{"gene":"SUN1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2006,"finding":"SUN1 is an integral inner nuclear membrane protein whose N-terminal nucleoplasmic domain binds lamin A (but not type B lamins) in a detergent-resistant manner, while its C-terminal luminal SUN domain interacts with the KASH domains of nesprins 1 and 2, forming a physical bridge between the nuclear lamina and the cytoskeleton.","method":"Yeast two-hybrid screen, co-immunoprecipitation, detergent fractionation, dominant-negative overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays with domain mapping, independently confirmed by a second lab (PMID:16079285) the same year using orthogonal methods","pmids":["16648470","16079285"],"is_preprint":false},{"year":2005,"finding":"SUN1 is required for nuclear envelope localization of Nesprin-2; the conserved C-terminal PPPX motif of nesprin-1/2 directly interacts with a C-terminal region of SUN1, and knockdown of SUN1 or dominant-negative SUN1 fragments mislocalize Nesprin-2 from the nuclear envelope.","method":"Co-immunoprecipitation, dominant-negative overexpression, siRNA knockdown, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, DN mutants, RNAi) in single lab, replicated by PMID:16648470","pmids":["16079285"],"is_preprint":false},{"year":2007,"finding":"SUN1 (but not SUN2) is intimately associated with nuclear pore complexes (NPCs) as demonstrated by immunofluorescence and immunoelectron microscopy; SUN1 is a type II integral protein of the inner nuclear membrane and NPC association requires synergy of both nucleoplasmic and lumenal domains. Depletion of SUN1 by RNAi or overexpression of dominant-negative SUN1 fragments causes NPC clustering.","method":"Immunofluorescence, immunoelectron microscopy, RNAi depletion, topology analysis, dominant-negative overexpression","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal imaging and functional methods in single study, specific phenotype with domain mapping","pmids":["17724119"],"is_preprint":false},{"year":2007,"finding":"SUN1 at the inner nuclear membrane specifically associates with telomeres during meiotic prophase I (leptotene to diplotene stages); genetic disruption of Sun1 in mice prevents telomere attachment to the nuclear envelope, blocks efficient homolog pairing and synapsis, and causes massive apoptosis abolishing spermatogenesis and oogenesis.","method":"Mouse knockout, immunofluorescence, FISH, co-localization studies","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with defined cellular phenotypes and molecular readouts, replicated by multiple subsequent studies","pmids":["17543860"],"is_preprint":false},{"year":2008,"finding":"SUN1 forms highly immobile oligomeric complexes at the nuclear envelope; the C-terminal coiled-coil segment can form dimers and tetramers via self-association, involves interchain disulfide bonds, and supports heterophilic association with SUN2. Both perinuclear and nucleoplasmic SUN1 segments are required for NE immobility.","method":"Inverse FRAP, co-immunoprecipitation, biochemical cross-linking, site-directed mutagenesis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — FRAP with mutagenesis and biochemical oligomerization assays in a single rigorous study","pmids":["18845190"],"is_preprint":false},{"year":2009,"finding":"SUN1 and SUN2 function redundantly in anchoring myonuclei in skeletal muscle; Sun1 single knockout partially disrupts synaptic nuclear anchorage, Sun1/Sun2 double knockout disrupts both synaptic and nonsynaptic nuclear organization, and Syne-1/Nesprin-1 localization at the nuclear envelope is lost in double knockout muscle cells.","method":"Mouse knockout (single and double), immunofluorescence, gene dosage analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis with graded allele series and defined molecular readout (Nesprin-1 mislocalization)","pmids":["19509342"],"is_preprint":false},{"year":2006,"finding":"The N-terminal ~300 amino acids of human SUN1 (UNC84A) are crucial for nuclear envelope localization, whereas the conserved C-terminal SUN domain is not required. SUN1 localization and anchoring at the NE is not dependent on lamin proteins, as shown by RNAi knockdown of lamins combined with immunofluorescence and FRAP.","method":"RNAi knockdown, truncation mutants, immunofluorescence, FRAP","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mapping plus RNAi with FRAP, single lab","pmids":["16445915"],"is_preprint":false},{"year":2011,"finding":"SUN1 is required for interphase NPC assembly; it co-localizes with POM121 at forming pore assembly sites, and depletion of Sun1 specifically impairs interphase (but not post-mitotic) NPC assembly.","method":"RNAi depletion, live imaging, immunofluorescence, cell-cycle staging","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with cell-cycle-specific phenotype, single lab, orthogonal imaging methods","pmids":["21727197"],"is_preprint":false},{"year":2012,"finding":"Accumulation of SUN1 protein is a common pathogenic event in laminopathies: in Lmna−/− and progeroid LmnaΔ9 mice, Sun1 accumulates at the NE; additional loss of Sun1 in these backgrounds markedly reduces tissue pathologies and extends lifespan. In human HGPS fibroblasts, reducing SUN1 overaccumulation corrects nuclear defects and cellular senescence.","method":"Double-knockout mice, siRNA knockdown in human cells, histopathology, cell biology assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic rescue experiments in multiple mouse models plus human cell validation, published in Cell","pmids":["22541428"],"is_preprint":false},{"year":2012,"finding":"The germ-cell-specific KASH domain protein KASH5 localizes to telomeres from leptotene to diplotene stages and directly interacts with SUN1 via KASH-related sequences; KASH5 also interacts with the dynein-dynactin complex, connecting the telomere-associated SUN1 to cytoplasmic force-generating machinery for meiotic chromosome movement.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, mouse genetics","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction mapping combined with in vivo genetic loss-of-function, replicated by subsequent structural studies","pmids":["22826121"],"is_preprint":false},{"year":2012,"finding":"SUN1 and SUN2 play redundant roles in the DNA damage response; Sun1/Sun2 double-knockout MEFs show premature S-phase arrest, increased apoptosis, DNA damage, decreased perinuclear heterochromatin, and impaired activation of ATM and H2A.X. Biochemical screen identified interactions between SUN1/SUN2 and the DNA-PK complex.","method":"Double-knockout MEFs, flow cytometry, immunofluorescence, co-immunoprecipitation, Western blotting","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with molecular readouts and Co-IP interaction, single lab","pmids":["22863315"],"is_preprint":false},{"year":2010,"finding":"SUN1 and SUN2 form complexes with Syne-2/Nesprin-2 at the nuclear envelope and are required for interkinetic nuclear migration (INM) and photoreceptor cell migration in mouse retina; double Sun1/Sun2 knockout causes severe reduction of the outer nuclear layer, photoreceptor mislocalization, and retinal dysfunction. Nesprin-2 complexes with SUN1/2 to connect the nucleus with dynein/dynactin and kinesin motors during nuclear migrations.","method":"Mouse double knockout, immunofluorescence, ERG, co-immunoprecipitation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mouse double knockout with defined cellular phenotypes and Co-IP showing molecular complex","pmids":["21177258"],"is_preprint":false},{"year":2011,"finding":"Farnesylated prelamin A recruits SUN1 to the nuclear envelope during myoblast differentiation; impairment of prelamin A farnesylation alters SUN1 recruitment, and reduced prelamin A and SUN1 levels in EDMD myoblasts correlate with defective myonuclear positioning.","method":"Immunofluorescence, pharmacological inhibition of farnesylation, Western blotting, cell fractionation in human myoblasts","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with pharmacological perturbation, single lab","pmids":["21311568"],"is_preprint":false},{"year":2014,"finding":"Mitotic phosphorylation of SUN1 at serines 48 and 333 (by Cdk1) and serine 138 (by Plk1) loosens SUN1's interaction with nucleoplasmic binding partners lamin A/C, emerin, and short nesprin-2 isoforms during mitosis, while the C-terminal SUN1-KASH domain interaction with nesprin-2 is maintained. A triple phosphomimetic SUN1 mutant shows increased solubility and reduced NE retention.","method":"Mass spectrometry phosphosite identification, site-directed mutagenesis, co-immunoprecipitation, kinase assays, immunofluorescence","journal":"Nucleus (Austin, Tex.)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — kinase identification with mutagenesis, Co-IP, and solubility assays; multiple orthogonal methods in single study","pmids":["25482198"],"is_preprint":false},{"year":2014,"finding":"The dysregulated interaction between SUN1 and progerin (farnesylated mutant lamin A) occurs in the ER during post-mitotic nuclear envelope reformation; farnesylation of progerin enhances its SUN1 interaction, reduces SUN1 mobility, and promotes aberrant ER membrane recruitment of progerin, causing cumulative SUN1 accumulation over successive cell divisions. Two domains of full-length lamin A associate with SUN1, with the farnesylated CaaX motif having stronger affinity.","method":"Light and electron microscopy, co-immunoprecipitation, FRAP, domain mapping, farnesylation mutants","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (EM, FRAP, Co-IP, mutagenesis) in a single mechanistic study","pmids":["24522183"],"is_preprint":false},{"year":2014,"finding":"SUN1 variants associated with muscular dystrophy (A203V and A614V) show reduced interaction with lamin A/C and emerin; patient fibroblasts and C2C12 myotubes expressing these variants display defective rearward nuclear repositioning, loss of pericentrin recruitment to the NE, and impaired microtubule nucleation at the NE, establishing a direct link between SUN1 mutation and defective nuclear-microtubule coupling and myonuclear positioning.","method":"Co-immunoprecipitation, immunofluorescence, nuclear repositioning assays, myotube differentiation","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cells plus C2C12 rescue experiments with multiple readouts, single lab","pmids":["25210889"],"is_preprint":false},{"year":2015,"finding":"SUN1 is required for efficient nuclear mRNA export via the NXF1-dependent pathway; SUN1 depletion causes nuclear accumulation of hnRNP F/H, hnRNP K/J, and poly(A)+ RNA. SUN1 directly interacts with NXF1 to recruit mRNP complexes to the NE, and associates with the NPC through direct interaction with Nup153.","method":"siRNA knockdown, co-immunoprecipitation, in situ hybridization for poly(A)+ RNA, leptomycin B treatment, GST pulldown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNAi, Co-IP, in situ hybridization, direct binding assays) establishing pathway position and direct interactions","pmids":["26476453"],"is_preprint":false},{"year":2017,"finding":"The SUN1-NXF1 interaction required for mRNA export is regulated by PKC phosphorylation of serine 113 in the SUN1 N-terminal domain; S113A mutation reduces mRNA export rescue efficiency, while S113D (phosphomimetic) efficiently restores export. Nesprin-2 knockdown also impairs mRNA export, but this effect is independent of SUN1's SUN domain.","method":"Site-directed mutagenesis, siRNA knockdown, poly(A)+ RNA in situ hybridization, co-immunoprecipitation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphosite mutagenesis with functional rescue assay, single lab","pmids":["28831067"],"is_preprint":false},{"year":2021,"finding":"SUN1 directly interacts with Speedy A (SPDYA), and the crystal structure of the human SUN1-SPDYA-CDK2 ternary complex was determined. SUN1-SPDYA interaction is required for telomere-LINC complex connection and assembly of a ring-shaped telomere supramolecular architecture at the NE, as demonstrated by SPDYA-binding-deficient SUN1 mutant mice that show defective homologous pairing and synapsis.","method":"X-ray crystallography, co-immunoprecipitation, mouse knock-in (SUN1 mutant), immunofluorescence, FISH","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ternary complex plus in vivo functional validation with knock-in mutant mice","pmids":["34039995"],"is_preprint":false},{"year":2016,"finding":"SUN1 splice variant SUN1_888, but not the predominant SUN1_916, activates directional cell migration when overexpressed; knockdown of SUN1_888 suppresses cell migration while depletion of SUN1_916 activates it, indicating non-redundant functions. SUN1 (but not SUN2) preferentially interacts with B-type lamins.","method":"siRNA knockdown of specific splice variants, overexpression, migration assays, co-immunoprecipitation","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional migration assays with isoform-specific RNAi and Co-IP, single lab","pmids":["27858498"],"is_preprint":false},{"year":2019,"finding":"A major muscle-specific isoform of SUN1 binds to and inhibits Drosha (a key microprocessor complex component for miRNA biogenesis); SUN1 null myotubes show altered miRNA profiles including decreased miR-127 (which inhibits RTL1 translation), implicating the LINC complex in muscle regeneration through regulation of miRNA processing.","method":"Co-immunoprecipitation, miRNA profiling comparison between WT and SUN1-null myotubes, Western blotting","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing direct SUN1-Drosha interaction combined with functional miRNA profiling in knockout, single lab","pmids":["31686651"],"is_preprint":false},{"year":2023,"finding":"SUN1 regulates vascular sprouting and endothelial cell-cell junction stability via microtubules; SUN1 depletion reduces peripheral microtubule density, increases catastrophes, and destabilizes junctions. Mechanistically, SUN1 loss activates Rho via the microtubule-regulated GEF-H1, increasing contractility. Depletion of GEF-H1 or nesprin-1 rescues defective junctions, placing SUN1 upstream of microtubule-GEF-H1-Rho signaling.","method":"Endothelial-specific mouse knockout, zebrafish morpholino, live imaging, microtubule dynamics analysis, siRNA rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple model systems (mouse, zebrafish, cell culture) with epistasis rescue experiments and live microtubule dynamics","pmids":["36989130"],"is_preprint":false},{"year":2020,"finding":"SUN1 depletion in VSMCs impairs RhoA activity and actomyosin contractility; inhibition of actomyosin activity (via ROCK inhibition or blebbistatin) reduces SUN2 mobility and decreases SUN2-lamin A association, indicating a mechanical feedback circuit between the LINC complex and RhoA-actomyosin.","method":"siRNA knockdown, FRAP, RhoA activity assays, isolated aortic VSMCs from SUN2 KO mice","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and RhoA activity assays with pharmacological inhibition and genetic KO VSMCs, single lab","pmids":["31935926"],"is_preprint":false},{"year":2023,"finding":"The crystal structure of a luminal trimeric coiled-coil domain of SUN1 was solved by X-ray crystallography; combined with light/X-ray scattering and molecular dynamics, a model of SUN1's entire luminal region reveals inherent flexibility between structured domains and suggests domain-swap interactions that may establish a LINC complex network.","method":"X-ray crystallography, small-angle X-ray scattering, molecular dynamics simulation","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with multiple orthogonal biophysical methods in a single study","pmids":["37416798"],"is_preprint":false},{"year":2024,"finding":"SUN1 facilitates nuclear influx of CHMP7 (ESCRT-III protein) in sporadic ALS neurons; impaired NPC permeability barrier and SUN1 interactions promote CHMP7 nuclear accumulation, which initiates NPC injury cascades leading to nucleoporin loss and TDP-43 mislocalization.","method":"iPSN model of sALS, co-immunoprecipitation, imaging, siRNA knockdown","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSN disease model with defined molecular mechanism (SUN1-CHMP7 interaction) and pathway placement, single lab","pmids":["37639327"],"is_preprint":false},{"year":2023,"finding":"LPS-induced M1 macrophage polarization decreases SUN1/2 protein levels via a CK2-βTrCP-dependent proteasomal degradation pathway; loss of SUN1/2 shrinks and softens the nucleus, altering chromatin accessibility for M1-associated gene expression. The transmembrane helix of SUN1/2 is required and sufficient for nuclear mechano-remodeling.","method":"siRNA/shRNA depletion, proteasome inhibitors, domain deletion mutants, ATAC-seq, AFM nuclear stiffness measurements, mouse tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical pathway dissection, chromatin accessibility, nuclear mechanics, in vivo mouse models) in a single study","pmids":["37828059"],"is_preprint":false},{"year":2022,"finding":"SUN1 is required for cytoskeletal force generation and focal adhesion maturation; SUN1 depletion reduces integrin β1 activation, impairs vinculin and zyxin incorporation into nascent focal adhesions, disrupts actin organization, and reduces traction force generation, while SUN2 cannot compensate.","method":"siRNA knockdown, traction force microscopy, immunofluorescence, integrin activation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — traction force microscopy plus focal adhesion analysis with isoform-specific depletion, single lab","pmids":["35663386"],"is_preprint":false},{"year":2011,"finding":"SUN1 depletion by siRNA removes DYT1 dystonia torsinA-ΔE (but not ATP-locked torsinA) from the nuclear envelope; torsinA-ΔE localization to the NE requires the torsinA membrane association domain and residue Y147, implicating an abnormal gain-of-function SUN1-torsinA interaction in DYT1 dystonia pathogenesis distinct from the LAP1-torsinA interaction.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence, site-directed mutagenesis","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with defined localization readout and mutagenesis, single lab","pmids":["21627841"],"is_preprint":false},{"year":2020,"finding":"SUN1 interacts with both MAJIN and SPDYA at overlapping N-terminal domain sites; MAJIN interaction is stronger than TERB1 interaction. SPDYA binds SUN1 via its Ringo domain and recruits CDK2; CDK2 inhibition decreases the SUN1-MAJIN interaction, suggesting CDK2-dependent regulation of telomere-NE tethering.","method":"Co-immunoprecipitation, GST pulldown, domain mapping, kinase inhibition","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct binding assays with domain mapping and pharmacological modulation, single lab","pmids":["33015044"],"is_preprint":false},{"year":2017,"finding":"Overexpression of SUN1 inhibits HIV-1 infection in a capsid (CA)-dependent manner, blocking nuclear import of viral cDNA; sensitivity to SUN1 depends on the interaction between HIV-1 CA and cyclophilin A (CypA), as cyclosporine treatment or CA-G89A mutation (which abrogates CypA binding) confers resistance. Both SUN1 overexpression and knockdown inhibit HIV-1 nuclear entry.","method":"Overexpression, CRISPR knockout, chimeric virus analysis, cyclosporine treatment, 2-LTR circle quantification","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple viral and cellular genetic tools with defined molecular mechanism (CypA-CA dependence), single lab","pmids":["29643244"],"is_preprint":false},{"year":2025,"finding":"Elevated SUN1 disrupts fibroblast front-rear cell polarity by mechanically coupling microtubules to the nuclear lamina via direct SUN1-lamin A interaction and force transmission through nesprin-2; stable microtubules are necessary and sufficient to inhibit cell polarity; chimeric SUN1-SUN2 proteins show the SUN domain determines their divergent roles in polarization.","method":"SUN1-SUN2 chimeric protein expression, siRNA knockdown, microtubule stabilization/depolymerization, nuclear repositioning assays, live imaging","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-swap chimeras with pharmacological and genetic perturbations, single lab, two parallel publications (PMID:41366027 and preprint)","pmids":["41366027"],"is_preprint":false},{"year":2023,"finding":"The common SUN1 variant H118Y undergoes increased proteasomal degradation relative to wild-type SUN1; cells expressing H118Y SUN1 exhibit insulin resistance and increased lipid accumulation.","method":"Proteasome inhibition, Western blotting, cell-based lipid accumulation and insulin signaling assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — variant protein stability and cellular functional assays, single lab","pmids":["37567366"],"is_preprint":false},{"year":2022,"finding":"A CCDC155 missense mutation blocks nuclear envelope distribution of SUN1 in human spermatocytes, demonstrating that the SUN1-CCDC155 complex is required for telomere attachment and NE anchoring during human meiosis; loss of this complex causes meiotic arrest in both sexes.","method":"Whole-exome sequencing, patient spermatocyte histology, immunofluorescence, co-localization, ex vivo and in vitro expression studies","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient genetic variant with cellular mechanistic validation showing SUN1 mislocalization, single lab","pmids":["35587281"],"is_preprint":false},{"year":2022,"finding":"SUN1 is required for NPC concentration along Actin/LINC/Lamin (ALL) nuclear lines in response to uniaxial cyclic stretch; CRISPR knockdown and knockout of SUN1 significantly diminishes NPC/ALL line integration, with reduced Pom121, TPR, and Nup153 fluorescence at ALL lines.","method":"CRISPR SUN1 KD/KO, cyclic stretch, live imaging, immunofluorescence quantification of nucleoporins","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout with defined NPC reorganization phenotype under mechanical stimulation, single lab","pmids":["36619427"],"is_preprint":false},{"year":2009,"finding":"Sun1 deficiency in mice leads to repression of meiotic reproductive gene expression in testes and absence of detectable piRNA, identifying an unrecognized role of Sun1 in selective gene expression during gametogenesis.","method":"Sun1 knockout mice, transcriptomic analysis, piRNA Northern blot","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with molecular gene expression readouts, single lab","pmids":["19211677"],"is_preprint":false},{"year":2025,"finding":"SUN1 interacts with CUL3 E3 ubiquitin ligase; wild-type SUN1 robustly interacts with CUL3 while H118Y SUN1 shows markedly diminished CUL3 interaction. SUN1 silencing or H118Y expression increases CUL3 neddylation, which promotes CRL-mediated ubiquitination of IRS proteins and insulin resistance; neddylation inhibition restores IRS-1 levels and insulin signaling.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, siRNA knockdown, neddylation inhibitors, Western blotting","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — AP-MS with biochemical validation and pharmacological rescue, single lab, preprint not yet peer-reviewed","pmids":["42079055"],"is_preprint":true}],"current_model":"SUN1 is an integral inner nuclear membrane protein that forms the nucleoplasmic half of the LINC complex by binding nuclear lamins (preferentially lamin A via its N-terminal domain and B-type lamins via splice-variant-specific interactions) and connecting through its trimeric coiled-coil luminal region and C-terminal SUN domain to the KASH domains of cytoplasmic nesprins, thereby mechanically coupling chromatin and the nuclear lamina to the actin, microtubule, and dynein/dynactin cytoskeleton; SUN1 also associates with nuclear pore complexes (promoting their interphase assembly and distribution), directly interacts with NXF1 and Nup153 to facilitate mRNA export via the NXF1-dependent pathway (regulated by PKC phosphorylation of S113), localizes to meiotic telomeres where it interacts with KASH5, MAJIN, and SPDYA-CDK2 to tether telomeres to the NE and enable chromosome movements required for homolog pairing, and undergoes mitotic phosphorylation by Cdk1 (S48, S333) and Plk1 (S138) that loosens its nucleoplasmic interactions while preserving the core LINC complex; pathologically, SUN1 accumulation driven by dysregulated interaction with farnesylated progerin contributes to laminopathy disease progression, and its depletion rescues nuclear defects in Hutchinson-Gilford progeria syndrome and EDMD models."},"narrative":{"mechanistic_narrative":"SUN1 is an integral inner nuclear membrane protein that forms the nucleoplasmic half of the LINC complex, mechanically coupling chromatin and the nuclear lamina to the cytoskeleton: its N-terminal nucleoplasmic domain binds lamin A and its C-terminal luminal SUN domain engages the KASH domains of nesprins, building a continuous bridge across the nuclear envelope [PMID:16648470, PMID:16079285]. SUN1 is required for nuclear-envelope retention of nesprins via the conserved PPPX motif, and it forms highly immobile oligomers through a self-associating C-terminal coiled-coil that also heterodimerizes with SUN2 [PMID:16079285, PMID:18845190]; its luminal region adopts a flexible trimeric coiled-coil architecture that may extend the LINC network through domain-swap interactions [PMID:37416798]. Through nesprin connections to dynein/dynactin and kinesin, SUN1 (acting redundantly with SUN2) anchors and moves nuclei during interkinetic nuclear migration, photoreceptor positioning, and myonuclear anchorage [PMID:19509342, PMID:21177258]. SUN1 couples microtubules to the lamina and tunes cytoskeletal signaling, regulating focal-adhesion maturation and integrin/traction force, endothelial junction stability via a microtubule–GEF-H1–Rho axis, and front-rear cell polarity through a SUN-domain-determined function distinct from SUN2 [PMID:35663386, PMID:36989130, PMID:41366027]. In meiosis, SUN1 specifically attaches telomeres to the nuclear envelope, interacting with the KASH protein KASH5/CCDC155, MAJIN, and a SPDYA-CDK2 module to assemble a telomere supramolecular ring that drives homolog pairing and synapsis; loss of Sun1 abolishes gametogenesis [PMID:17543860, PMID:22826121, PMID:34039995, PMID:33015044, PMID:35587281]. Beyond mechanical coupling, SUN1 associates with nuclear pore complexes to promote their interphase assembly and distribution, and it directly binds NXF1 and Nup153 to support NXF1-dependent mRNA export, a function regulated by PKC phosphorylation of S113 [PMID:17724119, PMID:21727197, PMID:26476453, PMID:28831067]. Mitotic phosphorylation by Cdk1 (S48, S333) and Plk1 (S138) loosens SUN1's nucleoplasmic interactions while preserving the core SUN-KASH bridge [PMID:25482198]. Pathologically, SUN1 over-accumulation driven by its dysregulated interaction with farnesylated progerin is a common event in laminopathies, and reducing SUN1 rescues nuclear defects in HGPS and EDMD models [PMID:22541428, PMID:24522183].","teleology":[{"year":2006,"claim":"Established the founding LINC architecture by showing SUN1 physically bridges the lamina to the cytoskeleton, answering how the inner nuclear membrane connects to cytoplasmic structures.","evidence":"Yeast two-hybrid, Co-IP, and domain mapping defining lamin A binding by the N-terminus and nesprin KASH binding by the SUN domain, confirmed by an independent lab the same year","pmids":["16648470","16079285"],"confidence":"High","gaps":["Stoichiometry and structure of the SUN-KASH interface not resolved","Whether B-type lamins also engage SUN1 not addressed here"]},{"year":2006,"claim":"Mapped the determinants of SUN1 NE targeting, showing the N-terminal ~300 residues are required and the SUN domain dispensable, and that anchoring is lamin-independent.","evidence":"Truncation mutants, RNAi lamin knockdown, immunofluorescence and FRAP","pmids":["16445915"],"confidence":"Medium","gaps":["The molecular retention partner within the N-terminus not identified","Apparent tension with later lamin-dependent recruitment models not reconciled"]},{"year":2007,"claim":"Extended SUN1's role beyond the LINC bridge to nuclear pore complex organization, showing it associates with NPCs and maintains their even distribution.","evidence":"Immunofluorescence, immunoelectron microscopy, RNAi, and topology analysis showing NPC clustering on SUN1 loss","pmids":["17724119"],"confidence":"High","gaps":["Direct NPC-binding partner not identified at this stage","Mechanism distinguishing SUN1 from SUN2 in NPC association unknown"]},{"year":2007,"claim":"Defined a meiotic function by showing SUN1 tethers telomeres to the NE for homolog pairing, explaining a non-somatic role of the LINC complex.","evidence":"Sun1 knockout mice with FISH and immunofluorescence showing failed telomere attachment, pairing, and sterility","pmids":["17543860"],"confidence":"High","gaps":["The telomere-side and force-generating partners not yet identified","How telomere movement couples to the cytoskeleton unresolved"]},{"year":2008,"claim":"Explained SUN1's immobility and network potential by demonstrating disulfide-linked self-oligomerization and heterophilic association with SUN2.","evidence":"Inverse FRAP, cross-linking, and mutagenesis defining coiled-coil dimers/tetramers","pmids":["18845190"],"confidence":"High","gaps":["Physiological oligomeric state in intact LINC complexes not defined","Functional consequence of SUN1-SUN2 heteromers unclear"]},{"year":2009,"claim":"Demonstrated genetic redundancy of SUN1 and SUN2 in nuclear anchoring and connected the complex to nesprin localization in muscle.","evidence":"Single and double Sun1/Sun2 knockout mice with graded phenotypes and Nesprin-1 mislocalization","pmids":["19509342"],"confidence":"High","gaps":["Isoform-specific contributions within muscle not dissected","Mechanical force requirements not measured"]},{"year":2009,"claim":"Identified a transcriptional/gene-regulatory dimension of SUN1 in gametogenesis, showing it is needed for meiotic gene expression and piRNA production.","evidence":"Sun1 knockout transcriptomics and piRNA Northern blot in testes","pmids":["19211677"],"confidence":"Medium","gaps":["Whether the gene-expression defect is secondary to telomere/pairing failure unresolved","No direct SUN1-chromatin mechanism shown"]},{"year":2011,"claim":"Placed SUN1 in NPC biogenesis by showing it is specifically required for interphase, not post-mitotic, pore assembly.","evidence":"RNAi with cell-cycle staging and co-localization with POM121 at assembly sites","pmids":["21727197"],"confidence":"Medium","gaps":["Direct molecular role at the assembly intermediate not defined","Relationship to NPC clustering phenotype not integrated"]},{"year":2010,"claim":"Connected SUN1/SUN2-nesprin-2 complexes to motor-driven nuclear migration in vivo, explaining tissue-level consequences of LINC disruption.","evidence":"Sun1/Sun2 double knockout mice with retinal phenotypes, ERG, and Co-IP linking nesprin-2 to dynein/dynactin and kinesin","pmids":["21177258"],"confidence":"High","gaps":["Direct vs indirect SUN1-motor coupling not separated","Force magnitudes during INM not quantified"]},{"year":2012,"claim":"Identified the SPDYA/KASH5-dynein axis as the meiotic telomere force machinery downstream of SUN1.","evidence":"Yeast two-hybrid, Co-IP, and mouse genetics showing KASH5 binds SUN1 and recruits dynein-dynactin","pmids":["22826121"],"confidence":"High","gaps":["Stoichiometry of the telomere-LINC assembly not yet resolved","Regulation of attachment timing unknown"]},{"year":2012,"claim":"Revealed a DNA-damage-response role for SUN proteins, linking them to ATM/H2A.X activation and DNA-PK.","evidence":"Sun1/Sun2 double knockout MEFs with S-phase arrest and Co-IP with DNA-PK components","pmids":["22863315"],"confidence":"Medium","gaps":["Direct vs indirect SUN-DNA-PK interaction not validated reciprocally","Whether the phenotype reflects mechanics or signaling unresolved"]},{"year":2012,"claim":"Established SUN1 over-accumulation as a common pathogenic driver in laminopathies and a therapeutic target, by showing SUN1 removal rescues disease.","evidence":"Sun1 loss in Lmna-/- and progeroid mice extending lifespan, plus SUN1 reduction correcting HGPS fibroblast defects","pmids":["22541428"],"confidence":"High","gaps":["Molecular basis of SUN1 accumulation not defined in this study","Tissue-specific contributions to rescue not separated"]},{"year":2014,"claim":"Defined the mechanism of pathological SUN1 accumulation as a farnesylation-enhanced progerin-SUN1 interaction occurring during NE reformation.","evidence":"EM, FRAP, Co-IP, and farnesylation mutants showing progerin retains SUN1 in the ER","pmids":["24522183"],"confidence":"High","gaps":["Why accumulation is cumulative across divisions not fully mechanistic","Whether this drives all laminopathy pathologies unresolved"]},{"year":2014,"claim":"Showed mitotic kinases dynamically remodel SUN1 interactions, explaining how the LINC complex is regulated through the cell cycle.","evidence":"Mass spectrometry phosphosite mapping, kinase assays, and phosphomimetic mutants altering solubility and NE retention","pmids":["25482198"],"confidence":"High","gaps":["Functional consequence for mitotic nuclear envelope breakdown not measured in vivo","Phosphatase that reverses these marks unknown"]},{"year":2014,"claim":"Linked SUN1 point mutations to muscular dystrophy through defective nuclear-microtubule coupling and myonuclear positioning.","evidence":"Patient fibroblasts and C2C12 myotubes expressing A203V/A614V variants with impaired lamin A/C and emerin binding and pericentrin recruitment","pmids":["25210889"],"confidence":"Medium","gaps":["Causality of variants in patients not established by family genetics here","Microtubule nucleation mechanism at the NE not molecularly defined"]},{"year":2011,"claim":"Connected SUN1 to farnesylated prelamin A recruitment during myoblast differentiation, relevant to EDMD pathology.","evidence":"Immunofluorescence and pharmacological farnesylation inhibition in human myoblasts","pmids":["21311568"],"confidence":"Medium","gaps":["Direct prelamin A-SUN1 binding not biochemically isolated","Causal link to myonuclear positioning correlative"]},{"year":2015,"claim":"Assigned SUN1 a direct role in mRNA export, showing it recruits mRNP complexes to the NPC via NXF1 and Nup153.","evidence":"siRNA, Co-IP, GST pulldown, and poly(A)+ RNA in situ hybridization showing nuclear RNA retention on SUN1 loss","pmids":["26476453"],"confidence":"High","gaps":["Whether export and LINC functions are separable not fully resolved","Quantitative contribution of SUN1 to bulk export unknown"]},{"year":2017,"claim":"Identified PKC phosphorylation of S113 as the switch governing the export-competent SUN1-NXF1 interaction.","evidence":"S113A/S113D mutagenesis with poly(A)+ RNA in situ rescue assays","pmids":["28831067"],"confidence":"Medium","gaps":["Upstream signals activating PKC toward SUN1 unknown","In vivo relevance not tested"]},{"year":2021,"claim":"Provided structural and in vivo proof that the SUN1-SPDYA-CDK2 module builds the telomere supramolecular ring needed for meiotic pairing.","evidence":"Crystal structure of the ternary complex plus SPDYA-binding-deficient SUN1 knock-in mice","pmids":["34039995"],"confidence":"High","gaps":["How CDK2 activity is timed to attachment not fully defined","Ring assembly dynamics not visualized live"]},{"year":2020,"claim":"Mapped overlapping MAJIN/SPDYA binding sites on the SUN1 N-terminus and showed CDK2-dependent regulation of telomere tethering.","evidence":"Co-IP, GST pulldown, domain mapping, and CDK2 inhibition","pmids":["33015044"],"confidence":"Medium","gaps":["Competition vs cooperation among partners at overlapping sites unresolved","Direct binding affinities not quantified"]},{"year":2023,"claim":"Solved the luminal trimeric coiled-coil structure, providing a model for SUN1 flexibility and LINC network formation.","evidence":"X-ray crystallography, SAXS, and molecular dynamics of the luminal region","pmids":["37416798"],"confidence":"High","gaps":["Domain-swap network model not validated in cells","Coupling to KASH binding in the full-length protein not shown"]},{"year":2016,"claim":"Revealed isoform-specific SUN1 functions, with splice variants exerting opposing effects on directional cell migration and B-type lamin binding.","evidence":"Isoform-specific siRNA, overexpression, migration assays, and Co-IP","pmids":["27858498"],"confidence":"Medium","gaps":["Structural basis of isoform-specific lamin binding unknown","Mechanism of opposing migration effects not defined"]},{"year":2022,"claim":"Showed SUN1 is required for cytoskeletal force generation, integrin activation, and focal adhesion maturation, with SUN2 unable to compensate.","evidence":"siRNA, traction force microscopy, and focal adhesion/integrin assays","pmids":["35663386"],"confidence":"Medium","gaps":["Molecular link from SUN1 to integrin activation not defined","SUN1-specific determinant of this role not mapped"]},{"year":2022,"claim":"Demonstrated SUN1 organizes NPC concentration along mechanically induced ALL nuclear lines, linking it to mechanoresponsive pore positioning.","evidence":"CRISPR KD/KO under cyclic stretch with nucleoporin quantification","pmids":["36619427"],"confidence":"Medium","gaps":["Direct nucleoporin partners at ALL lines not all identified","Physiological role of ALL-line NPCs unknown"]},{"year":2023,"claim":"Placed SUN1 upstream of microtubule-GEF-H1-Rho signaling controlling endothelial junction stability and vascular sprouting.","evidence":"Endothelial knockout mice, zebrafish morpholino, live microtubule imaging, and GEF-H1/nesprin-1 rescue epistasis","pmids":["36989130"],"confidence":"High","gaps":["How SUN1 controls peripheral microtubule stability mechanistically unresolved","Direct vs indirect GEF-H1 regulation not separated"]},{"year":2020,"claim":"Identified a mechanical feedback circuit between the LINC complex and RhoA-actomyosin in vascular smooth muscle.","evidence":"siRNA, FRAP, RhoA activity assays, and pharmacological actomyosin inhibition in VSMCs","pmids":["31935926"],"confidence":"Medium","gaps":["Directionality of the feedback not fully causal","SUN1 vs SUN2 specific contributions intertwined"]},{"year":2023,"claim":"Linked SUN1/SUN2 turnover to inflammatory nuclear mechano-remodeling, showing CK2-βTrCP degradation softens the nucleus to enable M1 gene expression.","evidence":"shRNA/siRNA, proteasome inhibitors, ATAC-seq, AFM stiffness, and tumor models showing the transmembrane helix is sufficient","pmids":["37828059"],"confidence":"High","gaps":["How the transmembrane helix alone remodels nuclear mechanics not mechanistic","Generality beyond macrophages untested"]},{"year":2019,"claim":"Uncovered a non-canonical SUN1 role in miRNA biogenesis, with a muscle isoform binding and inhibiting Drosha.","evidence":"Co-IP and miRNA profiling in WT vs SUN1-null myotubes","pmids":["31686651"],"confidence":"Medium","gaps":["Direct vs indirect Drosha inhibition not fully resolved","How a NE protein accesses the microprocessor unclear"]},{"year":2025,"claim":"Showed elevated SUN1 disrupts cell polarity by coupling stable microtubules to the lamina, with the SUN domain dictating divergence from SUN2.","evidence":"SUN1-SUN2 chimeras, siRNA, microtubule perturbation, and nuclear repositioning assays","pmids":["41366027"],"confidence":"Medium","gaps":["Why microtubule stabilization inhibits polarity not mechanistic","In vivo relevance not tested"]},{"year":2017,"claim":"Implicated SUN1 in restricting HIV-1 nuclear import in a capsid- and cyclophilin A-dependent manner.","evidence":"Overexpression, CRISPR knockout, chimeric viruses, cyclosporine, and 2-LTR circle quantification","pmids":["29643244"],"confidence":"Medium","gaps":["Direct SUN1-capsid interaction not demonstrated","Why both overexpression and knockdown inhibit import unexplained"]},{"year":2011,"claim":"Connected SUN1 to DYT1 dystonia by showing it abnormally retains torsinA-ΔE at the NE.","evidence":"siRNA, Co-IP, immunofluorescence, and mutagenesis","pmids":["21627841"],"confidence":"Medium","gaps":["Whether the SUN1-torsinA interaction is direct unclear","Pathogenic significance in patients not established"]},{"year":2022,"claim":"Demonstrated in human meiosis that the SUN1-CCDC155 complex is required for telomere NE anchoring, extending the mouse model to human fertility disease.","evidence":"Whole-exome sequencing of patients with a CCDC155 mutation and spermatocyte immunofluorescence showing SUN1 mislocalization","pmids":["35587281"],"confidence":"Medium","gaps":["Single-family genetic evidence","Direct mutation effect on binding not biochemically isolated"]},{"year":2023,"claim":"Linked a common SUN1 variant H118Y to metabolic dysfunction through increased SUN1 degradation, insulin resistance, and lipid accumulation.","evidence":"Proteasome inhibition and cell-based insulin/lipid assays","pmids":["37567366"],"confidence":"Medium","gaps":["Mechanism connecting SUN1 loss to insulin signaling not defined here","In vivo metabolic validation absent"]},{"year":2025,"claim":"Proposed a metabolic mechanism whereby SUN1-CUL3 binding restrains CUL3 neddylation and IRS ubiquitination, with H118Y impairing this control.","evidence":"AP-MS, Co-IP, neddylation inhibitors, and Western blotting (preprint)","pmids":["42079055"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How a NE protein regulates cytoplasmic CRL activity unresolved"]},{"year":null,"claim":"How SUN1's many separable functions — mechanical LINC coupling, NPC assembly, mRNA export, miRNA processing, and metabolic E3-ligase regulation — are partitioned, regulated, and prioritized within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model separating mechanical from biochemical SUN1 functions","Isoform- and tissue-specific function allocation incompletely mapped","Structure of the full-length, membrane-embedded SUN1 in an intact LINC complex not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[15,21,30]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[20,35]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,9,18,32]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[16,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,7,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,11,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,14,15]}],"complexes":["LINC complex","telomere-LINC supramolecular ring (SUN1-KASH5-SPDYA-CDK2)"],"partners":["LMNA","SYNE2","KASH5","NXF1","NUP153","SPDYA","MAJIN","CUL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94901","full_name":"SUN domain-containing protein 1","aliases":["Protein unc-84 homolog A","Sad1/unc-84 protein-like 1"],"length_aa":785,"mass_kda":87.1,"function":"As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton (PubMed:18039933, PubMed:18396275). The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning (By similarity). Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration (By similarity). Involved in telomere attachment to nuclear envelope in the prophase of meiosis implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly (By similarity). Required for gametogenesis and involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis (By similarity). Helps to define the distribution of nuclear pore complexes (NPCs) (By similarity). Required for efficient localization of SYNE4 in the nuclear envelope (By similarity). May be involved in nuclear remodeling during sperm head formation in spermatogenesis (By similarity). May play a role in DNA repair by suppressing non-homologous end joining repair to facilitate the repair of DNA cross-links (PubMed:24375709)","subcellular_location":"Nucleus inner membrane","url":"https://www.uniprot.org/uniprotkb/O94901/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SUN1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SUN1","total_profiled":1310},"omim":[{"mim_id":"620548","title":"PREMATURE OVARIAN FAILURE 22; POF22","url":"https://www.omim.org/entry/620548"},{"mim_id":"620547","title":"SPERMATOGENIC FAILURE 88; SPGF88","url":"https://www.omim.org/entry/620547"},{"mim_id":"618984","title":"SAD1 AND UNC84 DOMAIN-CONTAINING PROTEIN 3; SUN3","url":"https://www.omim.org/entry/618984"},{"mim_id":"618125","title":"KASH DOMAIN-CONTAINING PROTEIN 5; KASH5","url":"https://www.omim.org/entry/618125"},{"mim_id":"617332","title":"TELOMERE REPEAT-BINDING BOUQUET FORMATION PROTEIN 1; TERB1","url":"https://www.omim.org/entry/617332"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUN1"},"hgnc":{"alias_symbol":["KIAA0810","FLJ12407"],"prev_symbol":["UNC84A"]},"alphafold":{"accession":"O94901","domains":[{"cath_id":"2.60.120.260","chopping":"640-811","consensus_level":"high","plddt":87.2749,"start":640,"end":811},{"cath_id":"1.10.10","chopping":"570-635","consensus_level":"medium","plddt":64.8497,"start":570,"end":635}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94901","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94901-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94901-F1-predicted_aligned_error_v6.png","plddt_mean":60.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUN1","jax_strain_url":"https://www.jax.org/strain/search?query=SUN1"},"sequence":{"accession":"O94901","fasta_url":"https://rest.uniprot.org/uniprotkb/O94901.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94901/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94901"}},"corpus_meta":[{"pmid":"16648470","id":"PMC_16648470","title":"SUN1 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N-terminal nucleoplasmic domain binds lamin A (but not type B lamins) in a detergent-resistant manner, while its C-terminal luminal SUN domain interacts with the KASH domains of nesprins 1 and 2, forming a physical bridge between the nuclear lamina and the cytoskeleton.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, detergent fractionation, dominant-negative overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays with domain mapping, independently confirmed by a second lab (PMID:16079285) the same year using orthogonal methods\",\n      \"pmids\": [\"16648470\", \"16079285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SUN1 is required for nuclear envelope localization of Nesprin-2; the conserved C-terminal PPPX motif of nesprin-1/2 directly interacts with a C-terminal region of SUN1, and knockdown of SUN1 or dominant-negative SUN1 fragments mislocalize Nesprin-2 from the nuclear envelope.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, DN mutants, RNAi) in single lab, replicated by PMID:16648470\",\n      \"pmids\": [\"16079285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SUN1 (but not SUN2) is intimately associated with nuclear pore complexes (NPCs) as demonstrated by immunofluorescence and immunoelectron microscopy; SUN1 is a type II integral protein of the inner nuclear membrane and NPC association requires synergy of both nucleoplasmic and lumenal domains. Depletion of SUN1 by RNAi or overexpression of dominant-negative SUN1 fragments causes NPC clustering.\",\n      \"method\": \"Immunofluorescence, immunoelectron microscopy, RNAi depletion, topology analysis, dominant-negative overexpression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal imaging and functional methods in single study, specific phenotype with domain mapping\",\n      \"pmids\": [\"17724119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SUN1 at the inner nuclear membrane specifically associates with telomeres during meiotic prophase I (leptotene to diplotene stages); genetic disruption of Sun1 in mice prevents telomere attachment to the nuclear envelope, blocks efficient homolog pairing and synapsis, and causes massive apoptosis abolishing spermatogenesis and oogenesis.\",\n      \"method\": \"Mouse knockout, immunofluorescence, FISH, co-localization studies\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with defined cellular phenotypes and molecular readouts, replicated by multiple subsequent studies\",\n      \"pmids\": [\"17543860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUN1 forms highly immobile oligomeric complexes at the nuclear envelope; the C-terminal coiled-coil segment can form dimers and tetramers via self-association, involves interchain disulfide bonds, and supports heterophilic association with SUN2. Both perinuclear and nucleoplasmic SUN1 segments are required for NE immobility.\",\n      \"method\": \"Inverse FRAP, co-immunoprecipitation, biochemical cross-linking, site-directed mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — FRAP with mutagenesis and biochemical oligomerization assays in a single rigorous study\",\n      \"pmids\": [\"18845190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SUN1 and SUN2 function redundantly in anchoring myonuclei in skeletal muscle; Sun1 single knockout partially disrupts synaptic nuclear anchorage, Sun1/Sun2 double knockout disrupts both synaptic and nonsynaptic nuclear organization, and Syne-1/Nesprin-1 localization at the nuclear envelope is lost in double knockout muscle cells.\",\n      \"method\": \"Mouse knockout (single and double), immunofluorescence, gene dosage analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis with graded allele series and defined molecular readout (Nesprin-1 mislocalization)\",\n      \"pmids\": [\"19509342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal ~300 amino acids of human SUN1 (UNC84A) are crucial for nuclear envelope localization, whereas the conserved C-terminal SUN domain is not required. SUN1 localization and anchoring at the NE is not dependent on lamin proteins, as shown by RNAi knockdown of lamins combined with immunofluorescence and FRAP.\",\n      \"method\": \"RNAi knockdown, truncation mutants, immunofluorescence, FRAP\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mapping plus RNAi with FRAP, single lab\",\n      \"pmids\": [\"16445915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUN1 is required for interphase NPC assembly; it co-localizes with POM121 at forming pore assembly sites, and depletion of Sun1 specifically impairs interphase (but not post-mitotic) NPC assembly.\",\n      \"method\": \"RNAi depletion, live imaging, immunofluorescence, cell-cycle staging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with cell-cycle-specific phenotype, single lab, orthogonal imaging methods\",\n      \"pmids\": [\"21727197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Accumulation of SUN1 protein is a common pathogenic event in laminopathies: in Lmna−/− and progeroid LmnaΔ9 mice, Sun1 accumulates at the NE; additional loss of Sun1 in these backgrounds markedly reduces tissue pathologies and extends lifespan. In human HGPS fibroblasts, reducing SUN1 overaccumulation corrects nuclear defects and cellular senescence.\",\n      \"method\": \"Double-knockout mice, siRNA knockdown in human cells, histopathology, cell biology assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic rescue experiments in multiple mouse models plus human cell validation, published in Cell\",\n      \"pmids\": [\"22541428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The germ-cell-specific KASH domain protein KASH5 localizes to telomeres from leptotene to diplotene stages and directly interacts with SUN1 via KASH-related sequences; KASH5 also interacts with the dynein-dynactin complex, connecting the telomere-associated SUN1 to cytoplasmic force-generating machinery for meiotic chromosome movement.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, mouse genetics\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction mapping combined with in vivo genetic loss-of-function, replicated by subsequent structural studies\",\n      \"pmids\": [\"22826121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUN1 and SUN2 play redundant roles in the DNA damage response; Sun1/Sun2 double-knockout MEFs show premature S-phase arrest, increased apoptosis, DNA damage, decreased perinuclear heterochromatin, and impaired activation of ATM and H2A.X. Biochemical screen identified interactions between SUN1/SUN2 and the DNA-PK complex.\",\n      \"method\": \"Double-knockout MEFs, flow cytometry, immunofluorescence, co-immunoprecipitation, Western blotting\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with molecular readouts and Co-IP interaction, single lab\",\n      \"pmids\": [\"22863315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SUN1 and SUN2 form complexes with Syne-2/Nesprin-2 at the nuclear envelope and are required for interkinetic nuclear migration (INM) and photoreceptor cell migration in mouse retina; double Sun1/Sun2 knockout causes severe reduction of the outer nuclear layer, photoreceptor mislocalization, and retinal dysfunction. Nesprin-2 complexes with SUN1/2 to connect the nucleus with dynein/dynactin and kinesin motors during nuclear migrations.\",\n      \"method\": \"Mouse double knockout, immunofluorescence, ERG, co-immunoprecipitation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mouse double knockout with defined cellular phenotypes and Co-IP showing molecular complex\",\n      \"pmids\": [\"21177258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Farnesylated prelamin A recruits SUN1 to the nuclear envelope during myoblast differentiation; impairment of prelamin A farnesylation alters SUN1 recruitment, and reduced prelamin A and SUN1 levels in EDMD myoblasts correlate with defective myonuclear positioning.\",\n      \"method\": \"Immunofluorescence, pharmacological inhibition of farnesylation, Western blotting, cell fractionation in human myoblasts\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with pharmacological perturbation, single lab\",\n      \"pmids\": [\"21311568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mitotic phosphorylation of SUN1 at serines 48 and 333 (by Cdk1) and serine 138 (by Plk1) loosens SUN1's interaction with nucleoplasmic binding partners lamin A/C, emerin, and short nesprin-2 isoforms during mitosis, while the C-terminal SUN1-KASH domain interaction with nesprin-2 is maintained. A triple phosphomimetic SUN1 mutant shows increased solubility and reduced NE retention.\",\n      \"method\": \"Mass spectrometry phosphosite identification, site-directed mutagenesis, co-immunoprecipitation, kinase assays, immunofluorescence\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — kinase identification with mutagenesis, Co-IP, and solubility assays; multiple orthogonal methods in single study\",\n      \"pmids\": [\"25482198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The dysregulated interaction between SUN1 and progerin (farnesylated mutant lamin A) occurs in the ER during post-mitotic nuclear envelope reformation; farnesylation of progerin enhances its SUN1 interaction, reduces SUN1 mobility, and promotes aberrant ER membrane recruitment of progerin, causing cumulative SUN1 accumulation over successive cell divisions. Two domains of full-length lamin A associate with SUN1, with the farnesylated CaaX motif having stronger affinity.\",\n      \"method\": \"Light and electron microscopy, co-immunoprecipitation, FRAP, domain mapping, farnesylation mutants\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (EM, FRAP, Co-IP, mutagenesis) in a single mechanistic study\",\n      \"pmids\": [\"24522183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUN1 variants associated with muscular dystrophy (A203V and A614V) show reduced interaction with lamin A/C and emerin; patient fibroblasts and C2C12 myotubes expressing these variants display defective rearward nuclear repositioning, loss of pericentrin recruitment to the NE, and impaired microtubule nucleation at the NE, establishing a direct link between SUN1 mutation and defective nuclear-microtubule coupling and myonuclear positioning.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, nuclear repositioning assays, myotube differentiation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cells plus C2C12 rescue experiments with multiple readouts, single lab\",\n      \"pmids\": [\"25210889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SUN1 is required for efficient nuclear mRNA export via the NXF1-dependent pathway; SUN1 depletion causes nuclear accumulation of hnRNP F/H, hnRNP K/J, and poly(A)+ RNA. SUN1 directly interacts with NXF1 to recruit mRNP complexes to the NE, and associates with the NPC through direct interaction with Nup153.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, in situ hybridization for poly(A)+ RNA, leptomycin B treatment, GST pulldown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNAi, Co-IP, in situ hybridization, direct binding assays) establishing pathway position and direct interactions\",\n      \"pmids\": [\"26476453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The SUN1-NXF1 interaction required for mRNA export is regulated by PKC phosphorylation of serine 113 in the SUN1 N-terminal domain; S113A mutation reduces mRNA export rescue efficiency, while S113D (phosphomimetic) efficiently restores export. Nesprin-2 knockdown also impairs mRNA export, but this effect is independent of SUN1's SUN domain.\",\n      \"method\": \"Site-directed mutagenesis, siRNA knockdown, poly(A)+ RNA in situ hybridization, co-immunoprecipitation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphosite mutagenesis with functional rescue assay, single lab\",\n      \"pmids\": [\"28831067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SUN1 directly interacts with Speedy A (SPDYA), and the crystal structure of the human SUN1-SPDYA-CDK2 ternary complex was determined. SUN1-SPDYA interaction is required for telomere-LINC complex connection and assembly of a ring-shaped telomere supramolecular architecture at the NE, as demonstrated by SPDYA-binding-deficient SUN1 mutant mice that show defective homologous pairing and synapsis.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, mouse knock-in (SUN1 mutant), immunofluorescence, FISH\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ternary complex plus in vivo functional validation with knock-in mutant mice\",\n      \"pmids\": [\"34039995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SUN1 splice variant SUN1_888, but not the predominant SUN1_916, activates directional cell migration when overexpressed; knockdown of SUN1_888 suppresses cell migration while depletion of SUN1_916 activates it, indicating non-redundant functions. SUN1 (but not SUN2) preferentially interacts with B-type lamins.\",\n      \"method\": \"siRNA knockdown of specific splice variants, overexpression, migration assays, co-immunoprecipitation\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional migration assays with isoform-specific RNAi and Co-IP, single lab\",\n      \"pmids\": [\"27858498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A major muscle-specific isoform of SUN1 binds to and inhibits Drosha (a key microprocessor complex component for miRNA biogenesis); SUN1 null myotubes show altered miRNA profiles including decreased miR-127 (which inhibits RTL1 translation), implicating the LINC complex in muscle regeneration through regulation of miRNA processing.\",\n      \"method\": \"Co-immunoprecipitation, miRNA profiling comparison between WT and SUN1-null myotubes, Western blotting\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing direct SUN1-Drosha interaction combined with functional miRNA profiling in knockout, single lab\",\n      \"pmids\": [\"31686651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUN1 regulates vascular sprouting and endothelial cell-cell junction stability via microtubules; SUN1 depletion reduces peripheral microtubule density, increases catastrophes, and destabilizes junctions. Mechanistically, SUN1 loss activates Rho via the microtubule-regulated GEF-H1, increasing contractility. Depletion of GEF-H1 or nesprin-1 rescues defective junctions, placing SUN1 upstream of microtubule-GEF-H1-Rho signaling.\",\n      \"method\": \"Endothelial-specific mouse knockout, zebrafish morpholino, live imaging, microtubule dynamics analysis, siRNA rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple model systems (mouse, zebrafish, cell culture) with epistasis rescue experiments and live microtubule dynamics\",\n      \"pmids\": [\"36989130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUN1 depletion in VSMCs impairs RhoA activity and actomyosin contractility; inhibition of actomyosin activity (via ROCK inhibition or blebbistatin) reduces SUN2 mobility and decreases SUN2-lamin A association, indicating a mechanical feedback circuit between the LINC complex and RhoA-actomyosin.\",\n      \"method\": \"siRNA knockdown, FRAP, RhoA activity assays, isolated aortic VSMCs from SUN2 KO mice\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and RhoA activity assays with pharmacological inhibition and genetic KO VSMCs, single lab\",\n      \"pmids\": [\"31935926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The crystal structure of a luminal trimeric coiled-coil domain of SUN1 was solved by X-ray crystallography; combined with light/X-ray scattering and molecular dynamics, a model of SUN1's entire luminal region reveals inherent flexibility between structured domains and suggests domain-swap interactions that may establish a LINC complex network.\",\n      \"method\": \"X-ray crystallography, small-angle X-ray scattering, molecular dynamics simulation\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with multiple orthogonal biophysical methods in a single study\",\n      \"pmids\": [\"37416798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUN1 facilitates nuclear influx of CHMP7 (ESCRT-III protein) in sporadic ALS neurons; impaired NPC permeability barrier and SUN1 interactions promote CHMP7 nuclear accumulation, which initiates NPC injury cascades leading to nucleoporin loss and TDP-43 mislocalization.\",\n      \"method\": \"iPSN model of sALS, co-immunoprecipitation, imaging, siRNA knockdown\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSN disease model with defined molecular mechanism (SUN1-CHMP7 interaction) and pathway placement, single lab\",\n      \"pmids\": [\"37639327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LPS-induced M1 macrophage polarization decreases SUN1/2 protein levels via a CK2-βTrCP-dependent proteasomal degradation pathway; loss of SUN1/2 shrinks and softens the nucleus, altering chromatin accessibility for M1-associated gene expression. The transmembrane helix of SUN1/2 is required and sufficient for nuclear mechano-remodeling.\",\n      \"method\": \"siRNA/shRNA depletion, proteasome inhibitors, domain deletion mutants, ATAC-seq, AFM nuclear stiffness measurements, mouse tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical pathway dissection, chromatin accessibility, nuclear mechanics, in vivo mouse models) in a single study\",\n      \"pmids\": [\"37828059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUN1 is required for cytoskeletal force generation and focal adhesion maturation; SUN1 depletion reduces integrin β1 activation, impairs vinculin and zyxin incorporation into nascent focal adhesions, disrupts actin organization, and reduces traction force generation, while SUN2 cannot compensate.\",\n      \"method\": \"siRNA knockdown, traction force microscopy, immunofluorescence, integrin activation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — traction force microscopy plus focal adhesion analysis with isoform-specific depletion, single lab\",\n      \"pmids\": [\"35663386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUN1 depletion by siRNA removes DYT1 dystonia torsinA-ΔE (but not ATP-locked torsinA) from the nuclear envelope; torsinA-ΔE localization to the NE requires the torsinA membrane association domain and residue Y147, implicating an abnormal gain-of-function SUN1-torsinA interaction in DYT1 dystonia pathogenesis distinct from the LAP1-torsinA interaction.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence, site-directed mutagenesis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with defined localization readout and mutagenesis, single lab\",\n      \"pmids\": [\"21627841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUN1 interacts with both MAJIN and SPDYA at overlapping N-terminal domain sites; MAJIN interaction is stronger than TERB1 interaction. SPDYA binds SUN1 via its Ringo domain and recruits CDK2; CDK2 inhibition decreases the SUN1-MAJIN interaction, suggesting CDK2-dependent regulation of telomere-NE tethering.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, domain mapping, kinase inhibition\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct binding assays with domain mapping and pharmacological modulation, single lab\",\n      \"pmids\": [\"33015044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of SUN1 inhibits HIV-1 infection in a capsid (CA)-dependent manner, blocking nuclear import of viral cDNA; sensitivity to SUN1 depends on the interaction between HIV-1 CA and cyclophilin A (CypA), as cyclosporine treatment or CA-G89A mutation (which abrogates CypA binding) confers resistance. Both SUN1 overexpression and knockdown inhibit HIV-1 nuclear entry.\",\n      \"method\": \"Overexpression, CRISPR knockout, chimeric virus analysis, cyclosporine treatment, 2-LTR circle quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple viral and cellular genetic tools with defined molecular mechanism (CypA-CA dependence), single lab\",\n      \"pmids\": [\"29643244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Elevated SUN1 disrupts fibroblast front-rear cell polarity by mechanically coupling microtubules to the nuclear lamina via direct SUN1-lamin A interaction and force transmission through nesprin-2; stable microtubules are necessary and sufficient to inhibit cell polarity; chimeric SUN1-SUN2 proteins show the SUN domain determines their divergent roles in polarization.\",\n      \"method\": \"SUN1-SUN2 chimeric protein expression, siRNA knockdown, microtubule stabilization/depolymerization, nuclear repositioning assays, live imaging\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-swap chimeras with pharmacological and genetic perturbations, single lab, two parallel publications (PMID:41366027 and preprint)\",\n      \"pmids\": [\"41366027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The common SUN1 variant H118Y undergoes increased proteasomal degradation relative to wild-type SUN1; cells expressing H118Y SUN1 exhibit insulin resistance and increased lipid accumulation.\",\n      \"method\": \"Proteasome inhibition, Western blotting, cell-based lipid accumulation and insulin signaling assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — variant protein stability and cellular functional assays, single lab\",\n      \"pmids\": [\"37567366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A CCDC155 missense mutation blocks nuclear envelope distribution of SUN1 in human spermatocytes, demonstrating that the SUN1-CCDC155 complex is required for telomere attachment and NE anchoring during human meiosis; loss of this complex causes meiotic arrest in both sexes.\",\n      \"method\": \"Whole-exome sequencing, patient spermatocyte histology, immunofluorescence, co-localization, ex vivo and in vitro expression studies\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient genetic variant with cellular mechanistic validation showing SUN1 mislocalization, single lab\",\n      \"pmids\": [\"35587281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SUN1 is required for NPC concentration along Actin/LINC/Lamin (ALL) nuclear lines in response to uniaxial cyclic stretch; CRISPR knockdown and knockout of SUN1 significantly diminishes NPC/ALL line integration, with reduced Pom121, TPR, and Nup153 fluorescence at ALL lines.\",\n      \"method\": \"CRISPR SUN1 KD/KO, cyclic stretch, live imaging, immunofluorescence quantification of nucleoporins\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout with defined NPC reorganization phenotype under mechanical stimulation, single lab\",\n      \"pmids\": [\"36619427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sun1 deficiency in mice leads to repression of meiotic reproductive gene expression in testes and absence of detectable piRNA, identifying an unrecognized role of Sun1 in selective gene expression during gametogenesis.\",\n      \"method\": \"Sun1 knockout mice, transcriptomic analysis, piRNA Northern blot\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with molecular gene expression readouts, single lab\",\n      \"pmids\": [\"19211677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUN1 interacts with CUL3 E3 ubiquitin ligase; wild-type SUN1 robustly interacts with CUL3 while H118Y SUN1 shows markedly diminished CUL3 interaction. SUN1 silencing or H118Y expression increases CUL3 neddylation, which promotes CRL-mediated ubiquitination of IRS proteins and insulin resistance; neddylation inhibition restores IRS-1 levels and insulin signaling.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, siRNA knockdown, neddylation inhibitors, Western blotting\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — AP-MS with biochemical validation and pharmacological rescue, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"42079055\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SUN1 is an integral inner nuclear membrane protein that forms the nucleoplasmic half of the LINC complex by binding nuclear lamins (preferentially lamin A via its N-terminal domain and B-type lamins via splice-variant-specific interactions) and connecting through its trimeric coiled-coil luminal region and C-terminal SUN domain to the KASH domains of cytoplasmic nesprins, thereby mechanically coupling chromatin and the nuclear lamina to the actin, microtubule, and dynein/dynactin cytoskeleton; SUN1 also associates with nuclear pore complexes (promoting their interphase assembly and distribution), directly interacts with NXF1 and Nup153 to facilitate mRNA export via the NXF1-dependent pathway (regulated by PKC phosphorylation of S113), localizes to meiotic telomeres where it interacts with KASH5, MAJIN, and SPDYA-CDK2 to tether telomeres to the NE and enable chromosome movements required for homolog pairing, and undergoes mitotic phosphorylation by Cdk1 (S48, S333) and Plk1 (S138) that loosens its nucleoplasmic interactions while preserving the core LINC complex; pathologically, SUN1 accumulation driven by dysregulated interaction with farnesylated progerin contributes to laminopathy disease progression, and its depletion rescues nuclear defects in Hutchinson-Gilford progeria syndrome and EDMD models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUN1 is an integral inner nuclear membrane protein that forms the nucleoplasmic half of the LINC complex, mechanically coupling chromatin and the nuclear lamina to the cytoskeleton: its N-terminal nucleoplasmic domain binds lamin A and its C-terminal luminal SUN domain engages the KASH domains of nesprins, building a continuous bridge across the nuclear envelope [#0]. SUN1 is required for nuclear-envelope retention of nesprins via the conserved PPPX motif, and it forms highly immobile oligomers through a self-associating C-terminal coiled-coil that also heterodimerizes with SUN2 [#1, #4]; its luminal region adopts a flexible trimeric coiled-coil architecture that may extend the LINC network through domain-swap interactions [#23]. Through nesprin connections to dynein/dynactin and kinesin, SUN1 (acting redundantly with SUN2) anchors and moves nuclei during interkinetic nuclear migration, photoreceptor positioning, and myonuclear anchorage [#5, #11]. SUN1 couples microtubules to the lamina and tunes cytoskeletal signaling, regulating focal-adhesion maturation and integrin/traction force, endothelial junction stability via a microtubule–GEF-H1–Rho axis, and front-rear cell polarity through a SUN-domain-determined function distinct from SUN2 [#26, #21, #30]. In meiosis, SUN1 specifically attaches telomeres to the nuclear envelope, interacting with the KASH protein KASH5/CCDC155, MAJIN, and a SPDYA-CDK2 module to assemble a telomere supramolecular ring that drives homolog pairing and synapsis; loss of Sun1 abolishes gametogenesis [#3, #9, #18, #28, #32]. Beyond mechanical coupling, SUN1 associates with nuclear pore complexes to promote their interphase assembly and distribution, and it directly binds NXF1 and Nup153 to support NXF1-dependent mRNA export, a function regulated by PKC phosphorylation of S113 [#2, #7, #16, #17]. Mitotic phosphorylation by Cdk1 (S48, S333) and Plk1 (S138) loosens SUN1's nucleoplasmic interactions while preserving the core SUN-KASH bridge [#13]. Pathologically, SUN1 over-accumulation driven by its dysregulated interaction with farnesylated progerin is a common event in laminopathies, and reducing SUN1 rescues nuclear defects in HGPS and EDMD models [#8, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the founding LINC architecture by showing SUN1 physically bridges the lamina to the cytoskeleton, answering how the inner nuclear membrane connects to cytoplasmic structures.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and domain mapping defining lamin A binding by the N-terminus and nesprin KASH binding by the SUN domain, confirmed by an independent lab the same year\",\n      \"pmids\": [\"16648470\", \"16079285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the SUN-KASH interface not resolved\", \"Whether B-type lamins also engage SUN1 not addressed here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped the determinants of SUN1 NE targeting, showing the N-terminal ~300 residues are required and the SUN domain dispensable, and that anchoring is lamin-independent.\",\n      \"evidence\": \"Truncation mutants, RNAi lamin knockdown, immunofluorescence and FRAP\",\n      \"pmids\": [\"16445915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular retention partner within the N-terminus not identified\", \"Apparent tension with later lamin-dependent recruitment models not reconciled\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended SUN1's role beyond the LINC bridge to nuclear pore complex organization, showing it associates with NPCs and maintains their even distribution.\",\n      \"evidence\": \"Immunofluorescence, immunoelectron microscopy, RNAi, and topology analysis showing NPC clustering on SUN1 loss\",\n      \"pmids\": [\"17724119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NPC-binding partner not identified at this stage\", \"Mechanism distinguishing SUN1 from SUN2 in NPC association unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined a meiotic function by showing SUN1 tethers telomeres to the NE for homolog pairing, explaining a non-somatic role of the LINC complex.\",\n      \"evidence\": \"Sun1 knockout mice with FISH and immunofluorescence showing failed telomere attachment, pairing, and sterility\",\n      \"pmids\": [\"17543860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The telomere-side and force-generating partners not yet identified\", \"How telomere movement couples to the cytoskeleton unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Explained SUN1's immobility and network potential by demonstrating disulfide-linked self-oligomerization and heterophilic association with SUN2.\",\n      \"evidence\": \"Inverse FRAP, cross-linking, and mutagenesis defining coiled-coil dimers/tetramers\",\n      \"pmids\": [\"18845190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological oligomeric state in intact LINC complexes not defined\", \"Functional consequence of SUN1-SUN2 heteromers unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated genetic redundancy of SUN1 and SUN2 in nuclear anchoring and connected the complex to nesprin localization in muscle.\",\n      \"evidence\": \"Single and double Sun1/Sun2 knockout mice with graded phenotypes and Nesprin-1 mislocalization\",\n      \"pmids\": [\"19509342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific contributions within muscle not dissected\", \"Mechanical force requirements not measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a transcriptional/gene-regulatory dimension of SUN1 in gametogenesis, showing it is needed for meiotic gene expression and piRNA production.\",\n      \"evidence\": \"Sun1 knockout transcriptomics and piRNA Northern blot in testes\",\n      \"pmids\": [\"19211677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the gene-expression defect is secondary to telomere/pairing failure unresolved\", \"No direct SUN1-chromatin mechanism shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed SUN1 in NPC biogenesis by showing it is specifically required for interphase, not post-mitotic, pore assembly.\",\n      \"evidence\": \"RNAi with cell-cycle staging and co-localization with POM121 at assembly sites\",\n      \"pmids\": [\"21727197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role at the assembly intermediate not defined\", \"Relationship to NPC clustering phenotype not integrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected SUN1/SUN2-nesprin-2 complexes to motor-driven nuclear migration in vivo, explaining tissue-level consequences of LINC disruption.\",\n      \"evidence\": \"Sun1/Sun2 double knockout mice with retinal phenotypes, ERG, and Co-IP linking nesprin-2 to dynein/dynactin and kinesin\",\n      \"pmids\": [\"21177258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect SUN1-motor coupling not separated\", \"Force magnitudes during INM not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the SPDYA/KASH5-dynein axis as the meiotic telomere force machinery downstream of SUN1.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and mouse genetics showing KASH5 binds SUN1 and recruits dynein-dynactin\",\n      \"pmids\": [\"22826121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the telomere-LINC assembly not yet resolved\", \"Regulation of attachment timing unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a DNA-damage-response role for SUN proteins, linking them to ATM/H2A.X activation and DNA-PK.\",\n      \"evidence\": \"Sun1/Sun2 double knockout MEFs with S-phase arrest and Co-IP with DNA-PK components\",\n      \"pmids\": [\"22863315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect SUN-DNA-PK interaction not validated reciprocally\", \"Whether the phenotype reflects mechanics or signaling unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established SUN1 over-accumulation as a common pathogenic driver in laminopathies and a therapeutic target, by showing SUN1 removal rescues disease.\",\n      \"evidence\": \"Sun1 loss in Lmna-/- and progeroid mice extending lifespan, plus SUN1 reduction correcting HGPS fibroblast defects\",\n      \"pmids\": [\"22541428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of SUN1 accumulation not defined in this study\", \"Tissue-specific contributions to rescue not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the mechanism of pathological SUN1 accumulation as a farnesylation-enhanced progerin-SUN1 interaction occurring during NE reformation.\",\n      \"evidence\": \"EM, FRAP, Co-IP, and farnesylation mutants showing progerin retains SUN1 in the ER\",\n      \"pmids\": [\"24522183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why accumulation is cumulative across divisions not fully mechanistic\", \"Whether this drives all laminopathy pathologies unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed mitotic kinases dynamically remodel SUN1 interactions, explaining how the LINC complex is regulated through the cell cycle.\",\n      \"evidence\": \"Mass spectrometry phosphosite mapping, kinase assays, and phosphomimetic mutants altering solubility and NE retention\",\n      \"pmids\": [\"25482198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for mitotic nuclear envelope breakdown not measured in vivo\", \"Phosphatase that reverses these marks unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked SUN1 point mutations to muscular dystrophy through defective nuclear-microtubule coupling and myonuclear positioning.\",\n      \"evidence\": \"Patient fibroblasts and C2C12 myotubes expressing A203V/A614V variants with impaired lamin A/C and emerin binding and pericentrin recruitment\",\n      \"pmids\": [\"25210889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality of variants in patients not established by family genetics here\", \"Microtubule nucleation mechanism at the NE not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected SUN1 to farnesylated prelamin A recruitment during myoblast differentiation, relevant to EDMD pathology.\",\n      \"evidence\": \"Immunofluorescence and pharmacological farnesylation inhibition in human myoblasts\",\n      \"pmids\": [\"21311568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct prelamin A-SUN1 binding not biochemically isolated\", \"Causal link to myonuclear positioning correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Assigned SUN1 a direct role in mRNA export, showing it recruits mRNP complexes to the NPC via NXF1 and Nup153.\",\n      \"evidence\": \"siRNA, Co-IP, GST pulldown, and poly(A)+ RNA in situ hybridization showing nuclear RNA retention on SUN1 loss\",\n      \"pmids\": [\"26476453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether export and LINC functions are separable not fully resolved\", \"Quantitative contribution of SUN1 to bulk export unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PKC phosphorylation of S113 as the switch governing the export-competent SUN1-NXF1 interaction.\",\n      \"evidence\": \"S113A/S113D mutagenesis with poly(A)+ RNA in situ rescue assays\",\n      \"pmids\": [\"28831067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals activating PKC toward SUN1 unknown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided structural and in vivo proof that the SUN1-SPDYA-CDK2 module builds the telomere supramolecular ring needed for meiotic pairing.\",\n      \"evidence\": \"Crystal structure of the ternary complex plus SPDYA-binding-deficient SUN1 knock-in mice\",\n      \"pmids\": [\"34039995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CDK2 activity is timed to attachment not fully defined\", \"Ring assembly dynamics not visualized live\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped overlapping MAJIN/SPDYA binding sites on the SUN1 N-terminus and showed CDK2-dependent regulation of telomere tethering.\",\n      \"evidence\": \"Co-IP, GST pulldown, domain mapping, and CDK2 inhibition\",\n      \"pmids\": [\"33015044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition vs cooperation among partners at overlapping sites unresolved\", \"Direct binding affinities not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Solved the luminal trimeric coiled-coil structure, providing a model for SUN1 flexibility and LINC network formation.\",\n      \"evidence\": \"X-ray crystallography, SAXS, and molecular dynamics of the luminal region\",\n      \"pmids\": [\"37416798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain-swap network model not validated in cells\", \"Coupling to KASH binding in the full-length protein not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed isoform-specific SUN1 functions, with splice variants exerting opposing effects on directional cell migration and B-type lamin binding.\",\n      \"evidence\": \"Isoform-specific siRNA, overexpression, migration assays, and Co-IP\",\n      \"pmids\": [\"27858498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of isoform-specific lamin binding unknown\", \"Mechanism of opposing migration effects not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SUN1 is required for cytoskeletal force generation, integrin activation, and focal adhesion maturation, with SUN2 unable to compensate.\",\n      \"evidence\": \"siRNA, traction force microscopy, and focal adhesion/integrin assays\",\n      \"pmids\": [\"35663386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from SUN1 to integrin activation not defined\", \"SUN1-specific determinant of this role not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated SUN1 organizes NPC concentration along mechanically induced ALL nuclear lines, linking it to mechanoresponsive pore positioning.\",\n      \"evidence\": \"CRISPR KD/KO under cyclic stretch with nucleoporin quantification\",\n      \"pmids\": [\"36619427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nucleoporin partners at ALL lines not all identified\", \"Physiological role of ALL-line NPCs unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SUN1 upstream of microtubule-GEF-H1-Rho signaling controlling endothelial junction stability and vascular sprouting.\",\n      \"evidence\": \"Endothelial knockout mice, zebrafish morpholino, live microtubule imaging, and GEF-H1/nesprin-1 rescue epistasis\",\n      \"pmids\": [\"36989130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUN1 controls peripheral microtubule stability mechanistically unresolved\", \"Direct vs indirect GEF-H1 regulation not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a mechanical feedback circuit between the LINC complex and RhoA-actomyosin in vascular smooth muscle.\",\n      \"evidence\": \"siRNA, FRAP, RhoA activity assays, and pharmacological actomyosin inhibition in VSMCs\",\n      \"pmids\": [\"31935926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of the feedback not fully causal\", \"SUN1 vs SUN2 specific contributions intertwined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked SUN1/SUN2 turnover to inflammatory nuclear mechano-remodeling, showing CK2-βTrCP degradation softens the nucleus to enable M1 gene expression.\",\n      \"evidence\": \"shRNA/siRNA, proteasome inhibitors, ATAC-seq, AFM stiffness, and tumor models showing the transmembrane helix is sufficient\",\n      \"pmids\": [\"37828059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the transmembrane helix alone remodels nuclear mechanics not mechanistic\", \"Generality beyond macrophages untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a non-canonical SUN1 role in miRNA biogenesis, with a muscle isoform binding and inhibiting Drosha.\",\n      \"evidence\": \"Co-IP and miRNA profiling in WT vs SUN1-null myotubes\",\n      \"pmids\": [\"31686651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Drosha inhibition not fully resolved\", \"How a NE protein accesses the microprocessor unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed elevated SUN1 disrupts cell polarity by coupling stable microtubules to the lamina, with the SUN domain dictating divergence from SUN2.\",\n      \"evidence\": \"SUN1-SUN2 chimeras, siRNA, microtubule perturbation, and nuclear repositioning assays\",\n      \"pmids\": [\"41366027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why microtubule stabilization inhibits polarity not mechanistic\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated SUN1 in restricting HIV-1 nuclear import in a capsid- and cyclophilin A-dependent manner.\",\n      \"evidence\": \"Overexpression, CRISPR knockout, chimeric viruses, cyclosporine, and 2-LTR circle quantification\",\n      \"pmids\": [\"29643244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SUN1-capsid interaction not demonstrated\", \"Why both overexpression and knockdown inhibit import unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected SUN1 to DYT1 dystonia by showing it abnormally retains torsinA-ΔE at the NE.\",\n      \"evidence\": \"siRNA, Co-IP, immunofluorescence, and mutagenesis\",\n      \"pmids\": [\"21627841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the SUN1-torsinA interaction is direct unclear\", \"Pathogenic significance in patients not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in human meiosis that the SUN1-CCDC155 complex is required for telomere NE anchoring, extending the mouse model to human fertility disease.\",\n      \"evidence\": \"Whole-exome sequencing of patients with a CCDC155 mutation and spermatocyte immunofluorescence showing SUN1 mislocalization\",\n      \"pmids\": [\"35587281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-family genetic evidence\", \"Direct mutation effect on binding not biochemically isolated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked a common SUN1 variant H118Y to metabolic dysfunction through increased SUN1 degradation, insulin resistance, and lipid accumulation.\",\n      \"evidence\": \"Proteasome inhibition and cell-based insulin/lipid assays\",\n      \"pmids\": [\"37567366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting SUN1 loss to insulin signaling not defined here\", \"In vivo metabolic validation absent\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a metabolic mechanism whereby SUN1-CUL3 binding restrains CUL3 neddylation and IRS ubiquitination, with H118Y impairing this control.\",\n      \"evidence\": \"AP-MS, Co-IP, neddylation inhibitors, and Western blotting (preprint)\",\n      \"pmids\": [\"42079055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How a NE protein regulates cytoplasmic CRL activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SUN1's many separable functions — mechanical LINC coupling, NPC assembly, mRNA export, miRNA processing, and metabolic E3-ligase regulation — are partitioned, regulated, and prioritized within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model separating mechanical from biochemical SUN1 functions\", \"Isoform- and tissue-specific function allocation incompletely mapped\", \"Structure of the full-length, membrane-embedded SUN1 in an intact LINC complex not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [15, 21, 30]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [20, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 9, 18, 32]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 7, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 11, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 14, 15]}\n    ],\n    \"complexes\": [\"LINC complex\", \"telomere-LINC supramolecular ring (SUN1-KASH5-SPDYA-CDK2)\"],\n    \"partners\": [\"LMNA\", \"SYNE2\", \"KASH5\", \"NXF1\", \"NUP153\", \"SPDYA\", \"MAJIN\", \"CUL3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}