{"gene":"LIN54","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"LIN54 is a core subunit of the mammalian DREAM complex (containing p130, E2F4, DP, and MuvB proteins LIN9, LIN37, LIN52, LIN54, RBBP4), which binds to more than 800 human promoters in G0 and is required for repression of E2F target genes in quiescence. In S phase, MuvB proteins (including LIN54) dissociate from p130 and form a submodule that binds MYB.","method":"Proteomics (mass spectrometry), genomics (ChIP-chip), co-immunoprecipitation, bioinformatic analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP, proteomic identification, replicated in multiple organisms","pmids":["17531812"],"is_preprint":false},{"year":2006,"finding":"C. elegans LIN-54 protein is a component of the synMuvB complex containing LIN-35/Rb, and LIN-54 is required for the stable formation of this complex, as shown by biochemical analysis of mutants.","method":"Genetic analysis, biochemical co-immunoprecipitation of complex components in C. elegans mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex analysis with mutants, foundational characterization replicated in other organisms","pmids":["17075059"],"is_preprint":false},{"year":2009,"finding":"LIN54 contains a CXC (cysteine-rich) domain that functions as a novel sequence-specific DNA-binding domain binding to the cdc2 promoter at two sites, one overlapping the cell cycle homology region (CHR) at the transcription start site. A helix-coil-helix motif mediates interaction with p130 and B-MYB. LIN54 is required for cell cycle progression.","method":"Gel shift assay (EMSA), protein interaction studies (co-IP/pulldown with deletion mutants), cell cycle analysis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro DNA binding assays with domain mapping, protein interaction studies, functional cell cycle readout in single lab with multiple orthogonal methods","pmids":["19725879"],"is_preprint":false},{"year":2011,"finding":"DYRK1A phosphorylates LIN52 on serine 28, which is required for DREAM complex assembly. LIN54 is a stable core subunit of the MuvB complex. Inhibiting DYRK1A or mutating LIN52-S28 disrupts DREAM assembly and reduces cell entry into quiescence or Ras-induced senescence.","method":"Mass spectrometry (phosphorylation site identification), kinase assay, point mutation, DREAM complex co-IP, cell cycle/senescence assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — kinase assay with mutagenesis, complex assembly by Co-IP, functional quiescence/senescence readout, multiple orthogonal methods","pmids":["21498570"],"is_preprint":false},{"year":2011,"finding":"In C. elegans, LIN-54 DNA-binding activity recruits the DRM complex to promoters enriched for adjacent E2F/DP and LIN-54 binding sites. LIN-54 promotes expression of reproduction genes in germline but prevents ectopic activation of germline-specific genes in embryonic soma.","method":"Genome-wide ChIP, gene expression profiling, genetic analysis of lin-54 mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus gene expression profiling in mutants, replicated across organisms","pmids":["21589891"],"is_preprint":false},{"year":2016,"finding":"The LIN54 DNA-binding domain comprises two tandem cysteine-rich regions (CXC domains) both required for high-affinity DNA binding. The CHR consensus sequence is TTYRAA. A crystal structure revealed that sequence specificity is conferred by two tyrosine residues that insert into the minor groove of the DNA duplex. Tyrosine-mediated DNA binding is necessary for MuvB recruitment to target promoters.","method":"Biochemical DNA binding assays, X-ray crystallography of LIN54 DBD in complex with CHR DNA, mutagenesis, ChIP","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis and ChIP validation, multiple orthogonal methods in one study","pmids":["27465258"],"is_preprint":false},{"year":2012,"finding":"Wild-type LIN54 localizes predominantly to the nucleus via two nuclear localization signals. The CXC domain is required for nuclear retention; point mutations abolishing DNA binding (C525Y, C611Y) increase cytoplasmic localization. CRM1-mediated nuclear export of LIN54 occurs when DNA binding is disrupted. Cytoplasmic LIN54 mutants inhibit cell cycle progression and decrease expression of G2/M genes.","method":"Subcellular fractionation, fluorescence microscopy, leptomycin B treatment (CRM1 inhibition), cell cycle analysis, NLS deletion mutants","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiments with multiple mutants and pharmacological inhibitor, single lab with orthogonal approaches","pmids":["22895175"],"is_preprint":false},{"year":2018,"finding":"Overexpression of B-Myb disrupts the DREAM complex in human cells in a manner dependent on its intact MuvB-binding domain. B-Myb overexpression regulates protein expression levels of LIN52 (a key adapter for both DREAM and MMB assembly) via a mechanism requiring LIN52 S28 phosphorylation.","method":"Co-immunoprecipitation, overexpression and knockdown experiments, immunoblotting, domain deletion mutants","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP of complex components with domain mutants, functional cell cycle readout, single lab","pmids":["30206359"],"is_preprint":false},{"year":2011,"finding":"In HPV16-transformed cervical cancer cells, p130-DREAM complex is greatly diminished. Depletion of E7 restores p130-DREAM and arrests the cell cycle. The cell cycle arrest upon E7 depletion depends on p130-DREAM reformation, as co-depletion of LIN-54 and p130 partially rescued the arrest, demonstrating LIN54 is required for repressive DREAM function in these cells.","method":"shRNA knockdown, co-immunoprecipitation, flow cytometry cell cycle analysis","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis by double knockdown with cell cycle readout, single lab","pmids":["21813705"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, the dREAM complex component Mip120 (LIN54 homolog) is required for chromosomal recruitment of L(3)mbt chromatin reader. Mip120 is specifically required for L(3)mbt recruitment to chromosomes, while Mip130 and E2f2 are not required for recruitment but are essential for repression. Loss of l(3)mbt or MMB components causes similar spurious gene expression including piwi in differentiated cells.","method":"Genetic epistasis, immunofluorescence/cytological analysis of polytene chromosomes, mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with cytological localization, single lab, Drosophila model","pmids":["25249635"],"is_preprint":false},{"year":2021,"finding":"LIN54 and FOXM1 are components of the MMB-FOXM1 complex required for CHK1 inhibitor-induced premature mitosis. Knockout of LIN54 reduces CHK1 inhibitor-induced DNA replication stress markers and premature mitosis during Late S phase, demonstrating LIN54 is required for the feedback loop between MMB-FOXM1 and CDK1 that drives replication catastrophe.","method":"Genome-wide CRISPR-Cas9 screens, gene knockout, immunoblotting for replication stress markers, cell cycle analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined molecular phenotype (replication stress markers) and cell cycle readout, single lab","pmids":["33657372"],"is_preprint":false},{"year":2022,"finding":"MuvB complex architecture determined: LIN9 and LIN37 are scaffolding proteins that arrange LIN52, LIN54, and RBAP48 for transcription factor, DNA, and histone binding, respectively. MuvB binds nucleosomes through an interface distinct from LIN54-CHR DNA recognition. MuvB increases nucleosome occupancy in a reconstituted promoter system and associates with the +1 nucleosome downstream of the TSS to repress gene expression.","method":"Cryo-EM/crystal structure of MuvB subcomplex, biochemical reconstitution, nucleosome binding assays, ChIP in arrested cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro reconstitution, nucleosome binding assays, and ChIP validation with multiple orthogonal methods","pmids":["35082292"],"is_preprint":false},{"year":2022,"finding":"In mouse embryonic stem cells, CRISPR-mediated deletion of Lin54 (but not Lin9 or Lin37) causes G2/M arrest, loss of pluripotency, and spontaneous differentiation. The cell cycle arrest was partially rescued by ectopic co-expression of Cyclin B1 and Cdk1, placing LIN54 upstream of G2/M gene regulation.","method":"CRISPR/Cas9 knockout, cell cycle analysis (flow cytometry), pluripotency marker assays, rescue by cyclin B1/Cdk1 overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype and partial rescue establishing pathway position, single lab","pmids":["35148988"],"is_preprint":false},{"year":2021,"finding":"Simultaneous expression of MMB-FOXM1 complex components efficiently bypasses cellular senescence; LIN52 (non-phosphorylated form that disrupts DREAM), B-MYB, and FOXM1 are the crucial components. Non-phosphorylated LIN52 disrupts DREAM complex (which contains LIN54), establishing a central role for DREAM assembly (involving LIN54) in maintaining senescence.","method":"Senescence bypass assay in conditionally immortalized fibroblasts, co-immunoprecipitation, overexpression of complex components","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional senescence bypass assay with multiple complex components, single lab","pmids":["34728711"],"is_preprint":false},{"year":2024,"finding":"IDH1 (isocitrate dehydrogenase 1) binds to FOXM1 and to MuvB subunits LIN-9 and LIN-54 in mitotic cells, and IDH1 depletion reduces canonical FOXM1-target gene expression in mitotic cells, suggesting IDH1 coordinates with the MMB-FOXM1 complex.","method":"Co-immunoprecipitation, siRNA knockdown, RT-qPCR","journal":"Histochemistry and cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up","pmids":["39039166"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, Mip120 (LIN54 homolog) is a core subunit of the MMB/dREAM complex. mip120 mutant females are sterile, and mutant males are also sterile. Myb accumulation and binding to polytene chromosomes depends on core MMB factors including Mip120.","method":"Genetic mutant analysis, immunofluorescence on polytene chromosomes, complex purification","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic analysis with cytological localization, complex purification, Drosophila model","pmids":["17403774"],"is_preprint":false},{"year":2009,"finding":"Mammalian Mip120/LIN-54 forms a core complex (MCC/LINC) with Mip130/LIN-9, Mip40/LIN-37, and Sin3b that is detectable in all cell cycle phases and recruits transcriptional repressors (p107, p130, E2F4, HDAC1) in G0/G1, and B-Myb in S-phase.","method":"Co-immunoprecipitation, cell cycle fractionation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP across cell cycle phases, single lab, corroborated by other studies","pmids":["19619530"],"is_preprint":false},{"year":2017,"finding":"Drosophila Mip120 (LIN54 homolog) regulates two aspects of oogenesis: (1) it is required for normal polytene chromosome decondensation and dispersion in ovarian nurse cells; (2) its absence causes dramatic increase in benign gonial cell neoplasm (bgcn) gene expression. The conserved C-terminal DNA-binding and protein-protein interaction domains are necessary but not sufficient for the chromosome dynamics function.","method":"Genetic analysis of mip120 mutants, immunofluorescence, gene expression analysis, domain deletion analysis","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic mutant with defined developmental phenotypes and domain analysis, Drosophila model","pmids":["28522430"],"is_preprint":false}],"current_model":"LIN54 is a core subunit of the MuvB complex that functions as a sequence-specific DNA-binding protein, directing the complex to cell cycle genes homology region (CHR) elements (consensus TTYRAA) via two tandem CXC domains whose specificity is conferred by tyrosine residues inserting into the DNA minor groove; within the MuvB scaffold (where LIN9/LIN37 are scaffolding proteins), LIN54 is positioned for DNA binding while LIN52 mediates transcription factor docking and RBAP48 mediates histone interaction, and the intact complex either represses cell cycle genes in quiescence as part of the DREAM complex (p130/E2F4/MuvB) or activates mitotic genes as part of MMB (B-MYB/MuvB) and MMB-FOXM1, with the switch between states regulated by DYRK1A phosphorylation of LIN52-S28 for DREAM assembly, and MuvB stabilizes the +1 nucleosome downstream of the TSS to mediate repression."},"narrative":{"mechanistic_narrative":"LIN54 is the sequence-specific DNA-binding subunit of the MuvB core complex, which directs cell-cycle-dependent transcriptional programs by recruiting MuvB to cell cycle genes homology region (CHR) elements [PMID:17531812, PMID:19725879, PMID:27465258]. LIN54 recognizes the CHR consensus TTYRAA through two tandem cysteine-rich CXC domains, with specificity conferred by two tyrosine residues that insert into the DNA minor groove; this tyrosine-mediated DNA binding is necessary for MuvB recruitment to target promoters [PMID:27465258]. Within the MuvB scaffold, LIN9 and LIN37 arrange LIN52, LIN54, and RBAP48 for transcription-factor, DNA, and histone binding respectively, and MuvB stabilizes the +1 nucleosome downstream of the TSS to repress transcription through an interface distinct from LIN54 CHR recognition [PMID:35082292]. The complex toggles between repressive and activating states: in quiescence LIN54-containing MuvB joins p130/E2F4 to form the repressive DREAM complex—assembly of which depends on DYRK1A phosphorylation of LIN52 at Ser28—while in S phase MuvB dissociates and binds B-MYB to form the activating MMB and MMB-FOXM1 complexes that drive mitotic gene expression [PMID:17531812, PMID:21498570, PMID:33657372]. Through this switch LIN54 is required for cell cycle progression, entry into quiescence and senescence, and proper G2/M gene expression: loss of LIN54 causes G2/M arrest rescuable by Cyclin B1/CDK1, and disruption of its DNA binding drives CRM1-mediated nuclear export and loss of mitotic gene expression [PMID:19725879, PMID:22895175, PMID:35148988]. The role is deeply conserved, with the C. elegans (LIN-54) and Drosophila (Mip120) orthologs serving equivalent DNA-targeting and complex-stabilizing functions in development and germline gene control [PMID:17075059, PMID:21589891, PMID:17403774].","teleology":[{"year":2006,"claim":"Established that LIN-54 is a structural requirement for assembly of an Rb-containing repressive complex, framing it as a core architectural subunit rather than a peripheral factor.","evidence":"Genetics and biochemical Co-IP of synMuvB/LIN-35-Rb complex in C. elegans mutants","pmids":["17075059"],"confidence":"High","gaps":["Did not define a biochemical activity for LIN-54 within the complex","Mammalian relevance not yet demonstrated"]},{"year":2007,"claim":"Defined LIN54 as a conserved core subunit of the mammalian DREAM complex that represses E2F targets in G0 and re-partitions to a MYB-bound submodule in S phase, establishing the cell-cycle-dependent switch.","evidence":"Mass spectrometry, ChIP-chip across >800 promoters, and reciprocal Co-IP in human cells","pmids":["17531812"],"confidence":"High","gaps":["Did not identify which subunit confers DNA sequence specificity","Molecular basis of the G0-to-S switch unresolved"]},{"year":2009,"claim":"Identified the LIN54 CXC domain as a novel sequence-specific DNA-binding module targeting CHR elements and mapped a helix-coil-helix motif for p130/B-MYB interaction, assigning LIN54 the DNA-recognition role in the complex.","evidence":"EMSA on the cdc2 promoter, Co-IP/pulldown with deletion mutants, cell cycle analysis","pmids":["19725879"],"confidence":"High","gaps":["Structural basis of CHR specificity not determined","Single-CXC vs tandem-domain contribution unclear"]},{"year":2011,"claim":"Resolved the assembly trigger for the repressive state by showing DYRK1A phosphorylation of LIN52-S28 is required for DREAM formation, linking a kinase signal to LIN54-containing complex repression and senescence.","evidence":"Phospho-site mapping by MS, kinase assay, point mutation, DREAM Co-IP, senescence/quiescence assays","pmids":["21498570"],"confidence":"High","gaps":["How phosphorylation reorganizes the complex structurally not shown","Did not address activating MMB assembly mechanism"]},{"year":2011,"claim":"Demonstrated in vivo that LIN-54 DNA-binding activity recruits the complex to E2F/DP-adjacent sites genome-wide and controls developmental and germline gene programs, validating recruitment function in an organismal context.","evidence":"Genome-wide ChIP, expression profiling, and genetics of lin-54 mutants in C. elegans","pmids":["21589891"],"confidence":"High","gaps":["Mammalian genome-wide recruitment dependence on LIN54 binding not directly tested here"]},{"year":2011,"claim":"Provided functional epistasis showing LIN54 is required for repressive DREAM function in a disease (HPV) context, where E7 disrupts and its loss restores p130-DREAM-mediated arrest.","evidence":"shRNA double knockdown of LIN-54 and p130, Co-IP, flow cytometry in cervical cancer cells","pmids":["21813705"],"confidence":"Medium","gaps":["Partial rescue only; other arrest pathways may contribute","Single cell-line context"]},{"year":2012,"claim":"Connected LIN54 DNA-binding to its subcellular fate, showing CXC-dependent nuclear retention and CRM1-mediated export when binding is disrupted, coupling DNA engagement to function in G2/M gene expression.","evidence":"Fractionation, microscopy, leptomycin B treatment, NLS/DNA-binding mutants, cell cycle analysis","pmids":["22895175"],"confidence":"Medium","gaps":["Physiological signal that triggers export not identified","Single lab"]},{"year":2016,"claim":"Provided atomic-level mechanism for CHR recognition: tandem CXC domains and two minor-groove-inserting tyrosines define the TTYRAA-specific binding required for MuvB recruitment.","evidence":"X-ray crystallography of LIN54 DBD-CHR DNA, DNA-binding assays, mutagenesis, ChIP","pmids":["27465258"],"confidence":"High","gaps":["Structure of full MuvB on DNA not resolved here","Does not explain repression-vs-activation output"]},{"year":2018,"claim":"Showed B-MYB overexpression disrupts DREAM via its MuvB-binding domain and modulates LIN52 levels, linking activator abundance to dynamic competition over the LIN54-containing core.","evidence":"Co-IP, overexpression/knockdown, domain-deletion mutants, immunoblotting","pmids":["30206359"],"confidence":"Medium","gaps":["Direct effect on LIN54 conformation/binding not measured","Single lab"]},{"year":2021,"claim":"Placed LIN54 in the activating MMB-FOXM1 arm driving CHK1-inhibitor-induced premature mitosis and replication catastrophe, expanding its role beyond repression to an MMB-FOXM1/CDK1 feedback loop.","evidence":"Genome-wide CRISPR screens, LIN54 knockout, replication-stress immunoblots, cell cycle analysis","pmids":["33657372"],"confidence":"Medium","gaps":["Direct LIN54-FOXM1 contacts not mapped","Single lab"]},{"year":2021,"claim":"Demonstrated that DREAM disassembly (via non-phosphorylated LIN52) together with MMB-FOXM1 components bypasses senescence, establishing the LIN54-containing DREAM as a senescence-maintaining hub.","evidence":"Senescence bypass assay in immortalized fibroblasts, Co-IP, complex-component overexpression","pmids":["34728711"],"confidence":"Medium","gaps":["Specific LIN54 contribution not isolated from other subunits","Single lab"]},{"year":2022,"claim":"Resolved MuvB architecture and a repression mechanism: LIN9/LIN37 scaffold LIN54, LIN52, and RBAP48 for DNA, TF, and histone binding, and MuvB stabilizes the +1 nucleosome to repress transcription.","evidence":"Cryo-EM/crystal structure, in vitro reconstitution, nucleosome-binding assays, ChIP in arrested cells","pmids":["35082292"],"confidence":"High","gaps":["Structure of the full DREAM/MMB on chromatin not solved","Switch to activation not structurally explained"]},{"year":2022,"claim":"Established a non-redundant requirement for LIN54 specifically (not LIN9 or LIN37) in G2/M progression and pluripotency, with rescue by Cyclin B1/CDK1 placing LIN54 upstream of mitotic gene regulation.","evidence":"CRISPR knockout in mouse ES cells, flow cytometry, pluripotency markers, cyclin B1/Cdk1 rescue","pmids":["35148988"],"confidence":"Medium","gaps":["Why LIN54 loss differs from LIN9/LIN37 loss mechanistically unclear","Single lab/model"]},{"year":2024,"claim":"Reported IDH1 association with FOXM1 and MuvB subunits LIN-9/LIN-54 in mitosis, hinting at metabolic coordination of MMB-FOXM1 target expression.","evidence":"Single Co-IP, siRNA knockdown, RT-qPCR","pmids":["39039166"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation; direct LIN54-IDH1 contact unproven","Functional significance for LIN54 not established","Single lab"]},{"year":null,"claim":"How CHR-bound LIN54 mechanistically dictates the switch between MuvB-mediated repression (DREAM) and activation (MMB/MMB-FOXM1) at the same promoters remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full DREAM or MMB engaged on CHR chromatin","Signals controlling LIN54-dependent nucleosome repositioning vs activation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,4,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,10,12]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11]}],"complexes":["MuvB core complex","DREAM complex","MMB (B-MYB-MuvB)","MMB-FOXM1"],"partners":["LIN9","LIN37","LIN52","RBBP4","E2F4","MYBL2","FOXM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6MZP7","full_name":"Protein lin-54 homolog","aliases":["CXC domain-containing protein 1"],"length_aa":749,"mass_kda":79.5,"function":"Component of the DREAM complex, a multiprotein complex that can both act as a transcription activator or repressor depending on the context (PubMed:17531812, PubMed:17671431). In G0 phase, the complex binds to more than 800 promoters and is required for repression of E2F target genes (PubMed:17531812, PubMed:17671431). In S phase, the complex selectively binds to the promoters of G2/M genes whose products are required for mitosis and participates in their cell cycle dependent activation (PubMed:17531812, PubMed:17671431). In the complex, acts as a DNA-binding protein that binds the promoter of CDK1 in a sequence-specific manner (PubMed:19725879). Specifically recognizes the consensus motif 5'-TTYRAA-3' in target DNA (PubMed:27465258)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6MZP7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIN54","classification":"Not Classified","n_dependent_lines":358,"n_total_lines":1208,"dependency_fraction":0.29635761589403975},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LIN54","total_profiled":1310},"omim":[{"mim_id":"621288","title":"LIN52 DREAM MUVB CORE COMPLEX COMPONENT; LIN52","url":"https://www.omim.org/entry/621288"},{"mim_id":"621287","title":"LIN37 DREAM MUVB CORE COMPLEX COMPONENT; LIN37","url":"https://www.omim.org/entry/621287"},{"mim_id":"613367","title":"LIN54, C. ELEGANS, HOMOLOG OF; LIN54","url":"https://www.omim.org/entry/613367"},{"mim_id":"609375","title":"LIN9 DREAM MUVB CORE COMPLEX COMPONENT; LIN9","url":"https://www.omim.org/entry/609375"},{"mim_id":"602923","title":"RETINOBLASTOMA-BINDING PROTEIN 4; RBBP4","url":"https://www.omim.org/entry/602923"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIN54"},"hgnc":{"alias_symbol":["MIP120","DKFZp686L1814","JC8.6","CXCDC1","TCX1"],"prev_symbol":[]},"alphafold":{"accession":"Q6MZP7","domains":[{"cath_id":"-","chopping":"523-580","consensus_level":"medium","plddt":96.6436,"start":523,"end":580},{"cath_id":"-","chopping":"592-633","consensus_level":"medium","plddt":94.5926,"start":592,"end":633},{"cath_id":"-","chopping":"690-736","consensus_level":"medium","plddt":92.7306,"start":690,"end":736},{"cath_id":"1.20.5","chopping":"636-671","consensus_level":"medium","plddt":84.7356,"start":636,"end":671}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6MZP7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6MZP7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6MZP7-F1-predicted_aligned_error_v6.png","plddt_mean":53.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIN54","jax_strain_url":"https://www.jax.org/strain/search?query=LIN54"},"sequence":{"accession":"Q6MZP7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6MZP7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6MZP7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6MZP7"}},"corpus_meta":[{"pmid":"17531812","id":"PMC_17531812","title":"Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17531812","citation_count":341,"is_preprint":false},{"pmid":"21498570","id":"PMC_21498570","title":"DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly.","date":"2011","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21498570","citation_count":249,"is_preprint":false},{"pmid":"17075059","id":"PMC_17075059","title":"Some C. elegans class B synthetic multivulva proteins encode a conserved LIN-35 Rb-containing complex distinct from a NuRD-like complex.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17075059","citation_count":121,"is_preprint":false},{"pmid":"19725879","id":"PMC_19725879","title":"LIN54 is an essential core subunit of the DREAM/LINC complex that binds to the cdc2 promoter in a sequence-specific manner.","date":"2009","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/19725879","citation_count":85,"is_preprint":false},{"pmid":"17403774","id":"PMC_17403774","title":"Discovery of tMAC: a Drosophila testis-specific meiotic arrest complex paralogous to Myb-Muv B.","date":"2007","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/17403774","citation_count":80,"is_preprint":false},{"pmid":"27465258","id":"PMC_27465258","title":"Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27465258","citation_count":54,"is_preprint":false},{"pmid":"30206359","id":"PMC_30206359","title":"The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic 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In S phase, MuvB proteins (including LIN54) dissociate from p130 and form a submodule that binds MYB.\",\n      \"method\": \"Proteomics (mass spectrometry), genomics (ChIP-chip), co-immunoprecipitation, bioinformatic analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genome-wide ChIP, proteomic identification, replicated in multiple organisms\",\n      \"pmids\": [\"17531812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans LIN-54 protein is a component of the synMuvB complex containing LIN-35/Rb, and LIN-54 is required for the stable formation of this complex, as shown by biochemical analysis of mutants.\",\n      \"method\": \"Genetic analysis, biochemical co-immunoprecipitation of complex components in C. elegans mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex analysis with mutants, foundational characterization replicated in other organisms\",\n      \"pmids\": [\"17075059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LIN54 contains a CXC (cysteine-rich) domain that functions as a novel sequence-specific DNA-binding domain binding to the cdc2 promoter at two sites, one overlapping the cell cycle homology region (CHR) at the transcription start site. A helix-coil-helix motif mediates interaction with p130 and B-MYB. LIN54 is required for cell cycle progression.\",\n      \"method\": \"Gel shift assay (EMSA), protein interaction studies (co-IP/pulldown with deletion mutants), cell cycle analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro DNA binding assays with domain mapping, protein interaction studies, functional cell cycle readout in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19725879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DYRK1A phosphorylates LIN52 on serine 28, which is required for DREAM complex assembly. LIN54 is a stable core subunit of the MuvB complex. Inhibiting DYRK1A or mutating LIN52-S28 disrupts DREAM assembly and reduces cell entry into quiescence or Ras-induced senescence.\",\n      \"method\": \"Mass spectrometry (phosphorylation site identification), kinase assay, point mutation, DREAM complex co-IP, cell cycle/senescence assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — kinase assay with mutagenesis, complex assembly by Co-IP, functional quiescence/senescence readout, multiple orthogonal methods\",\n      \"pmids\": [\"21498570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In C. elegans, LIN-54 DNA-binding activity recruits the DRM complex to promoters enriched for adjacent E2F/DP and LIN-54 binding sites. LIN-54 promotes expression of reproduction genes in germline but prevents ectopic activation of germline-specific genes in embryonic soma.\",\n      \"method\": \"Genome-wide ChIP, gene expression profiling, genetic analysis of lin-54 mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus gene expression profiling in mutants, replicated across organisms\",\n      \"pmids\": [\"21589891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The LIN54 DNA-binding domain comprises two tandem cysteine-rich regions (CXC domains) both required for high-affinity DNA binding. The CHR consensus sequence is TTYRAA. A crystal structure revealed that sequence specificity is conferred by two tyrosine residues that insert into the minor groove of the DNA duplex. Tyrosine-mediated DNA binding is necessary for MuvB recruitment to target promoters.\",\n      \"method\": \"Biochemical DNA binding assays, X-ray crystallography of LIN54 DBD in complex with CHR DNA, mutagenesis, ChIP\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis and ChIP validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27465258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wild-type LIN54 localizes predominantly to the nucleus via two nuclear localization signals. The CXC domain is required for nuclear retention; point mutations abolishing DNA binding (C525Y, C611Y) increase cytoplasmic localization. CRM1-mediated nuclear export of LIN54 occurs when DNA binding is disrupted. Cytoplasmic LIN54 mutants inhibit cell cycle progression and decrease expression of G2/M genes.\",\n      \"method\": \"Subcellular fractionation, fluorescence microscopy, leptomycin B treatment (CRM1 inhibition), cell cycle analysis, NLS deletion mutants\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiments with multiple mutants and pharmacological inhibitor, single lab with orthogonal approaches\",\n      \"pmids\": [\"22895175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of B-Myb disrupts the DREAM complex in human cells in a manner dependent on its intact MuvB-binding domain. B-Myb overexpression regulates protein expression levels of LIN52 (a key adapter for both DREAM and MMB assembly) via a mechanism requiring LIN52 S28 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown experiments, immunoblotting, domain deletion mutants\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP of complex components with domain mutants, functional cell cycle readout, single lab\",\n      \"pmids\": [\"30206359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In HPV16-transformed cervical cancer cells, p130-DREAM complex is greatly diminished. Depletion of E7 restores p130-DREAM and arrests the cell cycle. The cell cycle arrest upon E7 depletion depends on p130-DREAM reformation, as co-depletion of LIN-54 and p130 partially rescued the arrest, demonstrating LIN54 is required for repressive DREAM function in these cells.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, flow cytometry cell cycle analysis\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis by double knockdown with cell cycle readout, single lab\",\n      \"pmids\": [\"21813705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, the dREAM complex component Mip120 (LIN54 homolog) is required for chromosomal recruitment of L(3)mbt chromatin reader. Mip120 is specifically required for L(3)mbt recruitment to chromosomes, while Mip130 and E2f2 are not required for recruitment but are essential for repression. Loss of l(3)mbt or MMB components causes similar spurious gene expression including piwi in differentiated cells.\",\n      \"method\": \"Genetic epistasis, immunofluorescence/cytological analysis of polytene chromosomes, mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with cytological localization, single lab, Drosophila model\",\n      \"pmids\": [\"25249635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LIN54 and FOXM1 are components of the MMB-FOXM1 complex required for CHK1 inhibitor-induced premature mitosis. Knockout of LIN54 reduces CHK1 inhibitor-induced DNA replication stress markers and premature mitosis during Late S phase, demonstrating LIN54 is required for the feedback loop between MMB-FOXM1 and CDK1 that drives replication catastrophe.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screens, gene knockout, immunoblotting for replication stress markers, cell cycle analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined molecular phenotype (replication stress markers) and cell cycle readout, single lab\",\n      \"pmids\": [\"33657372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MuvB complex architecture determined: LIN9 and LIN37 are scaffolding proteins that arrange LIN52, LIN54, and RBAP48 for transcription factor, DNA, and histone binding, respectively. MuvB binds nucleosomes through an interface distinct from LIN54-CHR DNA recognition. MuvB increases nucleosome occupancy in a reconstituted promoter system and associates with the +1 nucleosome downstream of the TSS to repress gene expression.\",\n      \"method\": \"Cryo-EM/crystal structure of MuvB subcomplex, biochemical reconstitution, nucleosome binding assays, ChIP in arrested cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro reconstitution, nucleosome binding assays, and ChIP validation with multiple orthogonal methods\",\n      \"pmids\": [\"35082292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse embryonic stem cells, CRISPR-mediated deletion of Lin54 (but not Lin9 or Lin37) causes G2/M arrest, loss of pluripotency, and spontaneous differentiation. The cell cycle arrest was partially rescued by ectopic co-expression of Cyclin B1 and Cdk1, placing LIN54 upstream of G2/M gene regulation.\",\n      \"method\": \"CRISPR/Cas9 knockout, cell cycle analysis (flow cytometry), pluripotency marker assays, rescue by cyclin B1/Cdk1 overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype and partial rescue establishing pathway position, single lab\",\n      \"pmids\": [\"35148988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Simultaneous expression of MMB-FOXM1 complex components efficiently bypasses cellular senescence; LIN52 (non-phosphorylated form that disrupts DREAM), B-MYB, and FOXM1 are the crucial components. Non-phosphorylated LIN52 disrupts DREAM complex (which contains LIN54), establishing a central role for DREAM assembly (involving LIN54) in maintaining senescence.\",\n      \"method\": \"Senescence bypass assay in conditionally immortalized fibroblasts, co-immunoprecipitation, overexpression of complex components\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional senescence bypass assay with multiple complex components, single lab\",\n      \"pmids\": [\"34728711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IDH1 (isocitrate dehydrogenase 1) binds to FOXM1 and to MuvB subunits LIN-9 and LIN-54 in mitotic cells, and IDH1 depletion reduces canonical FOXM1-target gene expression in mitotic cells, suggesting IDH1 coordinates with the MMB-FOXM1 complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, RT-qPCR\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"39039166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, Mip120 (LIN54 homolog) is a core subunit of the MMB/dREAM complex. mip120 mutant females are sterile, and mutant males are also sterile. Myb accumulation and binding to polytene chromosomes depends on core MMB factors including Mip120.\",\n      \"method\": \"Genetic mutant analysis, immunofluorescence on polytene chromosomes, complex purification\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic analysis with cytological localization, complex purification, Drosophila model\",\n      \"pmids\": [\"17403774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian Mip120/LIN-54 forms a core complex (MCC/LINC) with Mip130/LIN-9, Mip40/LIN-37, and Sin3b that is detectable in all cell cycle phases and recruits transcriptional repressors (p107, p130, E2F4, HDAC1) in G0/G1, and B-Myb in S-phase.\",\n      \"method\": \"Co-immunoprecipitation, cell cycle fractionation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP across cell cycle phases, single lab, corroborated by other studies\",\n      \"pmids\": [\"19619530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila Mip120 (LIN54 homolog) regulates two aspects of oogenesis: (1) it is required for normal polytene chromosome decondensation and dispersion in ovarian nurse cells; (2) its absence causes dramatic increase in benign gonial cell neoplasm (bgcn) gene expression. The conserved C-terminal DNA-binding and protein-protein interaction domains are necessary but not sufficient for the chromosome dynamics function.\",\n      \"method\": \"Genetic analysis of mip120 mutants, immunofluorescence, gene expression analysis, domain deletion analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic mutant with defined developmental phenotypes and domain analysis, Drosophila model\",\n      \"pmids\": [\"28522430\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIN54 is a core subunit of the MuvB complex that functions as a sequence-specific DNA-binding protein, directing the complex to cell cycle genes homology region (CHR) elements (consensus TTYRAA) via two tandem CXC domains whose specificity is conferred by tyrosine residues inserting into the DNA minor groove; within the MuvB scaffold (where LIN9/LIN37 are scaffolding proteins), LIN54 is positioned for DNA binding while LIN52 mediates transcription factor docking and RBAP48 mediates histone interaction, and the intact complex either represses cell cycle genes in quiescence as part of the DREAM complex (p130/E2F4/MuvB) or activates mitotic genes as part of MMB (B-MYB/MuvB) and MMB-FOXM1, with the switch between states regulated by DYRK1A phosphorylation of LIN52-S28 for DREAM assembly, and MuvB stabilizes the +1 nucleosome downstream of the TSS to mediate repression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIN54 is the sequence-specific DNA-binding subunit of the MuvB core complex, which directs cell-cycle-dependent transcriptional programs by recruiting MuvB to cell cycle genes homology region (CHR) elements [#0, #2, #5]. LIN54 recognizes the CHR consensus TTYRAA through two tandem cysteine-rich CXC domains, with specificity conferred by two tyrosine residues that insert into the DNA minor groove; this tyrosine-mediated DNA binding is necessary for MuvB recruitment to target promoters [#5]. Within the MuvB scaffold, LIN9 and LIN37 arrange LIN52, LIN54, and RBAP48 for transcription-factor, DNA, and histone binding respectively, and MuvB stabilizes the +1 nucleosome downstream of the TSS to repress transcription through an interface distinct from LIN54 CHR recognition [#11]. The complex toggles between repressive and activating states: in quiescence LIN54-containing MuvB joins p130/E2F4 to form the repressive DREAM complex—assembly of which depends on DYRK1A phosphorylation of LIN52 at Ser28—while in S phase MuvB dissociates and binds B-MYB to form the activating MMB and MMB-FOXM1 complexes that drive mitotic gene expression [#0, #3, #10]. Through this switch LIN54 is required for cell cycle progression, entry into quiescence and senescence, and proper G2/M gene expression: loss of LIN54 causes G2/M arrest rescuable by Cyclin B1/CDK1, and disruption of its DNA binding drives CRM1-mediated nuclear export and loss of mitotic gene expression [#2, #6, #12]. The role is deeply conserved, with the C. elegans (LIN-54) and Drosophila (Mip120) orthologs serving equivalent DNA-targeting and complex-stabilizing functions in development and germline gene control [#1, #4, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that LIN-54 is a structural requirement for assembly of an Rb-containing repressive complex, framing it as a core architectural subunit rather than a peripheral factor.\",\n      \"evidence\": \"Genetics and biochemical Co-IP of synMuvB/LIN-35-Rb complex in C. elegans mutants\",\n      \"pmids\": [\"17075059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define a biochemical activity for LIN-54 within the complex\", \"Mammalian relevance not yet demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined LIN54 as a conserved core subunit of the mammalian DREAM complex that represses E2F targets in G0 and re-partitions to a MYB-bound submodule in S phase, establishing the cell-cycle-dependent switch.\",\n      \"evidence\": \"Mass spectrometry, ChIP-chip across >800 promoters, and reciprocal Co-IP in human cells\",\n      \"pmids\": [\"17531812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which subunit confers DNA sequence specificity\", \"Molecular basis of the G0-to-S switch unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the LIN54 CXC domain as a novel sequence-specific DNA-binding module targeting CHR elements and mapped a helix-coil-helix motif for p130/B-MYB interaction, assigning LIN54 the DNA-recognition role in the complex.\",\n      \"evidence\": \"EMSA on the cdc2 promoter, Co-IP/pulldown with deletion mutants, cell cycle analysis\",\n      \"pmids\": [\"19725879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CHR specificity not determined\", \"Single-CXC vs tandem-domain contribution unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the assembly trigger for the repressive state by showing DYRK1A phosphorylation of LIN52-S28 is required for DREAM formation, linking a kinase signal to LIN54-containing complex repression and senescence.\",\n      \"evidence\": \"Phospho-site mapping by MS, kinase assay, point mutation, DREAM Co-IP, senescence/quiescence assays\",\n      \"pmids\": [\"21498570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation reorganizes the complex structurally not shown\", \"Did not address activating MMB assembly mechanism\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated in vivo that LIN-54 DNA-binding activity recruits the complex to E2F/DP-adjacent sites genome-wide and controls developmental and germline gene programs, validating recruitment function in an organismal context.\",\n      \"evidence\": \"Genome-wide ChIP, expression profiling, and genetics of lin-54 mutants in C. elegans\",\n      \"pmids\": [\"21589891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian genome-wide recruitment dependence on LIN54 binding not directly tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided functional epistasis showing LIN54 is required for repressive DREAM function in a disease (HPV) context, where E7 disrupts and its loss restores p130-DREAM-mediated arrest.\",\n      \"evidence\": \"shRNA double knockdown of LIN-54 and p130, Co-IP, flow cytometry in cervical cancer cells\",\n      \"pmids\": [\"21813705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial rescue only; other arrest pathways may contribute\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected LIN54 DNA-binding to its subcellular fate, showing CXC-dependent nuclear retention and CRM1-mediated export when binding is disrupted, coupling DNA engagement to function in G2/M gene expression.\",\n      \"evidence\": \"Fractionation, microscopy, leptomycin B treatment, NLS/DNA-binding mutants, cell cycle analysis\",\n      \"pmids\": [\"22895175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological signal that triggers export not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided atomic-level mechanism for CHR recognition: tandem CXC domains and two minor-groove-inserting tyrosines define the TTYRAA-specific binding required for MuvB recruitment.\",\n      \"evidence\": \"X-ray crystallography of LIN54 DBD-CHR DNA, DNA-binding assays, mutagenesis, ChIP\",\n      \"pmids\": [\"27465258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full MuvB on DNA not resolved here\", \"Does not explain repression-vs-activation output\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed B-MYB overexpression disrupts DREAM via its MuvB-binding domain and modulates LIN52 levels, linking activator abundance to dynamic competition over the LIN54-containing core.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, domain-deletion mutants, immunoblotting\",\n      \"pmids\": [\"30206359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect on LIN54 conformation/binding not measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed LIN54 in the activating MMB-FOXM1 arm driving CHK1-inhibitor-induced premature mitosis and replication catastrophe, expanding its role beyond repression to an MMB-FOXM1/CDK1 feedback loop.\",\n      \"evidence\": \"Genome-wide CRISPR screens, LIN54 knockout, replication-stress immunoblots, cell cycle analysis\",\n      \"pmids\": [\"33657372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LIN54-FOXM1 contacts not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that DREAM disassembly (via non-phosphorylated LIN52) together with MMB-FOXM1 components bypasses senescence, establishing the LIN54-containing DREAM as a senescence-maintaining hub.\",\n      \"evidence\": \"Senescence bypass assay in immortalized fibroblasts, Co-IP, complex-component overexpression\",\n      \"pmids\": [\"34728711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific LIN54 contribution not isolated from other subunits\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved MuvB architecture and a repression mechanism: LIN9/LIN37 scaffold LIN54, LIN52, and RBAP48 for DNA, TF, and histone binding, and MuvB stabilizes the +1 nucleosome to repress transcription.\",\n      \"evidence\": \"Cryo-EM/crystal structure, in vitro reconstitution, nucleosome-binding assays, ChIP in arrested cells\",\n      \"pmids\": [\"35082292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full DREAM/MMB on chromatin not solved\", \"Switch to activation not structurally explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a non-redundant requirement for LIN54 specifically (not LIN9 or LIN37) in G2/M progression and pluripotency, with rescue by Cyclin B1/CDK1 placing LIN54 upstream of mitotic gene regulation.\",\n      \"evidence\": \"CRISPR knockout in mouse ES cells, flow cytometry, pluripotency markers, cyclin B1/Cdk1 rescue\",\n      \"pmids\": [\"35148988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why LIN54 loss differs from LIN9/LIN37 loss mechanistically unclear\", \"Single lab/model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported IDH1 association with FOXM1 and MuvB subunits LIN-9/LIN-54 in mitosis, hinting at metabolic coordination of MMB-FOXM1 target expression.\",\n      \"evidence\": \"Single Co-IP, siRNA knockdown, RT-qPCR\",\n      \"pmids\": [\"39039166\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation; direct LIN54-IDH1 contact unproven\", \"Functional significance for LIN54 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHR-bound LIN54 mechanistically dictates the switch between MuvB-mediated repression (DREAM) and activation (MMB/MMB-FOXM1) at the same promoters remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full DREAM or MMB engaged on CHR chromatin\", \"Signals controlling LIN54-dependent nucleosome repositioning vs activation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 10, 12]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\"MuvB core complex\", \"DREAM complex\", \"MMB (B-MYB-MuvB)\", \"MMB-FOXM1\"],\n    \"partners\": [\"LIN9\", \"LIN37\", \"LIN52\", \"RBBP4\", \"E2F4\", \"MYBL2\", \"FOXM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}