Affinage

LIN54

Protein lin-54 homolog · UniProt Q6MZP7

Length
749 aa
Mass
79.5 kDa
Annotated
2026-06-10
37 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    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

    PMID:17075059

    Open questions at the time
    • Did not define a biochemical activity for LIN-54 within the complex
    • Mammalian relevance not yet demonstrated
  2. 2007 High

    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

    PMID:17531812

    Open questions at the time
    • Did not identify which subunit confers DNA sequence specificity
    • Molecular basis of the G0-to-S switch unresolved
  3. 2009 High

    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

    PMID:19725879

    Open questions at the time
    • Structural basis of CHR specificity not determined
    • Single-CXC vs tandem-domain contribution unclear
  4. 2011 High

    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

    PMID:21498570

    Open questions at the time
    • How phosphorylation reorganizes the complex structurally not shown
    • Did not address activating MMB assembly mechanism
  5. 2011 High

    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

    PMID:21589891

    Open questions at the time
    • Mammalian genome-wide recruitment dependence on LIN54 binding not directly tested here
  6. 2011 Medium

    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

    PMID:21813705

    Open questions at the time
    • Partial rescue only; other arrest pathways may contribute
    • Single cell-line context
  7. 2012 Medium

    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

    PMID:22895175

    Open questions at the time
    • Physiological signal that triggers export not identified
    • Single lab
  8. 2016 High

    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

    PMID:27465258

    Open questions at the time
    • Structure of full MuvB on DNA not resolved here
    • Does not explain repression-vs-activation output
  9. 2018 Medium

    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

    PMID:30206359

    Open questions at the time
    • Direct effect on LIN54 conformation/binding not measured
    • Single lab
  10. 2021 Medium

    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

    PMID:33657372

    Open questions at the time
    • Direct LIN54-FOXM1 contacts not mapped
    • Single lab
  11. 2021 Medium

    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

    PMID:34728711

    Open questions at the time
    • Specific LIN54 contribution not isolated from other subunits
    • Single lab
  12. 2022 High

    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

    PMID:35082292

    Open questions at the time
    • Structure of the full DREAM/MMB on chromatin not solved
    • Switch to activation not structurally explained
  13. 2022 Medium

    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

    PMID:35148988

    Open questions at the time
    • Why LIN54 loss differs from LIN9/LIN37 loss mechanistically unclear
    • Single lab/model
  14. 2024 Low

    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

    PMID:39039166

    Open questions at the time
    • Single Co-IP without reciprocal validation; direct LIN54-IDH1 contact unproven
    • Functional significance for LIN54 not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHR-bound LIN54 mechanistically dictates the switch between MuvB-mediated repression (DREAM) and activation (MMB/MMB-FOXM1) at the same promoters remains unresolved.
  • No structure of full DREAM or MMB engaged on CHR chromatin
  • Signals controlling LIN54-dependent nucleosome repositioning vs activation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005654 nucleoplasm 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 1
Partners
E2F4FOXM1LIN37LIN52LIN9MYBL2RBBP4
Complex memberships
DREAM complexMMB (B-MYB-MuvB)MMB-FOXM1MuvB core complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. Proteomics (mass spectrometry), genomics (ChIP-chip), co-immunoprecipitation, bioinformatic analysis Molecular cell High 17531812
2006 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. Genetic analysis, biochemical co-immunoprecipitation of complex components in C. elegans mutants Proceedings of the National Academy of Sciences of the United States of America High 17075059
2009 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. Gel shift assay (EMSA), protein interaction studies (co-IP/pulldown with deletion mutants), cell cycle analysis The FEBS journal High 19725879
2011 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. Mass spectrometry (phosphorylation site identification), kinase assay, point mutation, DREAM complex co-IP, cell cycle/senescence assays Genes & development High 21498570
2011 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. Genome-wide ChIP, gene expression profiling, genetic analysis of lin-54 mutants PLoS genetics High 21589891
2016 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. Biochemical DNA binding assays, X-ray crystallography of LIN54 DBD in complex with CHR DNA, mutagenesis, ChIP Nature communications High 27465258
2012 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. Subcellular fractionation, fluorescence microscopy, leptomycin B treatment (CRM1 inhibition), cell cycle analysis, NLS deletion mutants Cell cycle (Georgetown, Tex.) Medium 22895175
2018 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. Co-immunoprecipitation, overexpression and knockdown experiments, immunoblotting, domain deletion mutants Oncogene Medium 30206359
2011 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. shRNA knockdown, co-immunoprecipitation, flow cytometry cell cycle analysis The Journal of general virology Medium 21813705
2014 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. Genetic epistasis, immunofluorescence/cytological analysis of polytene chromosomes, mutant analysis Proceedings of the National Academy of Sciences of the United States of America Medium 25249635
2021 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. Genome-wide CRISPR-Cas9 screens, gene knockout, immunoblotting for replication stress markers, cell cycle analysis Cell reports Medium 33657372
2022 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. Cryo-EM/crystal structure of MuvB subcomplex, biochemical reconstitution, nucleosome binding assays, ChIP in arrested cells Nature communications High 35082292
2022 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. CRISPR/Cas9 knockout, cell cycle analysis (flow cytometry), pluripotency marker assays, rescue by cyclin B1/Cdk1 overexpression The Journal of biological chemistry Medium 35148988
2021 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. Senescence bypass assay in conditionally immortalized fibroblasts, co-immunoprecipitation, overexpression of complex components Scientific reports Medium 34728711
2024 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. Co-immunoprecipitation, siRNA knockdown, RT-qPCR Histochemistry and cell biology Low 39039166
2007 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. Genetic mutant analysis, immunofluorescence on polytene chromosomes, complex purification Genes & development Medium 17403774
2009 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. Co-immunoprecipitation, cell cycle fractionation Experimental cell research Medium 19619530
2017 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. Genetic analysis of mip120 mutants, immunofluorescence, gene expression analysis, domain deletion analysis Biology open Medium 28522430

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Molecular cell 341 17531812
2011 DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes & development 249 21498570
2006 Some C. elegans class B synthetic multivulva proteins encode a conserved LIN-35 Rb-containing complex distinct from a NuRD-like complex. Proceedings of the National Academy of Sciences of the United States of America 121 17075059
2009 LIN54 is an essential core subunit of the DREAM/LINC complex that binds to the cdc2 promoter in a sequence-specific manner. The FEBS journal 85 19725879
2007 Discovery of tMAC: a Drosophila testis-specific meiotic arrest complex paralogous to Myb-Muv B. Genes & development 80 17403774
2018 The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb. Oncogene 54 30206359
2016 Structural basis for LIN54 recognition of CHR elements in cell cycle-regulated promoters. Nature communications 54 27465258
2011 Chromosome-biased binding and gene regulation by the Caenorhabditis elegans DRM complex. PLoS genetics 46 21589891
2011 Disruption of repressive p130-DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells. The Journal of general virology 46 21813705
2021 MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity. Cell reports 39 33657372
2021 DREAM On: Cell Cycle Control in Development and Disease. Annual review of genetics 36 34496610
2004 Homologs of Drosophila P transposons were mobile in zebrafish but have been domesticated in a common ancestor of chicken and human. Molecular biology and evolution 35 15616143
2015 Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma. Molecular cancer 28 25889361
2014 Loss of the mammalian DREAM complex deregulates chondrocyte proliferation. Molecular and cellular biology 27 24710275
2018 MuvB: A Key to Cell Cycle Control in Ovarian Cancer. Frontiers in oncology 25 29942794
2013 The complex containing Drosophila Myb and RB/E2F2 regulates cytokinesis in a histone H2Av-dependent manner. Molecular and cellular biology 24 23438598
2018 Transcriptomic Characterization of Endometrioid, Clear Cell, and High-Grade Serous Epithelial Ovarian Carcinoma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22 29967001
2022 The MuvB complex binds and stabilizes nucleosomes downstream of the transcription start site of cell-cycle dependent genes. Nature communications 19 35082292
2021 Functional characterization of RebL1 highlights the evolutionary conservation of oncogenic activities of the RBBP4/7 orthologue in Tetrahymena thermophila. Nucleic acids research 19 34086947
2021 Context-dependent transcriptional regulation of microglial proliferation. Glia 19 34862814
2012 LIN54 harboring a mutation in CHC domain is localized to the cytoplasm and inhibits cell cycle progression. Cell cycle (Georgetown, Tex.) 18 22895175
2014 Chromatin reader L(3)mbt requires the Myb-MuvB/DREAM transcriptional regulatory complex for chromosomal recruitment. Proceedings of the National Academy of Sciences of the United States of America 15 25249635
2009 Deletion of the p107/p130-binding domain of Mip130/LIN-9 bypasses the requirement for CDK4 activity for the dissociation of Mip130/LIN-9 from p107/p130-E2F4 complex. Experimental cell research 14 19619530
2021 Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence. Scientific reports 11 34728711
2017 A de novo deletion in a boy with cerebral palsy suggests a refined critical region for the 4q21.22 microdeletion syndrome. American journal of medical genetics. Part A 7 28371330
2020 ATP-Dependent Chromatin Remodeler CHD9 Controls the Proliferation of Embryonic Stem Cells in a Cell Culture Condition-Dependent Manner. Biology 6 33261017
2017 The Drosophila LIN54 homolog Mip120 controls two aspects of oogenesis. Biology open 5 28522430
2017 Comparative analysis of behavioral and transcriptional variation underlying CO2 sensory neuron function and development in Drosophila. Fly 5 28644712
2014 Rapid clearance of epigenetic protein reporters from wound edge cells in Drosophila larvae does not depend on the JNK or PDGFR/VEGFR signaling pathways. Regeneration (Oxford, England) 5 25114797
2022 The MuvB complex safeguards embryonic stem cell identity through regulation of the cell cycle machinery. The Journal of biological chemistry 4 35148988
2025 The Dysregulation of Tuning Receptors and Transcription Factors in the Antennae of Orco and Ir8a Mutants in Aedes aegypti Suggests a Chemoreceptor Regulatory Mechanism Involving the MMB/dREAM Complex. Insects 2 40559068
2025 Bacillus subtilis Strain TCX1 Isolated from Ambrosia artemisiifolia: Enhancing Cucumber Growth and Biocontrol Against Cucumber Fusarium Wilt. Plants (Basel, Switzerland) 2 41095209
2023 Overexpressed FOXM1 collaborates with MMB to increase WEE1 inhibitor sensitivity in NSCLC. Journal of thoracic disease 2 37426130
2014 A B-myb--DREAM complex is not critical to regulate the G2/M genes in HPV-transformed cell lines. Anticancer research 2 25368258
2010 Temperature and composition dependence of the Soret coefficient in Lennard-Jones mixtures presenting consolute critical phenomena. The Journal of chemical physics 2 20370138
2011 Temperature and composition dependence of the Soret coefficient in Lennard-Jones mixtures presenting evaporation/condensation phase transition. The Journal of chemical physics 1 21428637
2024 FOXM1 requires IDH1 for late genes expression in mitotic cells. Histochemistry and cell biology 0 39039166

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