a required effector for myeloid and lymphoid disease.\",\n      \"evidence\": \"Murine bone-marrow transplantation model with Y766F site-directed mutagenesis and disease phenotyping\",\n      \"pmids\": [\"15050920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ZMYM2 sequences modulate phenotype not dissected\", \"Did not address normal ZMYM2 hematopoietic function\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Began defining the normal nuclear interactome, identifying splicing-associated partners (PSF, hnRNP H3, hnRNP A2/B1, TLS/FUS, PTB) that fail to bind the cytoplasmic fusion.\",\n      \"evidence\": \"GFP-IP MALDI-TOF mass spectrometry with Western blot confirmation\",\n      \"pmids\": [\"15975576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of splicing-factor interactions unestablished\", \"No reciprocal validation of all interactions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established ZMYM2 as a SUMO-1-modified component of PML nuclear bodies whose SUMO-binding is required for PML body integrity, linking it to SUMO biology.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, confocal microscopy, SUMO-binding-site mutagenesis\",\n      \"pmids\": [\"17027752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact SUMO-binding determinant not yet mapped to MYM fingers\", \"Functional output of PML body localization unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the core chromatin function, showing ZMYM2 binds the intact LSD1-CoREST-HDAC1 complex mutually exclusively with REST and represses LSD1 targets, with binding domains in tandem MYM zinc fingers.\",\n      \"evidence\": \"Co-IP, ChIP, in vitro sumoylation, domain mapping, gene expression analysis\",\n      \"pmids\": [\"18806873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target repertoire not yet defined\", \"How SUMO modification gates complex selection only partially characterized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the molecular basis of SUMO recognition, demonstrating MYM zinc fingers function directly as SUMO-interacting motifs necessary for PML body targeting.\",\n      \"evidence\": \"In vitro SUMO-binding assays, domain truncation, immunofluorescence\",\n      \"pmids\": [\"25133527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo chromatin SUMO targets not enumerated\", \"Structural detail of MYM-SUMO interface limited\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined recruitment logic and turnover control, showing multi-SIM binding to multi-SUMO platforms drives chromatin recruitment while PLK1 phosphorylation (enhanced by HOTAIR) triggers degradation that destabilizes the corepressor complex.\",\n      \"evidence\": \"Multi-SUMO binding screen, SIM mutagenesis, ChIP, repression assays; phosphorylation/ubiquitination/CHX-chase assays with in vivo validation\",\n      \"pmids\": [\"26283374\", \"25855382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise PLK1 phosphosites and E3 ligase not fully defined\", \"How SUMO valency is sensed quantitatively unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established ZMYM2 as a master repressor of transposons and pluripotency in development, restraining MERVL/2C-like state, restricting ESC growth via the BHC/LSD1-CoREST complex, and as a CAKUT disease gene interacting with FOXP1.\",\n      \"evidence\": \"miRNA and morpholino loss-of-function in zygotes, ChIP, CRISPR KO screen and ChIP-seq/teratoma in ESCs, exome sequencing with mouse/Xenopus models and PPI assays\",\n      \"pmids\": [\"32032525\", \"32559458\", \"32891193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking renal phenotype to specific target genes incomplete\", \"Cell-cycle role identified in HepG2 (PMID 32439918) not mechanistically integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ZMYM2 into genome maintenance and clarified its stability control, showing PIAS4/SUMO-dependent recruitment to DSBs where it restricts 53BP1 to favor BRCA1/HR, and UBE2B/RAD18 monoubiquitination that stabilizes the protein.\",\n      \"evidence\": \"CRISPR/siRNA, live-cell DSB imaging, HR/NHEJ reporters, 53BP1-depletion epistasis, PARPi/IR sensitivity; co-IP, CHX-chase, ubiquitination assays, xenograft\",\n      \"pmids\": [\"35253893\", \"35313791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same SUMO-binding module is partitioned between repair and transcription unclear\", \"UBE2B/RAD18 monoubiquitination site not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved ZMYM2 into distinct repressive complexes and defined its epigenetic mechanism, showing ADNP- and SUMO-dependent TRIM28/KAP1 complexes that silence SINEs and LTRs within TADs and that ZMYM2 enables DNA methylation by limiting H3K4 methylation at germline and LINE-1 targets.\",\n      \"evidence\": \"Co-IP, ChIP-seq, Hi-C/TAD analysis, bisulfite methylation and RNA-seq in mouse and human ESC knockouts\",\n      \"pmids\": [\"37934570\", \"37395395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting LSD1-CoREST vs ADNP vs TRIM28 complexes per locus unresolved\", \"Order of events linking ZMYM2 binding to de novo methylation not fully ordered\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single SUMO-binding scaffold is dynamically allocated among transcriptional repression, DNA-damage repair, PML body organization, and its developmental and renal functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of how multivalent SUMO binding selects among partner complexes\", \"Causal chain from ZMYM2 loss to CAKUT not mapped to specific targets\", \"Interplay between PLK1-driven degradation and RAD18-driven stabilization not quantitatively integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 16, 19, 25]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 16, 22, 25]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [11, 22, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 17, 24, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 16, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 18, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 18]}\n    ],\n    \"complexes\": [\n      \"LSD1-CoREST-HDAC1 (BHC) complex\",\n      \"ZMYM2-ADNP complex\",\n      \"ZMYM2-TRIM28/KAP1 complex\",\n      \"PML nuclear bodies\"\n    ],\n    \"partners\": [\n      \"LSD1\",\n      \"HDAC1\",\n      \"CoREST\",\n      \"TRIM28\",\n      \"ADNP\",\n      \"PML\",\n      \"PIAS4\",\n      \"RAD18\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}