{"gene":"LBR","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1994,"finding":"Human LBR is an integral inner nuclear membrane protein with a nucleoplasmic amino-terminal domain (208 aa) followed by eight putative transmembrane segments. The amino-terminal domain directly binds lamin B (precipitated from nuclear extracts) and binds double-stranded DNA in a sequence-independent manner; the stretch between amino acids 71–100 (Ser-Arg-rich) is necessary for DNA binding.","method":"Recombinant fusion protein pulldown from nuclear extracts; nitrocellulose DNA-binding assay; deletion mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding reconstitution with deletion mutagenesis, replicated across binding partners (lamin B and DNA) in same study","pmids":["8157662"],"is_preprint":false},{"year":1997,"finding":"HP1-type chromodomain proteins interact with LBR via their chromo shadow domain (not the chromodomain). The interaction maps to a portion of the second globular domain of LBR's nucleoplasmic region. HP1–LBR binding is detectable both in vitro and in the yeast two-hybrid assay.","method":"Yeast two-hybrid assay; in vitro binding (GST pulldown); domain deletion mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — two orthogonal methods (yeast two-hybrid + in vitro binding) with domain mapping in same study","pmids":["9169472"],"is_preprint":false},{"year":1996,"finding":"LBR is the principal chromatin anchorage site at the nuclear envelope. Immunodepletion or chemical extraction of LBR from in vitro reconstituted nuclear envelope vesicles abolishes chromosome binding, and purified LBR binds directly to chromatin fragments and decorates chromosome surfaces.","method":"In vitro NE vesicle reconstitution; immunodepletion; direct chromatin binding assay with purified LBR","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution and immunodepletion with purified components establishing direct chromatin binding","pmids":["9003786"],"is_preprint":false},{"year":1994,"finding":"When human lamin B and chicken LBR are co-expressed in yeast, LBR integrates into membranes (resistant to 8 M urea extraction) and induces formation of membrane stacks. Lamin B co-localizes with LBR in these stacks and in the yeast nuclear envelope, consistent with direct protein–protein interaction in vivo.","method":"Heterologous expression in S. cerevisiae; immunofluorescence; immunoelectron microscopy; cell fractionation; urea extraction","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IEM, IFL, fractionation) with functional consequence (membrane stack induction)","pmids":["7937849"],"is_preprint":false},{"year":2001,"finding":"HP1 forms a quaternary complex with LBR and histone H3/H4 at the inner nuclear membrane. H3/H4 oligomers mediate the bridge between LBR and HP1 (LBR and HP1 do not interact directly). Hyperacetylation of H3/H4 by recombinant CBP strongly inhibits HP1 and LBR binding to core histones.","method":"In vitro binding assay with purified components; recombinant CBP acetylation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with purified components, acetylation-dependence tested biochemically, single lab","pmids":["11571267"],"is_preprint":false},{"year":2000,"finding":"The LBR amino-terminal domain binds linker DNA but not the nucleosome core particle. Binding is saturable, high-affinity (Kd ~4 nM), sequence-independent, and enhanced by DNA curvature and supercoiling.","method":"In vitro binding assay with recombinant GST-LBR-NT and reconstituted nucleosomes/DNA fragments; titration and competition studies","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative in vitro reconstitution with purified components and Kd determination, single lab","pmids":["10828963"],"is_preprint":false},{"year":2000,"finding":"During nuclear envelope reassembly in telophase, LBR-GFP is recruited to reforming nuclear membranes around chromosomes within ~5 minutes after anaphase onset, prior to recovery of nuclear import activity (~8 min). LBR and emerin initially accumulate at distinct chromosome locations before becoming uniformly distributed.","method":"Live fluorescence imaging of LBR-GFP in HeLa cells; time-lapse microscopy correlated with nuclear import function","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional readout (import activity), single lab, two orthogonal readouts","pmids":["10671368"],"is_preprint":false},{"year":1998,"finding":"The amino-terminal nucleoplasmic domain of LBR is specifically cleaved during apoptosis generating an ~20 kDa soluble fragment. LBR cleavage occurs as a late apoptotic event subsequent to lamin B cleavage, and LBR phosphorylation during apoptosis resembles interphase phosphorylation rather than mitotic phosphorylation.","method":"Immunoblotting of apoptotic cell lysates; comparison of cleavage timing with lamin B; phosphorylation analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with defined temporal ordering, single lab","pmids":["9570761"],"is_preprint":false},{"year":1999,"finding":"SRPK1 phosphorylates LBR on the same RS-repeat residues and with similar kinetics as the previously purified LBR-associated kinase from turkey erythrocyte nuclear envelopes, and these sites correspond to in vivo phosphorylation sites.","method":"In vitro kinase assay with synthetic LBR peptides and recombinant SRPK1; comparison to LBR-associated kinase; in vivo phosphorylation mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with defined substrates and in vivo validation, single lab","pmids":["10049757"],"is_preprint":false},{"year":2013,"finding":"LBR and lamin A/C provide sequential, mechanistically distinct heterochromatin tethers to the nuclear envelope during differentiation. Loss of LBR causes loss of peripheral heterochromatin in early differentiation stages, whereas lamin A/C loss affects later stages. Loss of both leads to full heterochromatin inversion (relocalization to nuclear interior). LBR-dependent and lamin-A-dependent tethers have opposite effects on muscle gene expression.","method":"Genetic mouse models (Lbr and Lmna single and double mutants); immunofluorescence; transcriptome analysis of myoblasts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double mutants, orthogonal readouts (imaging + transcriptomics), replicated across cell types and species","pmids":["23374351"],"is_preprint":false},{"year":2016,"finding":"Depletion of ELYS (a nuclear pore complex component) promotes LBR phosphorylation at CDK and SRPK1/2 sites, causing LBR mislocalization from the INM. Protein phosphatase 1 (PP1) counterbalances these phosphorylation events; PP1 depletion phenocopies ELYS depletion and mislocalizes LBR.","method":"siRNA depletion of ELYS and PP1 in cells; phosphorylation analysis by immunoblot; immunofluorescence localization of LBR","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via depletion, phosphorylation biochemistry, single lab, two orthogonal approaches","pmids":["27802161"],"is_preprint":false},{"year":2020,"finding":"LBR possesses Δ-14 sterol C14-reductase activity and is the constitutively active C14-sterol reductase (unlike its paralog DHCR14, which is rapidly turned over). LBR protein levels are stable under cholesterol-loading conditions that trigger rapid proteasomal degradation of DHCR14.","method":"Epitope-tagged stable expression in CHO-7 cells; cholesterol and sterol loading; proteasome inhibitor assays; sterol reductase activity measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity comparison with defined substrates and inhibitors, single lab","pmids":["31911440"],"is_preprint":false},{"year":2017,"finding":"LBR's diffusional mobility along the nuclear envelope is regionally variable, consistent with discrete LBR microdomains. Carboxy-terminally truncated LBR mutants retaining only the first four TM domains are hyper-mobile. The full-length protein's dynamics depend on long-range interactions between TM domain loops and the amino-terminal region.","method":"FRAP (fluorescence recovery after photobleaching) of LBR-GFP variants; structure–function analysis with truncation mutants","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP with systematic truncation mutants, single lab","pmids":["28118363"],"is_preprint":false},{"year":2026,"finding":"Lamin B1 or B2 expression is sufficient to anchor LBR at the nuclear envelope, whereas lamin A expression increases LBR lateral mobility and displaces it from the NE to the ER. This lamin A-induced displacement is mediated by phosphorylation of LBR and is recapitulated by lamin A overexpression in wild-type MEFs.","method":"Triple lamin knockout MEFs with reconstitution of individual lamin isoforms; FRAP; immunofluorescence; phosphorylation analysis","journal":"Nucleus (Austin, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic reconstitution in defined triple-KO background, multiple lamin isoforms tested, FRAP + imaging + biochemistry in one study","pmids":["42153377"],"is_preprint":false},{"year":2025,"finding":"cTAGE5/MEA6 physically interacts with LBR at ER structures (not only ER exit sites). Loss of cTAGE5 disrupts LBR localization from the INM, causing LBR retention and instability in the ER, leading to abnormal nuclear morphology and cellular senescence via P53/P21 pathway activation.","method":"Co-IP (cTAGE5–LBR interaction); conditional cTAGE5 knockout in mice/MEFs; immunofluorescence of LBR localization; senescence assays","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional KO with defined pathway readout (P53/P21), single lab","pmids":["40739853"],"is_preprint":false},{"year":2025,"finding":"LBR is a substrate of the GSK3β/FBW7-mediated proteasome degradation pathway. The disease-associated C337W mutation enhances LBR's interaction with FBW7, promoting its proteasomal degradation. Wild-type (but not C337W mutant) LBR is stabilized by WNT3A-mediated inactivation of GSK3β/FBW7, and LBR participates in WNT3A-activated Wnt signaling through cholesterol synthesis.","method":"Co-IP (LBR–FBW7 interaction); proteasome inhibitor assays; siRNA knockdown of LBR; cholesterol supplementation rescue; osteogenic differentiation assay (MC3T3-E1 cells)","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, functional rescue with cholesterol, single lab","pmids":["40355051"],"is_preprint":false},{"year":2026,"finding":"LBR and LAP2 are key factors for peripheral heterochromatin positioning in both differentiated and pluripotent mammalian cells. Long-term co-depletion of LBR and LAP2 causes global heterochromatin detachment from the NE, repositioning to the nuclear interior, reduction in H3K27me3, massive gene deregulation, activation of antiviral innate immunity, and defects in cell fate determination.","method":"siRNA/shRNA depletion of LBR and LAP2; Hi-C chromatin organization; ChIP-seq for H3K27me3; RNA-seq; cell differentiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genome-wide and functional methods, double depletion epistasis, functional cell fate consequences","pmids":["41735607"],"is_preprint":false},{"year":2024,"finding":"TOP2B depletion affects genome interactions with LBR more than with lamins. LBR depletion phenocopies TOP2B depletion effects on LAD/iLAD partitioning, and co-depletion of TOP2B and LBR causes partial LAD/iLAD inversion resembling oncogene-induced senescence, indicating complementary roles in organizing the genome at the nuclear lamina.","method":"ChIP-seq; DamID; siRNA depletion of LBR and/or TOP2B; genome partitioning analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via co-depletion with genome-wide readout, preprint, single lab","pmids":["bio_10.1101_2024.10.01.616012"],"is_preprint":true},{"year":2024,"finding":"Removal of three nuclear lamins and LBR in mouse ESCs causes heterochromatin detachment from the nuclear periphery, with loss of H3K9me2-gene repression and transposon silencing, and failure to differentiate into epiblast-like cells, establishing that the nuclear periphery controls the repressive capacity of H3K9me2 heterochromatin to shape cell fate.","method":"CRISPR/Cas9 quadruple knockout (3 lamins + LBR) in mESCs; immunofluorescence; H3K9me2 ChIP-seq; RNA-seq; differentiation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with genome-wide epigenomic and transcriptomic readouts, preprint, single lab","pmids":["bio_10.1101_2024.07.08.602542"],"is_preprint":true}],"current_model":"LBR is an inner nuclear membrane protein whose nucleoplasmic amino-terminal domain directly binds lamin B, linker DNA (Kd ~4 nM), and a histone H3/H4-mediated quaternary complex with HP1 (via its chromo shadow domain), thereby tethering peripheral heterochromatin to the nuclear envelope; its eight-TM-segment carboxyl domain harbors sterol C14-reductase activity essential for cholesterol biosynthesis; LBR is anchored at the INM by B-type lamins and displaced by lamin A-induced phosphorylation (countered by PP1 and modulated by ELYS), and is regulated post-translationally by SRPK1/2-mediated RS-domain phosphorylation and GSK3β/FBW7-mediated proteasomal degradation; loss of LBR (together with LAP2 or lamins) detaches heterochromatin from the nuclear periphery, reduces H3K27me3 and H3K9me2 repression, and impairs cell fate transitions, while its cleavage by an apoptosis-associated protease represents a late execution step linking nuclear architecture to programmed cell death."},"narrative":{"mechanistic_narrative":"LBR is an integral protein of the inner nuclear membrane (INM) that serves as a principal tether linking peripheral heterochromatin to the nuclear envelope and, through its membrane-embedded domain, contributes to sterol biosynthesis [PMID:8157662, PMID:9003786, PMID:31911440]. Its nucleoplasmic amino-terminal domain directly binds lamin B and binds double-stranded DNA in a sequence-independent manner, with a Ser-Arg-rich stretch (aa 71–100) required for DNA binding [PMID:8157662]; biochemically this domain engages linker DNA but not the nucleosome core with high affinity (Kd ~4 nM) and contacts HP1 indirectly through a histone H3/H4-bridged quaternary complex that is disrupted by histone hyperacetylation [PMID:11571267, PMID:10828963]. Through these contacts LBR is the principal chromatin anchorage site at the reconstituted nuclear envelope, where its depletion abolishes chromosome binding [PMID:9003786]. In differentiating and pluripotent cells LBR acts together with lamin A/C and LAP2 as sequential, mechanistically distinct heterochromatin tethers; loss of LBR (especially combined with LAP2 or lamins) detaches heterochromatin from the periphery, reduces H3K27me3 and H3K9me2 repression, deregulates genes, and impairs cell fate transitions [PMID:23374351, PMID:41735607]. LBR is anchored at the INM by B-type lamins and is displaced to the ER by lamin A through phosphorylation [PMID:42153377], with its INM residence further governed by ELYS/PP1-balanced phosphorylation and by ER factors such as cTAGE5 [PMID:27802161, PMID:40739853]. The carboxyl domain carries constitutively active Δ-14 sterol C14-reductase activity essential for cholesterol synthesis [PMID:31911440], and LBR stability is controlled by SRPK1-mediated RS-domain phosphorylation and GSK3β/FBW7-mediated proteasomal degradation [PMID:10049757, PMID:40355051]. During apoptosis the nucleoplasmic domain is cleaved as a late execution event subsequent to lamin B cleavage [PMID:9570761].","teleology":[{"year":1994,"claim":"Establishing LBR's domain architecture and its direct binding to lamin B and DNA defined how an INM protein could physically couple the nuclear lamina to chromatin.","evidence":"Recombinant fusion protein pulldown from nuclear extracts, nitrocellulose DNA-binding assay, and deletion mapping; corroborated by heterologous co-expression with lamin B in yeast","pmids":["8157662","7937849"],"confidence":"High","gaps":["Did not resolve the structural basis of lamin B recognition","DNA binding was sequence-independent, leaving genomic targeting unexplained"]},{"year":1996,"claim":"Demonstrating that LBR is the principal chromatin anchorage site at the NE established its functional, not merely correlative, role in tethering chromosomes.","evidence":"In vitro NE vesicle reconstitution with immunodepletion and direct chromatin binding by purified LBR","pmids":["9003786"],"confidence":"High","gaps":["Did not identify the chromatin features (histone marks vs DNA) recognized in vivo","Performed in reconstituted vesicles rather than intact nuclei"]},{"year":2001,"claim":"Resolving the LBR–HP1 connection as an indirect, histone H3/H4-bridged quaternary complex sensitive to acetylation linked LBR tethering to chromatin modification state.","evidence":"In vitro binding with purified components plus recombinant CBP-mediated histone acetylation; HP1 chromo shadow domain mapping by two-hybrid and GST pulldown","pmids":["11571267","9169472"],"confidence":"High","gaps":["Did not establish stoichiometry of the quaternary complex in vivo","Did not test which HP1 isoform predominates at the INM"]},{"year":2000,"claim":"Quantifying high-affinity (Kd ~4 nM) LBR binding to linker DNA but not nucleosome cores defined the molecular preference underlying its chromatin contact.","evidence":"In vitro titration and competition with recombinant GST-LBR-NT and reconstituted nucleosomes/DNA","pmids":["10828963"],"confidence":"High","gaps":["Sequence-independence leaves the basis of genomic locus selectivity unexplained","Did not address competition with lamin B or HP1 for the same domain"]},{"year":1998,"claim":"Mapping LBR cleavage as a late apoptotic event ordered nuclear envelope disassembly relative to lamin B cleavage.","evidence":"Immunoblotting of apoptotic lysates with temporal comparison to lamin B and phosphorylation analysis","pmids":["9570761"],"confidence":"Medium","gaps":["Did not identify the responsible protease","Functional consequence of the soluble ~20 kDa fragment unknown"]},{"year":1999,"claim":"Identifying SRPK1 as the kinase phosphorylating LBR's RS repeats at in vivo sites established a defined regulatory input to LBR.","evidence":"In vitro kinase assay with synthetic LBR peptides and recombinant SRPK1, with in vivo phosphosite mapping","pmids":["10049757"],"confidence":"Medium","gaps":["Did not establish how RS-domain phosphorylation alters LBR binding or localization","Single lab, in vitro substrate"]},{"year":2000,"claim":"Live imaging of LBR-GFP recruitment to chromosomes within ~5 min of anaphase, before nuclear import recovery, positioned LBR early in NE reassembly.","evidence":"Time-lapse fluorescence imaging of LBR-GFP in HeLa cells correlated with import function","pmids":["10671368"],"confidence":"Medium","gaps":["Did not define the targeting signal driving early recruitment","Single cell type"]},{"year":2013,"claim":"Genetic dissection in mice revealed LBR and lamin A/C as sequential, mechanistically distinct heterochromatin tethers acting at different differentiation stages.","evidence":"Lbr and Lmna single/double mutant mice with immunofluorescence and myoblast transcriptomics","pmids":["23374351"],"confidence":"High","gaps":["Did not resolve why the two tethers have opposite effects on muscle gene expression","Molecular trigger for the LBR-to-lamin-A switch unknown"]},{"year":2016,"claim":"Showing that ELYS and PP1 counterbalance LBR phosphorylation at CDK/SRPK1/2 sites linked LBR INM retention to a phosphorylation/dephosphorylation switch.","evidence":"siRNA depletion of ELYS and PP1 with phosphorylation immunoblots and LBR localization imaging","pmids":["27802161"],"confidence":"Medium","gaps":["Did not establish whether ELYS acts directly or via altered kinase access","Single lab"]},{"year":2017,"claim":"FRAP analysis demonstrated regionally variable LBR mobility and discrete microdomains dependent on TM-loop/N-terminal long-range interactions, revealing intramolecular control of dynamics.","evidence":"FRAP of LBR-GFP truncation variants with structure–function analysis","pmids":["28118363"],"confidence":"Medium","gaps":["Did not define the molecular partners constraining microdomain mobility","Microdomain function not established"]},{"year":2020,"claim":"Assigning constitutively active Δ-14 sterol C14-reductase activity to LBR, contrasting its stability with the rapidly degraded paralog DHCR14, defined its enzymatic role in cholesterol synthesis.","evidence":"Epitope-tagged stable expression in CHO-7 cells with sterol loading, proteasome inhibition, and reductase activity assay","pmids":["31911440"],"confidence":"Medium","gaps":["Did not connect catalytic activity to heterochromatin-tethering function","Single lab"]},{"year":2025,"claim":"Defining GSK3β/FBW7-mediated proteasomal degradation of LBR, enhanced by the disease C337W mutation and antagonized by WNT3A, linked LBR turnover to Wnt signaling and cholesterol synthesis.","evidence":"Co-IP of LBR–FBW7, proteasome inhibitor and cholesterol-rescue assays, and osteogenic differentiation in MC3T3-E1 cells","pmids":["40355051"],"confidence":"Medium","gaps":["Single Co-IP-based interaction without structural detail","Disease causality of C337W not formally established in this entry"]},{"year":2025,"claim":"Identifying cTAGE5/MEA6 as an ER-associated LBR interactor whose loss destabilizes LBR and triggers P53/P21 senescence connected ER trafficking to LBR INM residence and aging phenotypes.","evidence":"Co-IP, conditional cTAGE5 knockout in mice/MEFs, LBR localization imaging, and senescence assays","pmids":["40739853"],"confidence":"Medium","gaps":["Mechanism of cTAGE5-dependent LBR delivery to the INM unresolved","Single lab"]},{"year":2026,"claim":"Reconstitution in triple-lamin-knockout MEFs established that B-type lamins anchor LBR while lamin A displaces it via phosphorylation, defining isoform-specific control of LBR localization.","evidence":"Triple lamin KO MEFs reconstituted with individual lamin isoforms, FRAP, immunofluorescence, and phosphorylation analysis","pmids":["42153377"],"confidence":"High","gaps":["Did not identify the kinase mediating lamin-A-induced LBR phosphorylation","Functional consequence of LBR displacement for heterochromatin not assessed here"]},{"year":2026,"claim":"Co-depletion of LBR and LAP2 across differentiated and pluripotent cells established their combined necessity for peripheral heterochromatin positioning and proper cell fate, with detachment activating antiviral innate immunity.","evidence":"siRNA/shRNA co-depletion with Hi-C, H3K27me3 ChIP-seq, RNA-seq, and differentiation assays","pmids":["41735607"],"confidence":"High","gaps":["Did not separate direct tethering from downstream transcriptional effects","Mechanism coupling detachment to innate immune activation unresolved"]},{"year":null,"claim":"It remains unresolved how LBR's two functions — heterochromatin tethering and sterol C14-reductase catalysis — are coordinated, and which kinases and recruitment mechanisms direct LBR to specific genomic loci.","evidence":"No single study in the corpus integrates the enzymatic and chromatin-anchoring roles or defines locus-specific targeting","pmids":[],"confidence":"Low","gaps":["No structure of full-length LBR with chromatin","Kinase responsible for lamin-A-induced displacement unidentified","Basis of genomic locus selectivity unknown given sequence-independent DNA binding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,5]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9,16]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,9,16]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[13,14]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,18]}],"complexes":["LBR–lamin B–histone H3/H4–HP1 heterochromatin tether"],"partners":["LMNB1","LMNB2","CBX5","LMNA","TMEM168","FBXW7","AHCTF1","TMP21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14739","full_name":"Delta(14)-sterol reductase LBR","aliases":["3-beta-hydroxysterol Delta (14)-reductase","C-14 sterol reductase","C14SR","Integral nuclear envelope inner membrane protein","LMN2R","Lamin-B receptor","Sterol C14-reductase"],"length_aa":615,"mass_kda":70.7,"function":"Catalyzes the reduction of the C14-unsaturated bond of lanosterol, as part of the metabolic pathway leading to cholesterol biosynthesis (PubMed:12618959, PubMed:16784888, PubMed:21327084, PubMed:27336722, PubMed:9630650). Plays a critical role in myeloid cell cholesterol biosynthesis which is essential to both myeloid cell growth and functional maturation (By similarity). Mediates the activation of NADPH oxidases, perhaps by maintaining critical levels of cholesterol required for membrane lipid raft formation during neutrophil differentiation (By similarity). Anchors the lamina and the heterochromatin to the inner nuclear membrane (PubMed:10828963)","subcellular_location":"Nucleus inner membrane; Endoplasmic reticulum membrane; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14739/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LBR","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000143815","cell_line_id":"CID001906","localizations":[{"compartment":"nuclear_membrane","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"MBOAT7","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CBX1","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"C1QBP","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"LSM14A","stoichiometry":0.2},{"gene":"LSM14B","stoichiometry":0.2},{"gene":"MMGT1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001906","total_profiled":1310},"omim":[{"mim_id":"621234","title":"ICHAD SYNDROME; ICHAD","url":"https://www.omim.org/entry/621234"},{"mim_id":"620075","title":"NEURODEVELOPMENTAL DISORDER WITH FACIAL DYSMORPHISM, ABSENT LANGUAGE, AND PSEUDO-PELGER-HUET ANOMALY; NEDFLPH","url":"https://www.omim.org/entry/620075"},{"mim_id":"618019","title":"RHIZOMELIC SKELETAL DYSPLASIA WITH OR WITHOUT PELGER-HUET ANOMALY; SKPHA","url":"https://www.omim.org/entry/618019"},{"mim_id":"617858","title":"PROTEASOME INHIBITOR SUBUNIT 1; PSMF1","url":"https://www.omim.org/entry/617858"},{"mim_id":"617676","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 3; PSMD3","url":"https://www.omim.org/entry/617676"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LBR"},"hgnc":{"alias_symbol":["DHCR14B","TDRD18"],"prev_symbol":[]},"alphafold":{"accession":"Q14739","domains":[{"cath_id":"2.30.30.140","chopping":"11-60","consensus_level":"high","plddt":85.1088,"start":11,"end":60},{"cath_id":"-","chopping":"209-482","consensus_level":"medium","plddt":91.3895,"start":209,"end":482},{"cath_id":"-","chopping":"484-615","consensus_level":"medium","plddt":91.0846,"start":484,"end":615}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14739","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14739-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14739-F1-predicted_aligned_error_v6.png","plddt_mean":76.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LBR","jax_strain_url":"https://www.jax.org/strain/search?query=LBR"},"sequence":{"accession":"Q14739","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14739.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14739/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14739"}},"corpus_meta":[{"pmid":"23374351","id":"PMC_23374351","title":"LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23374351","citation_count":634,"is_preprint":false},{"pmid":"9169472","id":"PMC_9169472","title":"Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9169472","citation_count":302,"is_preprint":false},{"pmid":"8157662","id":"PMC_8157662","title":"Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8157662","citation_count":194,"is_preprint":false},{"pmid":"10671368","id":"PMC_10671368","title":"Live fluorescence imaging reveals early recruitment of emerin, LBR, RanBP2, and Nup153 to reforming functional nuclear envelopes.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10671368","citation_count":160,"is_preprint":false},{"pmid":"11571267","id":"PMC_11571267","title":"Histones H3/H4 form a tight complex with the inner nuclear membrane protein LBR and heterochromatin protein 1.","date":"2001","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/11571267","citation_count":154,"is_preprint":false},{"pmid":"9003786","id":"PMC_9003786","title":"The lamin B receptor (LBR) provides essential chromatin docking sites at the nuclear envelope.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9003786","citation_count":135,"is_preprint":false},{"pmid":"8838815","id":"PMC_8838815","title":"Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ 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The amino-terminal domain directly binds lamin B (precipitated from nuclear extracts) and binds double-stranded DNA in a sequence-independent manner; the stretch between amino acids 71–100 (Ser-Arg-rich) is necessary for DNA binding.\",\n      \"method\": \"Recombinant fusion protein pulldown from nuclear extracts; nitrocellulose DNA-binding assay; deletion mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding reconstitution with deletion mutagenesis, replicated across binding partners (lamin B and DNA) in same study\",\n      \"pmids\": [\"8157662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"HP1-type chromodomain proteins interact with LBR via their chromo shadow domain (not the chromodomain). The interaction maps to a portion of the second globular domain of LBR's nucleoplasmic region. HP1–LBR binding is detectable both in vitro and in the yeast two-hybrid assay.\",\n      \"method\": \"Yeast two-hybrid assay; in vitro binding (GST pulldown); domain deletion mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two orthogonal methods (yeast two-hybrid + in vitro binding) with domain mapping in same study\",\n      \"pmids\": [\"9169472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"LBR is the principal chromatin anchorage site at the nuclear envelope. Immunodepletion or chemical extraction of LBR from in vitro reconstituted nuclear envelope vesicles abolishes chromosome binding, and purified LBR binds directly to chromatin fragments and decorates chromosome surfaces.\",\n      \"method\": \"In vitro NE vesicle reconstitution; immunodepletion; direct chromatin binding assay with purified LBR\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution and immunodepletion with purified components establishing direct chromatin binding\",\n      \"pmids\": [\"9003786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"When human lamin B and chicken LBR are co-expressed in yeast, LBR integrates into membranes (resistant to 8 M urea extraction) and induces formation of membrane stacks. Lamin B co-localizes with LBR in these stacks and in the yeast nuclear envelope, consistent with direct protein–protein interaction in vivo.\",\n      \"method\": \"Heterologous expression in S. cerevisiae; immunofluorescence; immunoelectron microscopy; cell fractionation; urea extraction\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IEM, IFL, fractionation) with functional consequence (membrane stack induction)\",\n      \"pmids\": [\"7937849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HP1 forms a quaternary complex with LBR and histone H3/H4 at the inner nuclear membrane. H3/H4 oligomers mediate the bridge between LBR and HP1 (LBR and HP1 do not interact directly). Hyperacetylation of H3/H4 by recombinant CBP strongly inhibits HP1 and LBR binding to core histones.\",\n      \"method\": \"In vitro binding assay with purified components; recombinant CBP acetylation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with purified components, acetylation-dependence tested biochemically, single lab\",\n      \"pmids\": [\"11571267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The LBR amino-terminal domain binds linker DNA but not the nucleosome core particle. Binding is saturable, high-affinity (Kd ~4 nM), sequence-independent, and enhanced by DNA curvature and supercoiling.\",\n      \"method\": \"In vitro binding assay with recombinant GST-LBR-NT and reconstituted nucleosomes/DNA fragments; titration and competition studies\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative in vitro reconstitution with purified components and Kd determination, single lab\",\n      \"pmids\": [\"10828963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"During nuclear envelope reassembly in telophase, LBR-GFP is recruited to reforming nuclear membranes around chromosomes within ~5 minutes after anaphase onset, prior to recovery of nuclear import activity (~8 min). LBR and emerin initially accumulate at distinct chromosome locations before becoming uniformly distributed.\",\n      \"method\": \"Live fluorescence imaging of LBR-GFP in HeLa cells; time-lapse microscopy correlated with nuclear import function\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional readout (import activity), single lab, two orthogonal readouts\",\n      \"pmids\": [\"10671368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The amino-terminal nucleoplasmic domain of LBR is specifically cleaved during apoptosis generating an ~20 kDa soluble fragment. LBR cleavage occurs as a late apoptotic event subsequent to lamin B cleavage, and LBR phosphorylation during apoptosis resembles interphase phosphorylation rather than mitotic phosphorylation.\",\n      \"method\": \"Immunoblotting of apoptotic cell lysates; comparison of cleavage timing with lamin B; phosphorylation analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with defined temporal ordering, single lab\",\n      \"pmids\": [\"9570761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SRPK1 phosphorylates LBR on the same RS-repeat residues and with similar kinetics as the previously purified LBR-associated kinase from turkey erythrocyte nuclear envelopes, and these sites correspond to in vivo phosphorylation sites.\",\n      \"method\": \"In vitro kinase assay with synthetic LBR peptides and recombinant SRPK1; comparison to LBR-associated kinase; in vivo phosphorylation mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with defined substrates and in vivo validation, single lab\",\n      \"pmids\": [\"10049757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LBR and lamin A/C provide sequential, mechanistically distinct heterochromatin tethers to the nuclear envelope during differentiation. Loss of LBR causes loss of peripheral heterochromatin in early differentiation stages, whereas lamin A/C loss affects later stages. Loss of both leads to full heterochromatin inversion (relocalization to nuclear interior). LBR-dependent and lamin-A-dependent tethers have opposite effects on muscle gene expression.\",\n      \"method\": \"Genetic mouse models (Lbr and Lmna single and double mutants); immunofluorescence; transcriptome analysis of myoblasts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double mutants, orthogonal readouts (imaging + transcriptomics), replicated across cell types and species\",\n      \"pmids\": [\"23374351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Depletion of ELYS (a nuclear pore complex component) promotes LBR phosphorylation at CDK and SRPK1/2 sites, causing LBR mislocalization from the INM. Protein phosphatase 1 (PP1) counterbalances these phosphorylation events; PP1 depletion phenocopies ELYS depletion and mislocalizes LBR.\",\n      \"method\": \"siRNA depletion of ELYS and PP1 in cells; phosphorylation analysis by immunoblot; immunofluorescence localization of LBR\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via depletion, phosphorylation biochemistry, single lab, two orthogonal approaches\",\n      \"pmids\": [\"27802161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LBR possesses Δ-14 sterol C14-reductase activity and is the constitutively active C14-sterol reductase (unlike its paralog DHCR14, which is rapidly turned over). LBR protein levels are stable under cholesterol-loading conditions that trigger rapid proteasomal degradation of DHCR14.\",\n      \"method\": \"Epitope-tagged stable expression in CHO-7 cells; cholesterol and sterol loading; proteasome inhibitor assays; sterol reductase activity measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity comparison with defined substrates and inhibitors, single lab\",\n      \"pmids\": [\"31911440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LBR's diffusional mobility along the nuclear envelope is regionally variable, consistent with discrete LBR microdomains. Carboxy-terminally truncated LBR mutants retaining only the first four TM domains are hyper-mobile. The full-length protein's dynamics depend on long-range interactions between TM domain loops and the amino-terminal region.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching) of LBR-GFP variants; structure–function analysis with truncation mutants\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP with systematic truncation mutants, single lab\",\n      \"pmids\": [\"28118363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Lamin B1 or B2 expression is sufficient to anchor LBR at the nuclear envelope, whereas lamin A expression increases LBR lateral mobility and displaces it from the NE to the ER. This lamin A-induced displacement is mediated by phosphorylation of LBR and is recapitulated by lamin A overexpression in wild-type MEFs.\",\n      \"method\": \"Triple lamin knockout MEFs with reconstitution of individual lamin isoforms; FRAP; immunofluorescence; phosphorylation analysis\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic reconstitution in defined triple-KO background, multiple lamin isoforms tested, FRAP + imaging + biochemistry in one study\",\n      \"pmids\": [\"42153377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"cTAGE5/MEA6 physically interacts with LBR at ER structures (not only ER exit sites). Loss of cTAGE5 disrupts LBR localization from the INM, causing LBR retention and instability in the ER, leading to abnormal nuclear morphology and cellular senescence via P53/P21 pathway activation.\",\n      \"method\": \"Co-IP (cTAGE5–LBR interaction); conditional cTAGE5 knockout in mice/MEFs; immunofluorescence of LBR localization; senescence assays\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional KO with defined pathway readout (P53/P21), single lab\",\n      \"pmids\": [\"40739853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LBR is a substrate of the GSK3β/FBW7-mediated proteasome degradation pathway. The disease-associated C337W mutation enhances LBR's interaction with FBW7, promoting its proteasomal degradation. Wild-type (but not C337W mutant) LBR is stabilized by WNT3A-mediated inactivation of GSK3β/FBW7, and LBR participates in WNT3A-activated Wnt signaling through cholesterol synthesis.\",\n      \"method\": \"Co-IP (LBR–FBW7 interaction); proteasome inhibitor assays; siRNA knockdown of LBR; cholesterol supplementation rescue; osteogenic differentiation assay (MC3T3-E1 cells)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, functional rescue with cholesterol, single lab\",\n      \"pmids\": [\"40355051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LBR and LAP2 are key factors for peripheral heterochromatin positioning in both differentiated and pluripotent mammalian cells. Long-term co-depletion of LBR and LAP2 causes global heterochromatin detachment from the NE, repositioning to the nuclear interior, reduction in H3K27me3, massive gene deregulation, activation of antiviral innate immunity, and defects in cell fate determination.\",\n      \"method\": \"siRNA/shRNA depletion of LBR and LAP2; Hi-C chromatin organization; ChIP-seq for H3K27me3; RNA-seq; cell differentiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genome-wide and functional methods, double depletion epistasis, functional cell fate consequences\",\n      \"pmids\": [\"41735607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TOP2B depletion affects genome interactions with LBR more than with lamins. LBR depletion phenocopies TOP2B depletion effects on LAD/iLAD partitioning, and co-depletion of TOP2B and LBR causes partial LAD/iLAD inversion resembling oncogene-induced senescence, indicating complementary roles in organizing the genome at the nuclear lamina.\",\n      \"method\": \"ChIP-seq; DamID; siRNA depletion of LBR and/or TOP2B; genome partitioning analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via co-depletion with genome-wide readout, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.01.616012\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Removal of three nuclear lamins and LBR in mouse ESCs causes heterochromatin detachment from the nuclear periphery, with loss of H3K9me2-gene repression and transposon silencing, and failure to differentiate into epiblast-like cells, establishing that the nuclear periphery controls the repressive capacity of H3K9me2 heterochromatin to shape cell fate.\",\n      \"method\": \"CRISPR/Cas9 quadruple knockout (3 lamins + LBR) in mESCs; immunofluorescence; H3K9me2 ChIP-seq; RNA-seq; differentiation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with genome-wide epigenomic and transcriptomic readouts, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.07.08.602542\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LBR is an inner nuclear membrane protein whose nucleoplasmic amino-terminal domain directly binds lamin B, linker DNA (Kd ~4 nM), and a histone H3/H4-mediated quaternary complex with HP1 (via its chromo shadow domain), thereby tethering peripheral heterochromatin to the nuclear envelope; its eight-TM-segment carboxyl domain harbors sterol C14-reductase activity essential for cholesterol biosynthesis; LBR is anchored at the INM by B-type lamins and displaced by lamin A-induced phosphorylation (countered by PP1 and modulated by ELYS), and is regulated post-translationally by SRPK1/2-mediated RS-domain phosphorylation and GSK3β/FBW7-mediated proteasomal degradation; loss of LBR (together with LAP2 or lamins) detaches heterochromatin from the nuclear periphery, reduces H3K27me3 and H3K9me2 repression, and impairs cell fate transitions, while its cleavage by an apoptosis-associated protease represents a late execution step linking nuclear architecture to programmed cell death.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LBR is an integral protein of the inner nuclear membrane (INM) that serves as a principal tether linking peripheral heterochromatin to the nuclear envelope and, through its membrane-embedded domain, contributes to sterol biosynthesis [#0, #2, #11]. Its nucleoplasmic amino-terminal domain directly binds lamin B and binds double-stranded DNA in a sequence-independent manner, with a Ser-Arg-rich stretch (aa 71–100) required for DNA binding [#0]; biochemically this domain engages linker DNA but not the nucleosome core with high affinity (Kd ~4 nM) and contacts HP1 indirectly through a histone H3/H4-bridged quaternary complex that is disrupted by histone hyperacetylation [#4, #5]. Through these contacts LBR is the principal chromatin anchorage site at the reconstituted nuclear envelope, where its depletion abolishes chromosome binding [#2]. In differentiating and pluripotent cells LBR acts together with lamin A/C and LAP2 as sequential, mechanistically distinct heterochromatin tethers; loss of LBR (especially combined with LAP2 or lamins) detaches heterochromatin from the periphery, reduces H3K27me3 and H3K9me2 repression, deregulates genes, and impairs cell fate transitions [#9, #16]. LBR is anchored at the INM by B-type lamins and is displaced to the ER by lamin A through phosphorylation [#13], with its INM residence further governed by ELYS/PP1-balanced phosphorylation and by ER factors such as cTAGE5 [#10, #14]. The carboxyl domain carries constitutively active Δ-14 sterol C14-reductase activity essential for cholesterol synthesis [#11], and LBR stability is controlled by SRPK1-mediated RS-domain phosphorylation and GSK3β/FBW7-mediated proteasomal degradation [#8, #15]. During apoptosis the nucleoplasmic domain is cleaved as a late execution event subsequent to lamin B cleavage [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing LBR's domain architecture and its direct binding to lamin B and DNA defined how an INM protein could physically couple the nuclear lamina to chromatin.\",\n      \"evidence\": \"Recombinant fusion protein pulldown from nuclear extracts, nitrocellulose DNA-binding assay, and deletion mapping; corroborated by heterologous co-expression with lamin B in yeast\",\n      \"pmids\": [\"8157662\", \"7937849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of lamin B recognition\", \"DNA binding was sequence-independent, leaving genomic targeting unexplained\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that LBR is the principal chromatin anchorage site at the NE established its functional, not merely correlative, role in tethering chromosomes.\",\n      \"evidence\": \"In vitro NE vesicle reconstitution with immunodepletion and direct chromatin binding by purified LBR\",\n      \"pmids\": [\"9003786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chromatin features (histone marks vs DNA) recognized in vivo\", \"Performed in reconstituted vesicles rather than intact nuclei\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolving the LBR–HP1 connection as an indirect, histone H3/H4-bridged quaternary complex sensitive to acetylation linked LBR tethering to chromatin modification state.\",\n      \"evidence\": \"In vitro binding with purified components plus recombinant CBP-mediated histone acetylation; HP1 chromo shadow domain mapping by two-hybrid and GST pulldown\",\n      \"pmids\": [\"11571267\", \"9169472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish stoichiometry of the quaternary complex in vivo\", \"Did not test which HP1 isoform predominates at the INM\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Quantifying high-affinity (Kd ~4 nM) LBR binding to linker DNA but not nucleosome cores defined the molecular preference underlying its chromatin contact.\",\n      \"evidence\": \"In vitro titration and competition with recombinant GST-LBR-NT and reconstituted nucleosomes/DNA\",\n      \"pmids\": [\"10828963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence-independence leaves the basis of genomic locus selectivity unexplained\", \"Did not address competition with lamin B or HP1 for the same domain\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping LBR cleavage as a late apoptotic event ordered nuclear envelope disassembly relative to lamin B cleavage.\",\n      \"evidence\": \"Immunoblotting of apoptotic lysates with temporal comparison to lamin B and phosphorylation analysis\",\n      \"pmids\": [\"9570761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the responsible protease\", \"Functional consequence of the soluble ~20 kDa fragment unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying SRPK1 as the kinase phosphorylating LBR's RS repeats at in vivo sites established a defined regulatory input to LBR.\",\n      \"evidence\": \"In vitro kinase assay with synthetic LBR peptides and recombinant SRPK1, with in vivo phosphosite mapping\",\n      \"pmids\": [\"10049757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how RS-domain phosphorylation alters LBR binding or localization\", \"Single lab, in vitro substrate\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Live imaging of LBR-GFP recruitment to chromosomes within ~5 min of anaphase, before nuclear import recovery, positioned LBR early in NE reassembly.\",\n      \"evidence\": \"Time-lapse fluorescence imaging of LBR-GFP in HeLa cells correlated with import function\",\n      \"pmids\": [\"10671368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the targeting signal driving early recruitment\", \"Single cell type\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic dissection in mice revealed LBR and lamin A/C as sequential, mechanistically distinct heterochromatin tethers acting at different differentiation stages.\",\n      \"evidence\": \"Lbr and Lmna single/double mutant mice with immunofluorescence and myoblast transcriptomics\",\n      \"pmids\": [\"23374351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve why the two tethers have opposite effects on muscle gene expression\", \"Molecular trigger for the LBR-to-lamin-A switch unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that ELYS and PP1 counterbalance LBR phosphorylation at CDK/SRPK1/2 sites linked LBR INM retention to a phosphorylation/dephosphorylation switch.\",\n      \"evidence\": \"siRNA depletion of ELYS and PP1 with phosphorylation immunoblots and LBR localization imaging\",\n      \"pmids\": [\"27802161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether ELYS acts directly or via altered kinase access\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"FRAP analysis demonstrated regionally variable LBR mobility and discrete microdomains dependent on TM-loop/N-terminal long-range interactions, revealing intramolecular control of dynamics.\",\n      \"evidence\": \"FRAP of LBR-GFP truncation variants with structure–function analysis\",\n      \"pmids\": [\"28118363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular partners constraining microdomain mobility\", \"Microdomain function not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Assigning constitutively active Δ-14 sterol C14-reductase activity to LBR, contrasting its stability with the rapidly degraded paralog DHCR14, defined its enzymatic role in cholesterol synthesis.\",\n      \"evidence\": \"Epitope-tagged stable expression in CHO-7 cells with sterol loading, proteasome inhibition, and reductase activity assay\",\n      \"pmids\": [\"31911440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect catalytic activity to heterochromatin-tethering function\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining GSK3β/FBW7-mediated proteasomal degradation of LBR, enhanced by the disease C337W mutation and antagonized by WNT3A, linked LBR turnover to Wnt signaling and cholesterol synthesis.\",\n      \"evidence\": \"Co-IP of LBR–FBW7, proteasome inhibitor and cholesterol-rescue assays, and osteogenic differentiation in MC3T3-E1 cells\",\n      \"pmids\": [\"40355051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP-based interaction without structural detail\", \"Disease causality of C337W not formally established in this entry\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying cTAGE5/MEA6 as an ER-associated LBR interactor whose loss destabilizes LBR and triggers P53/P21 senescence connected ER trafficking to LBR INM residence and aging phenotypes.\",\n      \"evidence\": \"Co-IP, conditional cTAGE5 knockout in mice/MEFs, LBR localization imaging, and senescence assays\",\n      \"pmids\": [\"40739853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cTAGE5-dependent LBR delivery to the INM unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reconstitution in triple-lamin-knockout MEFs established that B-type lamins anchor LBR while lamin A displaces it via phosphorylation, defining isoform-specific control of LBR localization.\",\n      \"evidence\": \"Triple lamin KO MEFs reconstituted with individual lamin isoforms, FRAP, immunofluorescence, and phosphorylation analysis\",\n      \"pmids\": [\"42153377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the kinase mediating lamin-A-induced LBR phosphorylation\", \"Functional consequence of LBR displacement for heterochromatin not assessed here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Co-depletion of LBR and LAP2 across differentiated and pluripotent cells established their combined necessity for peripheral heterochromatin positioning and proper cell fate, with detachment activating antiviral innate immunity.\",\n      \"evidence\": \"siRNA/shRNA co-depletion with Hi-C, H3K27me3 ChIP-seq, RNA-seq, and differentiation assays\",\n      \"pmids\": [\"41735607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate direct tethering from downstream transcriptional effects\", \"Mechanism coupling detachment to innate immune activation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how LBR's two functions — heterochromatin tethering and sterol C14-reductase catalysis — are coordinated, and which kinases and recruitment mechanisms direct LBR to specific genomic loci.\",\n      \"evidence\": \"No single study in the corpus integrates the enzymatic and chromatin-anchoring roles or defines locus-specific targeting\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of full-length LBR with chromatin\", \"Kinase responsible for lamin-A-induced displacement unidentified\", \"Basis of genomic locus selectivity unknown given sequence-independent DNA binding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 9, 16]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 18]}\n    ],\n    \"complexes\": [\"LBR–lamin B–histone H3/H4–HP1 heterochromatin tether\"],\n    \"partners\": [\"LMNB1\", \"LMNB2\", \"CBX5\", \"LMNA\", \"TMEM168\", \"FBXW7\", \"AHCTF1\", \"TMP21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}