{"gene":"LIN52","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"LIN52 is a component of the mammalian DREAM (DP, RB-like, E2F, and MuvB) complex, which contains p130, E2F4, DP, and MuvB core proteins (LIN9, LIN37, LIN52, LIN54, RBBP4). DREAM binds to more than 800 human promoters in G0 and is required for repression of E2F target genes. In S phase, MuvB proteins (including LIN52) dissociate from p130 and form a distinct submodule that binds MYB.","method":"Proteomics (affinity purification/mass spectrometry), ChIP-on-chip genomics, siRNA knockdown, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, MS-based proteomics, ChIP-on-chip, functional KD; foundational study replicated by multiple subsequent labs","pmids":["17531812"],"is_preprint":false},{"year":2011,"finding":"DYRK1A specifically phosphorylates LIN52 on serine residue 28, and this phosphorylation is required for DREAM complex assembly. Point mutation of S28 or inhibition of DYRK1A disrupts DREAM assembly and reduces the ability of cells to enter quiescence or undergo Ras-induced senescence.","method":"Mass spectrometric phosphorylation site identification, in vitro kinase assay, point mutagenesis (S28A), DYRK1A inhibitor treatment, co-immunoprecipitation, cell cycle analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with defined substrate site, mutagenesis validation, functional rescue experiments; replicated in multiple subsequent studies","pmids":["21498570"],"is_preprint":false},{"year":2004,"finding":"The Drosophila homolog of LIN-52 co-purifies with Myb complex components, E2F2, DP, RBF1, RBF2, L(3)MBT, and Rpd3 (HDAC) to form the Myb-MuvB complex, which localizes to promoters and co-represses transcription of developmentally regulated genes.","method":"Affinity chromatography fractionation of Drosophila embryo extracts, co-purification, ChIP, transcriptional reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical co-purification, ChIP localization, functional repression assay; foundational Drosophila ortholog study","pmids":["15545624"],"is_preprint":false},{"year":2015,"finding":"LIN52 contains a sequence that binds directly to the pocket domains of p107 and p130 when phosphorylated at S28 (DYRK1A site). A crystal structure of the LIN52-p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phospho-S28 to bind the LxCxE cleft of the pocket domain with high affinity, explaining specificity for p107/p130 over Rb in DREAM. CDK phosphorylation of p130 weakens its LIN52 association, providing a mechanism for DREAM disassembly upon cell cycle entry.","method":"Crystal structure determination, in vitro binding assays, mutagenesis, biochemical reconstitution","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional biochemical validation and mutagenesis in single rigorous study","pmids":["25917549"],"is_preprint":false},{"year":2011,"finding":"LATS2, a Hippo pathway kinase, phosphorylates DYRK1A and enhances DYRK1A's ability to phosphorylate LIN52, thereby promoting DREAM complex assembly and E2F target gene silencing. Reduced LATS2 levels impair DREAM assembly at E2F-regulated promoters.","method":"shRNA screen, kinase assay (LATS2 phosphorylation of DYRK1A), ChIP, co-immunoprecipitation","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay and ChIP in single lab study; indirect link through DYRK1A","pmids":["21498571"],"is_preprint":false},{"year":2018,"finding":"A crystal structure reveals that B-Myb binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9 to form the Myb-MuvB (MMB) complex. LIN52 serves as the direct binding interface between B-Myb and the MuvB core.","method":"Crystal structure determination, biochemical binding assays, domain mapping mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation and mutagenesis of binding interface","pmids":["30224471"],"is_preprint":false},{"year":2018,"finding":"Overexpression of B-Myb disrupts DREAM complex assembly in human cells dependent on the intact MuvB-binding domain of B-Myb. Furthermore, B-Myb regulates LIN52 protein expression levels by a mechanism requiring the S28 phosphorylation site in LIN52.","method":"Co-immunoprecipitation, western blotting, B-Myb overexpression and MuvB-binding domain mutants, LIN52 S28 point mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutants, single lab, two orthogonal approaches","pmids":["30206359"],"is_preprint":false},{"year":2022,"finding":"Within MuvB, LIN9 and LIN37 act as 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-DNA consensus site recognition, and MuvB (including LIN52) increases nucleosome occupancy in a reconstituted promoter; in arrested cells, MuvB primarily associates with the +1 nucleosome near the TSS of MuvB-regulated genes.","method":"Crystal structure of MuvB subcomplex, biochemical reconstitution with nucleosomes, ChIP-seq in arrested cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus ChIP-seq, multiple orthogonal methods in single study","pmids":["35082292"],"is_preprint":false},{"year":2017,"finding":"The human cytomegalovirus kinase UL97 phosphorylates LIN52, a component of p107- and p130-assembled DREAM complexes, extending viral disruption of cell cycle control to DREAM complex components.","method":"In vitro kinase assay, phosphorylation mapping","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro kinase assay in single lab; functional consequence on DREAM assembly not fully characterized in same study","pmids":["28946006"],"is_preprint":false},{"year":2013,"finding":"DYRK1A-mediated phosphorylation of LIN52 is required for DREAM complex assembly in GIST cells. Depletion of LIN52 inhibits imatinib-induced quiescence and enhances imatinib-induced apoptosis, demonstrating LIN52's role in DREAM-mediated tumor cell quiescence.","method":"siRNA knockdown of LIN52, co-immunoprecipitation for DREAM assembly, cell viability and apoptosis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype and DREAM assembly readout, single lab","pmids":["23786773"],"is_preprint":false},{"year":2014,"finding":"In a gene-targeted mouse model uniquely deficient for DREAM assembly (p107 unable to bind MuvB combined with p130 deficiency), cells preferentially assemble BMYB-MuvB and fail to repress transcription. DREAM-deficient mice show defects in endochondral bone formation due to failure of chondrocytes to arrest proliferation. Pharmacologic DYRK kinase inhibition (blocking LIN52 S28 phosphorylation) phenocopies this defect in embryonic bone culture, confirming that DYRK1A phosphorylation of LIN52 is required for DREAM assembly in vivo.","method":"Gene-targeted mouse model, micro-CT, histology, DYRK kinase inhibitor treatment of embryonic bone cultures, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model plus pharmacological validation plus biochemical DREAM assembly assay; multiple orthogonal approaches","pmids":["24710275"],"is_preprint":false},{"year":2021,"finding":"Simultaneous expression of MMB-FOXM1 complex components (including non-phosphorylated LIN52) efficiently bypasses senescence. Non-phosphorylated LIN52 disrupts the DREAM complex, indicating that the phosphorylation state of LIN52 S28 is central to the switch between senescence (DREAM assembled) and proliferation (DREAM disassembled).","method":"Senescence bypass assay, overexpression of complex components, co-immunoprecipitation, LIN52 phospho-mutant analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional bypass assay with LIN52 mutants, single lab","pmids":["34728711"],"is_preprint":false},{"year":2021,"finding":"Replacement of the LxSxE motif in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, demonstrating that LIN52's LxSxE motif mediates direct binding to p130 and that E7 disrupts this interaction to promote cellular proliferation.","method":"LIN52 point mutagenesis (S20C), co-immunoprecipitation, cell proliferation assays in HPV-positive cells","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with biochemical and functional readout, single lab","pmids":["33513914"],"is_preprint":false},{"year":2012,"finding":"Drosophila lin-52 is required for viability and adult eye development. Genetic epistasis shows that lethality and eye defects caused by lin-52 null mutations are suppressed by mutations in other MMB/dREAM subunits, indicating that a partial MMB/dREAM complex lacking Lin-52 is responsible for these phenotypes, and that Lin-52 and Myb counteract the repressive activities of other complex members.","method":"P-element excision mutagenesis to generate null alleles, somatic and germ line mutant clone analysis, genetic epistasis (double mutants with other MMB subunits)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, Drosophila ortholog","pmids":["22688510"],"is_preprint":false},{"year":2014,"finding":"Drosophila dLin52 is required for transcriptional repression of the pro-apoptotic gene hid in developing photoreceptor neurons. dLin52 cooperates with dRBF and dE2F1/2 for recruitment of the repressor complex at the hid promoter; depletion of dlin52 induces hid expression and apoptosis in eye-antennal discs.","method":"RNAi knockdown of dlin52 in Drosophila eye discs, apoptosis assays, ChIP at hid promoter, genetic interaction with dRBF and dE2F mutants","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP promoter recruitment plus functional KD phenotype in Drosophila ortholog, single lab","pmids":["24863159"],"is_preprint":false},{"year":2003,"finding":"C. elegans lin-52 is a class B synthetic multivulva (synMuvB) gene that functions in the lin-35 Rb pathway to negatively regulate let-60 ras-mediated vulval induction, suggesting a conserved role for LIN-52 in Rb-mediated signaling.","method":"Genetic screen, mutant isolation, epistasis analysis, gene cloning","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans, foundational pathway placement but no biochemical mechanism","pmids":["12750327"],"is_preprint":false},{"year":2007,"finding":"C. elegans lin-52 acts with dpl-1 DP, efl-1 E2F, lin-35 Rb, and lin-37 in transcriptional regulation to promote programmed cell death (killing process), as determined by genetic epistasis in a sensitized ced-3 background.","method":"Genetic screen in sensitized ced-3 background, epistasis analysis, cell death scoring","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans, multiple allele combinations, defined cellular phenotype","pmids":["17237514"],"is_preprint":false},{"year":2022,"finding":"In C. elegans, a triple alanine substitution of LIN-52's LxCxE motif severs LIN-35 (Rb)-MuvB association and causes DREAM mutant phenotypes (synthetic multivulva, high-temperature arrest, ectopic germline gene expression in soma). However, disrupting LIN-35-MuvB association did not affect chromatin localization of E2F-DP, LIN-35, or MuvB components, suggesting the E2F-DP-LIN-35 interaction (not LIN-35-MuvB) promotes chromatin localization.","method":"CRISPR/Cas9 mutagenesis (LIN-52 LxCxE motif substitution), RNA-seq, ChIP, phenotypic analysis","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR mutagenesis with ChIP and RNA-seq readouts, single lab","pmids":["35554539"],"is_preprint":false},{"year":2020,"finding":"Drosophila Myb protein can bind to C. elegans LIN9-LIN52 proteins in vitro, and amino acids in LIN9 and LIN52 that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in C. elegans, demonstrating an evolutionarily conserved binding interface on LIN52 for Myb recruitment.","method":"In vitro binding assay (Drosophila Myb with C. elegans LIN9-LIN52), mutagenesis of MuvB-binding domain, in vivo synMuv phenotype assay in C. elegans","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus in vivo genetic readout, mutagenesis of interface; single lab","pmids":["32295830"],"is_preprint":false},{"year":2022,"finding":"In mouse embryonic stem cells, deficiency of LIN52 (but not LIN9 or LIN37) causes G2/M arrest, loss of pluripotency, and spontaneous differentiation. These phenotypes are partially rescued by ectopic co-expression of Cyclin B1 and Cdk1, placing LIN52 upstream of G2/M regulatory machinery in ESC fate determination.","method":"CRISPR/Cas9 knockout, cell cycle analysis, pluripotency marker assays, rescue by Cyclin B1/Cdk1 co-expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined phenotype and partial rescue, single lab; LIN52-specific effect distinguished from other MuvB subunits","pmids":["35148988"],"is_preprint":false}],"current_model":"LIN52 is a small adaptor subunit of the MuvB core complex that serves as a critical scaffold for assembly of the DREAM transcriptional repressor complex: when phosphorylated on serine 28 by DYRK1A (itself activated by LATS2), LIN52 binds directly via an LxSxExL motif to the LxCxE cleft of the p107/p130 pocket domain (but not pRB), nucleating DREAM assembly and repression of cell cycle genes during quiescence and senescence; upon cell cycle entry, CDK-mediated phosphorylation of p130 weakens this interaction and MuvB/LIN52 dissociates to recruit B-Myb (via a direct LIN52-LIN9 interface revealed by crystal structure) and later FoxM1 to form the activating MMB and MMB-FoxM1 complexes that drive G2/M gene expression; within MuvB, LIN52 is positioned by LIN9/LIN37 scaffolding to engage transcription factors while the complex stabilizes the +1 nucleosome downstream of target gene TSSs to repress transcription."},"narrative":{"mechanistic_narrative":"LIN52 is a small adaptor subunit of the evolutionarily conserved MuvB core that governs the assembly switch between transcriptional repression and activation of cell cycle genes [PMID:17531812, PMID:15545624]. As part of the mammalian DREAM complex (p130/E2F4/DP plus the MuvB core proteins LIN9, LIN37, LIN52, LIN54, RBBP4), LIN52 helps repress more than 800 E2F target promoters during quiescence [PMID:17531812]. DREAM assembly is gated by phosphorylation of LIN52 on serine 28 by DYRK1A: this modification is required for the complex to form and for cells to enter quiescence or undergo Ras-induced senescence [PMID:21498570], and DYRK1A activity toward LIN52 is itself enhanced by the Hippo kinase LATS2 [PMID:21498571]. Mechanistically, phospho-S28 together with a suboptimal LxSxExL motif allows LIN52 to bind the LxCxE cleft of the p107/p130 pocket domains—but not Rb—with high affinity, thereby nucleating DREAM and explaining its pocket-protein specificity; CDK phosphorylation of p130 weakens this contact to disassemble DREAM upon cell cycle entry [PMID:25917549, PMID:33513914]. Upon disassembly, LIN52 serves as the direct interface, alongside the LIN9 scaffold, that recruits B-Myb to form the activating MMB complex driving G2/M gene expression, and non-phosphorylated LIN52 favors this proliferative MMB/MMB-FoxM1 state over assembled DREAM [PMID:30224471, PMID:34728711]. Within MuvB, LIN9 and LIN37 position LIN52 for transcription-factor engagement while the complex stabilizes the +1 nucleosome downstream of target TSSs to enforce repression [PMID:35082292]. Loss of LIN52-dependent DREAM assembly has physiological consequences, including failure of chondrocyte cell-cycle arrest and defective endochondral bone formation in mice [PMID:24710275], and the LIN52 S28 axis is targeted by viral oncoproteins to override cell cycle control [PMID:28946006, PMID:33513914].","teleology":[{"year":2003,"claim":"Established LIN52 as a conserved component of an Rb-pathway regulatory module before any biochemical mechanism was known, placing it genetically in cell-fate control.","evidence":"Genetic screen and epistasis identifying lin-52 as a class B synMuv gene in the lin-35 Rb pathway in C. elegans","pmids":["12750327"],"confidence":"Medium","gaps":["No biochemical interaction or molecular function defined","Relationship to a defined protein complex unresolved"]},{"year":2004,"claim":"Demonstrated that the LIN52 ortholog is part of a physical Myb-MuvB repressor complex acting at developmental gene promoters, defining its biochemical context.","evidence":"Affinity co-purification of the Drosophila Myb-MuvB complex with ChIP and reporter assays","pmids":["15545624"],"confidence":"High","gaps":["Specific role of LIN52 within the complex not isolated","Mammalian complex composition not yet established"]},{"year":2007,"claim":"Defined the mammalian DREAM complex containing LIN52 and showed it represses E2F target promoters in G0 and exchanges to a Myb-bound module in S phase, framing LIN52 within the repression-to-activation switch.","evidence":"Affinity-MS proteomics, ChIP-on-chip, siRNA knockdown and Co-IP in human cells; parallel C. elegans genetics linking lin-52 to programmed cell death","pmids":["17531812","17237514"],"confidence":"High","gaps":["What signal triggers the DREAM-to-MMB switch unknown","Direct contacts of LIN52 within the complex unmapped"]},{"year":2011,"claim":"Identified the molecular trigger for DREAM assembly: DYRK1A phosphorylation of LIN52 S28, with LATS2 acting upstream, converting LIN52 into the regulatable node controlling quiescence and senescence.","evidence":"In vitro kinase assays, S28A mutagenesis, DYRK1A inhibition, Co-IP and cell cycle analysis; shRNA screen and kinase assay for the LATS2-DYRK1A link","pmids":["21498570","21498571"],"confidence":"High","gaps":["Structural basis of how phospho-S28 enables binding not yet resolved","LATS2 link is indirect through DYRK1A (Medium confidence)"]},{"year":2014,"claim":"Showed in vivo that LIN52-dependent DREAM assembly is physiologically required for proliferative arrest, demonstrating organismal consequences of the phospho-switch.","evidence":"Gene-targeted DREAM-deficient mouse model with micro-CT/histology and DYRK inhibitor phenocopy in embryonic bone culture; Drosophila lin-52 null epistasis","pmids":["24710275","22688510"],"confidence":"High","gaps":["Tissue-specific roles of LIN52 beyond chondrocytes not mapped","Mechanism connecting arrest failure to bone defect not detailed"]},{"year":2015,"claim":"Provided the structural mechanism for LIN52's pocket-protein specificity, showing phospho-S28 plus an LxSxExL motif binds the p107/p130 LxCxE cleft but not Rb, and that CDK phosphorylation of p130 drives disassembly.","evidence":"Crystal structure of LIN52-p107, in vitro binding, mutagenesis and reconstitution","pmids":["25917549"],"confidence":"High","gaps":["Dynamics of CDK-driven disassembly in cells not quantified","How the same motif is repurposed for MMB assembly unresolved"]},{"year":2018,"claim":"Resolved how LIN52 builds the activating complex, showing it is the direct interface (with LIN9) recruiting B-Myb to form MMB, and that B-Myb reciprocally modulates DREAM and LIN52 levels via the S28 site.","evidence":"Crystal structure of the B-Myb-LIN52-LIN9 interface with binding assays; Co-IP and overexpression with domain and S28 mutants","pmids":["30224471","30206359"],"confidence":"High","gaps":["Competition kinetics between DREAM and MMB assembly on LIN52 unquantified","B-Myb regulation of LIN52 levels mechanistically incomplete (Medium confidence)"]},{"year":2022,"claim":"Defined the architecture and chromatin engagement of MuvB, showing LIN9/LIN37 position LIN52 for transcription-factor binding while the complex stabilizes the +1 nucleosome to repress target genes.","evidence":"Crystal structure of a MuvB subcomplex, nucleosome reconstitution, and ChIP-seq in arrested cells; C. elegans LxCxE motif CRISPR mutagenesis with ChIP/RNA-seq","pmids":["35082292","35554539"],"confidence":"High","gaps":["How nucleosome stabilization mechanistically silences transcription not detailed","Chromatin recruitment shown to depend on E2F-DP-Rb rather than Rb-MuvB in worm (Medium confidence)"]},{"year":2022,"claim":"Revealed a LIN52-specific requirement distinct from other MuvB subunits in stem cell fate, linking LIN52 to G2/M control and pluripotency maintenance.","evidence":"CRISPR knockout in mouse ESCs with cell cycle and pluripotency assays and Cyclin B1/Cdk1 rescue","pmids":["35148988"],"confidence":"Medium","gaps":["Why LIN52 loss differs from LIN9/LIN37 loss mechanistically unexplained","Single lab, single cell type"]},{"year":null,"claim":"How the LIN52 S28 phosphorylation state is dynamically set and reset to time the DREAM-to-MMB transition during the cell cycle, and how viral kinases/oncoproteins quantitatively override it, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model of phospho-S28 dynamics across the cycle","Functional consequences of UL97 phosphorylation of LIN52 not fully characterized","Human disease relevance of the E7-LIN52 axis not established by family/causative genetics"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,11]}],"complexes":["DREAM complex","MuvB core","Myb-MuvB (MMB) complex"],"partners":["LIN9","P130","P107","B-MYB (MYBL2)","DYRK1A","LIN37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q52LA3","full_name":"Protein lin-52 homolog","aliases":[],"length_aa":112,"mass_kda":12.5,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q52LA3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LIN52","classification":"Common Essential","n_dependent_lines":733,"n_total_lines":1208,"dependency_fraction":0.6067880794701986},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LIN52","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":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIN52"},"hgnc":{"alias_symbol":[],"prev_symbol":["C14orf46"]},"alphafold":{"accession":"Q52LA3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q52LA3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q52LA3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q52LA3-F1-predicted_aligned_error_v6.png","plddt_mean":76.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIN52","jax_strain_url":"https://www.jax.org/strain/search?query=LIN52"},"sequence":{"accession":"Q52LA3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q52LA3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q52LA3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q52LA3"}},"corpus_meta":[{"pmid":"17531812","id":"PMC_17531812","title":"Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in 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nucleosomes downstream of the transcription start site of cell-cycle dependent genes.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35082292","citation_count":19,"is_preprint":false},{"pmid":"32600250","id":"PMC_32600250","title":"Genome-wide identification and comparison of differentially expressed profiles of miRNAs and lncRNAs with associated ceRNA networks in the gonads of Chinese soft-shelled turtle, Pelodiscus sinensis.","date":"2020","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32600250","citation_count":17,"is_preprint":false},{"pmid":"33513914","id":"PMC_33513914","title":"Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/33513914","citation_count":16,"is_preprint":false},{"pmid":"31387856","id":"PMC_31387856","title":"An RNAi Screen for Genes Required for Growth of Drosophila Wing 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complex, which contains p130, E2F4, DP, and MuvB core proteins (LIN9, LIN37, LIN52, LIN54, RBBP4). DREAM binds to more than 800 human promoters in G0 and is required for repression of E2F target genes. In S phase, MuvB proteins (including LIN52) dissociate from p130 and form a distinct submodule that binds MYB.\",\n      \"method\": \"Proteomics (affinity purification/mass spectrometry), ChIP-on-chip genomics, siRNA knockdown, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, MS-based proteomics, ChIP-on-chip, functional KD; foundational study replicated by multiple subsequent labs\",\n      \"pmids\": [\"17531812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DYRK1A specifically phosphorylates LIN52 on serine residue 28, and this phosphorylation is required for DREAM complex assembly. Point mutation of S28 or inhibition of DYRK1A disrupts DREAM assembly and reduces the ability of cells to enter quiescence or undergo Ras-induced senescence.\",\n      \"method\": \"Mass spectrometric phosphorylation site identification, in vitro kinase assay, point mutagenesis (S28A), DYRK1A inhibitor treatment, co-immunoprecipitation, cell cycle analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with defined substrate site, mutagenesis validation, functional rescue experiments; replicated in multiple subsequent studies\",\n      \"pmids\": [\"21498570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Drosophila homolog of LIN-52 co-purifies with Myb complex components, E2F2, DP, RBF1, RBF2, L(3)MBT, and Rpd3 (HDAC) to form the Myb-MuvB complex, which localizes to promoters and co-represses transcription of developmentally regulated genes.\",\n      \"method\": \"Affinity chromatography fractionation of Drosophila embryo extracts, co-purification, ChIP, transcriptional reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical co-purification, ChIP localization, functional repression assay; foundational Drosophila ortholog study\",\n      \"pmids\": [\"15545624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LIN52 contains a sequence that binds directly to the pocket domains of p107 and p130 when phosphorylated at S28 (DYRK1A site). A crystal structure of the LIN52-p107 complex reveals that LIN52 uses a suboptimal LxSxExL sequence together with the phospho-S28 to bind the LxCxE cleft of the pocket domain with high affinity, explaining specificity for p107/p130 over Rb in DREAM. CDK phosphorylation of p130 weakens its LIN52 association, providing a mechanism for DREAM disassembly upon cell cycle entry.\",\n      \"method\": \"Crystal structure determination, in vitro binding assays, mutagenesis, biochemical reconstitution\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional biochemical validation and mutagenesis in single rigorous study\",\n      \"pmids\": [\"25917549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LATS2, a Hippo pathway kinase, phosphorylates DYRK1A and enhances DYRK1A's ability to phosphorylate LIN52, thereby promoting DREAM complex assembly and E2F target gene silencing. Reduced LATS2 levels impair DREAM assembly at E2F-regulated promoters.\",\n      \"method\": \"shRNA screen, kinase assay (LATS2 phosphorylation of DYRK1A), ChIP, co-immunoprecipitation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay and ChIP in single lab study; indirect link through DYRK1A\",\n      \"pmids\": [\"21498571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A crystal structure reveals that B-Myb binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9 to form the Myb-MuvB (MMB) complex. LIN52 serves as the direct binding interface between B-Myb and the MuvB core.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, domain mapping mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation and mutagenesis of binding interface\",\n      \"pmids\": [\"30224471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of B-Myb disrupts DREAM complex assembly in human cells dependent on the intact MuvB-binding domain of B-Myb. Furthermore, B-Myb regulates LIN52 protein expression levels by a mechanism requiring the S28 phosphorylation site in LIN52.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, B-Myb overexpression and MuvB-binding domain mutants, LIN52 S28 point mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutants, single lab, two orthogonal approaches\",\n      \"pmids\": [\"30206359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Within MuvB, LIN9 and LIN37 act as 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-DNA consensus site recognition, and MuvB (including LIN52) increases nucleosome occupancy in a reconstituted promoter; in arrested cells, MuvB primarily associates with the +1 nucleosome near the TSS of MuvB-regulated genes.\",\n      \"method\": \"Crystal structure of MuvB subcomplex, biochemical reconstitution with nucleosomes, ChIP-seq in arrested cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus ChIP-seq, multiple orthogonal methods in single study\",\n      \"pmids\": [\"35082292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The human cytomegalovirus kinase UL97 phosphorylates LIN52, a component of p107- and p130-assembled DREAM complexes, extending viral disruption of cell cycle control to DREAM complex components.\",\n      \"method\": \"In vitro kinase assay, phosphorylation mapping\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro kinase assay in single lab; functional consequence on DREAM assembly not fully characterized in same study\",\n      \"pmids\": [\"28946006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DYRK1A-mediated phosphorylation of LIN52 is required for DREAM complex assembly in GIST cells. Depletion of LIN52 inhibits imatinib-induced quiescence and enhances imatinib-induced apoptosis, demonstrating LIN52's role in DREAM-mediated tumor cell quiescence.\",\n      \"method\": \"siRNA knockdown of LIN52, co-immunoprecipitation for DREAM assembly, cell viability and apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype and DREAM assembly readout, single lab\",\n      \"pmids\": [\"23786773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In a gene-targeted mouse model uniquely deficient for DREAM assembly (p107 unable to bind MuvB combined with p130 deficiency), cells preferentially assemble BMYB-MuvB and fail to repress transcription. DREAM-deficient mice show defects in endochondral bone formation due to failure of chondrocytes to arrest proliferation. Pharmacologic DYRK kinase inhibition (blocking LIN52 S28 phosphorylation) phenocopies this defect in embryonic bone culture, confirming that DYRK1A phosphorylation of LIN52 is required for DREAM assembly in vivo.\",\n      \"method\": \"Gene-targeted mouse model, micro-CT, histology, DYRK kinase inhibitor treatment of embryonic bone cultures, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model plus pharmacological validation plus biochemical DREAM assembly assay; multiple orthogonal approaches\",\n      \"pmids\": [\"24710275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Simultaneous expression of MMB-FOXM1 complex components (including non-phosphorylated LIN52) efficiently bypasses senescence. Non-phosphorylated LIN52 disrupts the DREAM complex, indicating that the phosphorylation state of LIN52 S28 is central to the switch between senescence (DREAM assembled) and proliferation (DREAM disassembled).\",\n      \"method\": \"Senescence bypass assay, overexpression of complex components, co-immunoprecipitation, LIN52 phospho-mutant analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional bypass assay with LIN52 mutants, single lab\",\n      \"pmids\": [\"34728711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Replacement of the LxSxE motif in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, demonstrating that LIN52's LxSxE motif mediates direct binding to p130 and that E7 disrupts this interaction to promote cellular proliferation.\",\n      \"method\": \"LIN52 point mutagenesis (S20C), co-immunoprecipitation, cell proliferation assays in HPV-positive cells\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with biochemical and functional readout, single lab\",\n      \"pmids\": [\"33513914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila lin-52 is required for viability and adult eye development. Genetic epistasis shows that lethality and eye defects caused by lin-52 null mutations are suppressed by mutations in other MMB/dREAM subunits, indicating that a partial MMB/dREAM complex lacking Lin-52 is responsible for these phenotypes, and that Lin-52 and Myb counteract the repressive activities of other complex members.\",\n      \"method\": \"P-element excision mutagenesis to generate null alleles, somatic and germ line mutant clone analysis, genetic epistasis (double mutants with other MMB subunits)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple allele combinations, Drosophila ortholog\",\n      \"pmids\": [\"22688510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila dLin52 is required for transcriptional repression of the pro-apoptotic gene hid in developing photoreceptor neurons. dLin52 cooperates with dRBF and dE2F1/2 for recruitment of the repressor complex at the hid promoter; depletion of dlin52 induces hid expression and apoptosis in eye-antennal discs.\",\n      \"method\": \"RNAi knockdown of dlin52 in Drosophila eye discs, apoptosis assays, ChIP at hid promoter, genetic interaction with dRBF and dE2F mutants\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP promoter recruitment plus functional KD phenotype in Drosophila ortholog, single lab\",\n      \"pmids\": [\"24863159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"C. elegans lin-52 is a class B synthetic multivulva (synMuvB) gene that functions in the lin-35 Rb pathway to negatively regulate let-60 ras-mediated vulval induction, suggesting a conserved role for LIN-52 in Rb-mediated signaling.\",\n      \"method\": \"Genetic screen, mutant isolation, epistasis analysis, gene cloning\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans, foundational pathway placement but no biochemical mechanism\",\n      \"pmids\": [\"12750327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C. elegans lin-52 acts with dpl-1 DP, efl-1 E2F, lin-35 Rb, and lin-37 in transcriptional regulation to promote programmed cell death (killing process), as determined by genetic epistasis in a sensitized ced-3 background.\",\n      \"method\": \"Genetic screen in sensitized ced-3 background, epistasis analysis, cell death scoring\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans, multiple allele combinations, defined cellular phenotype\",\n      \"pmids\": [\"17237514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C. elegans, a triple alanine substitution of LIN-52's LxCxE motif severs LIN-35 (Rb)-MuvB association and causes DREAM mutant phenotypes (synthetic multivulva, high-temperature arrest, ectopic germline gene expression in soma). However, disrupting LIN-35-MuvB association did not affect chromatin localization of E2F-DP, LIN-35, or MuvB components, suggesting the E2F-DP-LIN-35 interaction (not LIN-35-MuvB) promotes chromatin localization.\",\n      \"method\": \"CRISPR/Cas9 mutagenesis (LIN-52 LxCxE motif substitution), RNA-seq, ChIP, phenotypic analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR mutagenesis with ChIP and RNA-seq readouts, single lab\",\n      \"pmids\": [\"35554539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Drosophila Myb protein can bind to C. elegans LIN9-LIN52 proteins in vitro, and amino acids in LIN9 and LIN52 that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in C. elegans, demonstrating an evolutionarily conserved binding interface on LIN52 for Myb recruitment.\",\n      \"method\": \"In vitro binding assay (Drosophila Myb with C. elegans LIN9-LIN52), mutagenesis of MuvB-binding domain, in vivo synMuv phenotype assay in C. elegans\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus in vivo genetic readout, mutagenesis of interface; single lab\",\n      \"pmids\": [\"32295830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse embryonic stem cells, deficiency of LIN52 (but not LIN9 or LIN37) causes G2/M arrest, loss of pluripotency, and spontaneous differentiation. These phenotypes are partially rescued by ectopic co-expression of Cyclin B1 and Cdk1, placing LIN52 upstream of G2/M regulatory machinery in ESC fate determination.\",\n      \"method\": \"CRISPR/Cas9 knockout, cell cycle analysis, pluripotency marker assays, rescue by Cyclin B1/Cdk1 co-expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined phenotype and partial rescue, single lab; LIN52-specific effect distinguished from other MuvB subunits\",\n      \"pmids\": [\"35148988\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIN52 is a small adaptor subunit of the MuvB core complex that serves as a critical scaffold for assembly of the DREAM transcriptional repressor complex: when phosphorylated on serine 28 by DYRK1A (itself activated by LATS2), LIN52 binds directly via an LxSxExL motif to the LxCxE cleft of the p107/p130 pocket domain (but not pRB), nucleating DREAM assembly and repression of cell cycle genes during quiescence and senescence; upon cell cycle entry, CDK-mediated phosphorylation of p130 weakens this interaction and MuvB/LIN52 dissociates to recruit B-Myb (via a direct LIN52-LIN9 interface revealed by crystal structure) and later FoxM1 to form the activating MMB and MMB-FoxM1 complexes that drive G2/M gene expression; within MuvB, LIN52 is positioned by LIN9/LIN37 scaffolding to engage transcription factors while the complex stabilizes the +1 nucleosome downstream of target gene TSSs to repress transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIN52 is a small adaptor subunit of the evolutionarily conserved MuvB core that governs the assembly switch between transcriptional repression and activation of cell cycle genes [#0, #2]. As part of the mammalian DREAM complex (p130/E2F4/DP plus the MuvB core proteins LIN9, LIN37, LIN52, LIN54, RBBP4), LIN52 helps repress more than 800 E2F target promoters during quiescence [#0]. DREAM assembly is gated by phosphorylation of LIN52 on serine 28 by DYRK1A: this modification is required for the complex to form and for cells to enter quiescence or undergo Ras-induced senescence [#1], and DYRK1A activity toward LIN52 is itself enhanced by the Hippo kinase LATS2 [#4]. Mechanistically, phospho-S28 together with a suboptimal LxSxExL motif allows LIN52 to bind the LxCxE cleft of the p107/p130 pocket domains—but not Rb—with high affinity, thereby nucleating DREAM and explaining its pocket-protein specificity; CDK phosphorylation of p130 weakens this contact to disassemble DREAM upon cell cycle entry [#3, #12]. Upon disassembly, LIN52 serves as the direct interface, alongside the LIN9 scaffold, that recruits B-Myb to form the activating MMB complex driving G2/M gene expression, and non-phosphorylated LIN52 favors this proliferative MMB/MMB-FoxM1 state over assembled DREAM [#5, #11]. Within MuvB, LIN9 and LIN37 position LIN52 for transcription-factor engagement while the complex stabilizes the +1 nucleosome downstream of target TSSs to enforce repression [#7]. Loss of LIN52-dependent DREAM assembly has physiological consequences, including failure of chondrocyte cell-cycle arrest and defective endochondral bone formation in mice [#10], and the LIN52 S28 axis is targeted by viral oncoproteins to override cell cycle control [#8, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established LIN52 as a conserved component of an Rb-pathway regulatory module before any biochemical mechanism was known, placing it genetically in cell-fate control.\",\n      \"evidence\": \"Genetic screen and epistasis identifying lin-52 as a class B synMuv gene in the lin-35 Rb pathway in C. elegans\",\n      \"pmids\": [\"12750327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical interaction or molecular function defined\", \"Relationship to a defined protein complex unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that the LIN52 ortholog is part of a physical Myb-MuvB repressor complex acting at developmental gene promoters, defining its biochemical context.\",\n      \"evidence\": \"Affinity co-purification of the Drosophila Myb-MuvB complex with ChIP and reporter assays\",\n      \"pmids\": [\"15545624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific role of LIN52 within the complex not isolated\", \"Mammalian complex composition not yet established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the mammalian DREAM complex containing LIN52 and showed it represses E2F target promoters in G0 and exchanges to a Myb-bound module in S phase, framing LIN52 within the repression-to-activation switch.\",\n      \"evidence\": \"Affinity-MS proteomics, ChIP-on-chip, siRNA knockdown and Co-IP in human cells; parallel C. elegans genetics linking lin-52 to programmed cell death\",\n      \"pmids\": [\"17531812\", \"17237514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What signal triggers the DREAM-to-MMB switch unknown\", \"Direct contacts of LIN52 within the complex unmapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the molecular trigger for DREAM assembly: DYRK1A phosphorylation of LIN52 S28, with LATS2 acting upstream, converting LIN52 into the regulatable node controlling quiescence and senescence.\",\n      \"evidence\": \"In vitro kinase assays, S28A mutagenesis, DYRK1A inhibition, Co-IP and cell cycle analysis; shRNA screen and kinase assay for the LATS2-DYRK1A link\",\n      \"pmids\": [\"21498570\", \"21498571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how phospho-S28 enables binding not yet resolved\", \"LATS2 link is indirect through DYRK1A (Medium confidence)\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed in vivo that LIN52-dependent DREAM assembly is physiologically required for proliferative arrest, demonstrating organismal consequences of the phospho-switch.\",\n      \"evidence\": \"Gene-targeted DREAM-deficient mouse model with micro-CT/histology and DYRK inhibitor phenocopy in embryonic bone culture; Drosophila lin-52 null epistasis\",\n      \"pmids\": [\"24710275\", \"22688510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific roles of LIN52 beyond chondrocytes not mapped\", \"Mechanism connecting arrest failure to bone defect not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural mechanism for LIN52's pocket-protein specificity, showing phospho-S28 plus an LxSxExL motif binds the p107/p130 LxCxE cleft but not Rb, and that CDK phosphorylation of p130 drives disassembly.\",\n      \"evidence\": \"Crystal structure of LIN52-p107, in vitro binding, mutagenesis and reconstitution\",\n      \"pmids\": [\"25917549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of CDK-driven disassembly in cells not quantified\", \"How the same motif is repurposed for MMB assembly unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how LIN52 builds the activating complex, showing it is the direct interface (with LIN9) recruiting B-Myb to form MMB, and that B-Myb reciprocally modulates DREAM and LIN52 levels via the S28 site.\",\n      \"evidence\": \"Crystal structure of the B-Myb-LIN52-LIN9 interface with binding assays; Co-IP and overexpression with domain and S28 mutants\",\n      \"pmids\": [\"30224471\", \"30206359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Competition kinetics between DREAM and MMB assembly on LIN52 unquantified\", \"B-Myb regulation of LIN52 levels mechanistically incomplete (Medium confidence)\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the architecture and chromatin engagement of MuvB, showing LIN9/LIN37 position LIN52 for transcription-factor binding while the complex stabilizes the +1 nucleosome to repress target genes.\",\n      \"evidence\": \"Crystal structure of a MuvB subcomplex, nucleosome reconstitution, and ChIP-seq in arrested cells; C. elegans LxCxE motif CRISPR mutagenesis with ChIP/RNA-seq\",\n      \"pmids\": [\"35082292\", \"35554539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nucleosome stabilization mechanistically silences transcription not detailed\", \"Chromatin recruitment shown to depend on E2F-DP-Rb rather than Rb-MuvB in worm (Medium confidence)\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a LIN52-specific requirement distinct from other MuvB subunits in stem cell fate, linking LIN52 to G2/M control and pluripotency maintenance.\",\n      \"evidence\": \"CRISPR knockout in mouse ESCs with cell cycle and pluripotency assays and Cyclin B1/Cdk1 rescue\",\n      \"pmids\": [\"35148988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why LIN52 loss differs from LIN9/LIN37 loss mechanistically unexplained\", \"Single lab, single cell type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the LIN52 S28 phosphorylation state is dynamically set and reset to time the DREAM-to-MMB transition during the cell cycle, and how viral kinases/oncoproteins quantitatively override it, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of phospho-S28 dynamics across the cycle\", \"Functional consequences of UL97 phosphorylation of LIN52 not fully characterized\", \"Human disease relevance of the E7-LIN52 axis not established by family/causative genetics\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [\"DREAM complex\", \"MuvB core\", \"Myb-MuvB (MMB) complex\"],\n    \"partners\": [\"LIN9\", \"p130\", \"p107\", \"B-Myb (MYBL2)\", \"DYRK1A\", \"LIN37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}