{"gene":"SPIN1","run_date":"2026-06-10T07:46:40","timeline":{"discoveries":[{"year":2015,"finding":"SPIN1 directly enhances expression of GDNF (an activator of the RET signaling pathway) in cooperation with the transcription factor MAZ by binding to chromatin; a reader-domain mutation that interferes with chromatin binding reduces liposarcoma cell proliferation and survival, demonstrating that chromatin association is required for SPIN1's oncogenic function.","method":"Genome-wide chromatin binding (ChIP-seq), transcriptome analysis, knockdown of SPIN1/MAZ, active-site mutagenesis of the reader domain, xenograft mouse models","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, transcriptomics, mutagenesis, in vivo xenograft) in a single focused study","pmids":["25749382"],"is_preprint":false},{"year":2018,"finding":"SPIN1 sequesters the ribosomal protein uL18 (RPL5) in the nucleolus, preventing uL18 from interacting with MDM2 and thereby relieving uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 depletion increases free uL18 and uL5, which are required for SPIN1-depletion-induced p53 activation.","method":"Co-immunoprecipitation (SPIN1–uL18 binding), nucleolar fractionation, knockdown/ablation of SPIN1, epistasis with uL18/uL5 depletion, cell growth/apoptosis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, fractionation, genetic epistasis, multiple orthogonal functional readouts in a single rigorous study","pmids":["29547122"],"is_preprint":false},{"year":2019,"finding":"SPIN1 is a methyllysine reader protein; a potent and selective fragment-like inhibitor (MS31/compound 3) was developed that binds specifically to tudor domain II of SPIN1, blocking binding of trimethyllysine-containing peptides. Crystal structure of the SPIN1–MS31 complex confirmed tudor domain II selectivity.","method":"Biochemical binding assay (trimethyllysine peptide displacement), crystal structure determination (SPIN1–inhibitor complex), cellular target engagement assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, confirmed in cells, rigorous selectivity profiling","pmids":["31260300"],"is_preprint":false},{"year":2024,"finding":"SPIN1 co-crystal structure with compound 11 confirmed that inhibitors occupy one of the three Tudor domains of SPIN1. A SPIN1-selective inhibitor (MS8535/compound 18) disrupts SPIN1–H3 interactions in cells in a concentration-dependent manner and shows oral bioavailability in mice.","method":"Co-crystal structure (SPIN1–compound 11), selectivity panel (38 epigenetic targets), cellular NanoBRET/proximity assay, pharmacokinetic assessment in mice","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure confirmed mechanism, orthogonal selectivity and cellular engagement data","pmids":["38533580"],"is_preprint":false},{"year":2024,"finding":"CH3–π interactions between methyl groups of asymmetric dimethylarginine (H3R8me2a) and aromatic cage residues in the SPIN1 triple Tudor domain are electrostatically tunable (cation-π character), providing a mechanistic explanation for how arginine methylation creates a new binding epitope recognized by SPIN1.","method":"Quantitative binding assays with Tudor domain mutants, computational electrostatic analysis (cation-π), model peptide experiments (NMR/fluorescence)","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mechanistic in vitro study with mutagenesis and computation, single lab","pmids":["39023428"],"is_preprint":false},{"year":2024,"finding":"SPIN1 is recruited to DNA double-strand break lesions via its N-terminal intrinsically disordered region (IDR) that binds Poly-ADP-ribose (PAR). At damage sites, SPIN1 promotes H3K9me3 accumulation and enhances the interaction between H3K9me3 and Tip60, thereby activating ATM and homologous recombination (HR) repair.","method":"Laser micro-irradiation/live-cell imaging (recruitment assay), PAR binding assay, Co-IP (SPIN1–Tip60–H3K9me3), knockdown with DSB repair readouts (γH2AX, HR reporter), ATM activation assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, PAR binding, Co-IP, functional HR assay) in a single study establishing mechanism","pmids":["39090319"],"is_preprint":false},{"year":2024,"finding":"SPIN1's N-terminal IDR drives formation of liquid-like phase-separated condensates that recruit the histone methyltransferase MLL1, enrich H3K4 methylation marks, facilitate SPIN1 binding to H3K4me3, and enhance SPIN1 genome-wide chromatin binding at MAPK pathway genes.","method":"Phase separation assay in vitro and in cells (fluorescence microscopy, FRAP), Co-condensate assay (SPIN1–MLL1), ChIP-seq (genome-wide chromatin occupancy with and without IDR), H3K4me3 ChIP","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (FRAP, Co-IP, ChIP-seq), single lab","pmids":["38777743"],"is_preprint":false},{"year":2024,"finding":"SPIN1 facilitates MDM2-mediated ubiquitination and degradation of FOXO3a, leading to upregulation of FOXM1, which in turn promotes DNA double-strand break repair and NSCLC radioresistance.","method":"Knockdown/overexpression with cell proliferation, cell-cycle (G2/M), clonogenic, and DSB-repair assays; rescue experiments with FOXM1 restoration; ubiquitination assay for FOXO3a","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown-rescue epistasis with multiple functional readouts; single lab","pmids":["39548064"],"is_preprint":false},{"year":2024,"finding":"SPIN1 forms a stable complex with WDR76 while recognizing H3K4me3; cross-linking mass spectrometry and integrative structural modeling (Bayesian IMP) built a model of WDR76:SPIN1 bound to the nucleosome. Interaction network analysis of co-purifying proteins implicated this complex in the DNA damage response.","method":"Serial capture affinity purification (SCAP), cross-linking mass spectrometry, Bayesian Integrative Modeling Platform (IMP), co-purification of H3K4me3, fluorescence microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — SCAP isolation of specific complex, XL-MS, integrated structural modeling with experimental validation","pmids":["39116123"],"is_preprint":false},{"year":2025,"finding":"The SCMC component FILIA directly interacts with SPIN1 and retains it in the cytoplasm. Loss of FILIA causes residual SPIN1 to translocate to the nucleus, where it impairs H3K4me3 reprogramming and zygotic genome activation by competing with KDM5B for binding to H3K4me3.","method":"Co-immunoprecipitation (FILIA–SPIN1), subcellular fractionation/immunofluorescence (cytoplasmic vs. nuclear SPIN1), embryo live imaging, H3K4me3 ChIP in embryos, FILIA knockout mice, H3K4me3–SPIN1 interaction inhibition rescue experiment","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo fractionation, genetic KO, epistasis with KDM5B competition, functional embryo phenotype rescue","pmids":["40247146"],"is_preprint":false},{"year":2020,"finding":"SPIN1 sustains gastric cancer cell proliferation by binding to H3K4me3 at the MDM2 promoter region, activating MDM2 expression. E2F1 directly binds the SPIN1 promoter and activates SPIN1 transcription, forming a SPIN1–MDM2–p21–E2F1 positive feedback loop.","method":"ChIP (SPIN1 on MDM2 promoter H3K4me3), luciferase reporter (E2F1 on SPIN1 promoter), knockdown/overexpression with cell-cycle and proliferation assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay establish direct binding; single lab with two orthogonal methods","pmids":["32767629"],"is_preprint":false},{"year":2017,"finding":"Conditional ablation of Spin1 in murine myoblast precursors (Myf5-Cre) causes severe sarcomere disorganization, necrosis, and lethality, with genome-wide Spin1 chromatin occupancy revealing direct target genes including deregulated bHLH transcription factor networks, aberrant titin-associated proteins, and abnormal glycogen metabolism.","method":"Conditional Spin1 knockout mice (Myf5-Cre), ChIP-seq (primary myoblasts), transcriptome analysis at multiple embryonic stages, histology","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic KO with defined phenotypic readouts and genome-wide mechanistic data","pmids":["29168801"],"is_preprint":false},{"year":2019,"finding":"SPIN.DOC (Spindlin docking protein) directly interacts with SPIN1 via its C-terminal domain; SPIN.DOC overexpression increases SPIN1 expression and chromatin localization. SPIN.DOC knockdown slightly destabilizes SPIN1 without altering its chromatin localization. The SPIN.DOC–SPIN1 complex acts as a transcriptional repressor of Wnt signaling; a C-terminal deletion mutant of SPIN.DOC that cannot bind SPIN1 instead activates Wnt signaling.","method":"shRNA knockdown, Co-IP (SPIN.DOC–SPIN1), chromatin fractionation, TOPflash Wnt reporter assay, C-terminal deletion mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, chromatin fractionation, reporter assay with mutagenesis; single lab","pmids":["30803761"],"is_preprint":false},{"year":2021,"finding":"Spindoc (the Spin1-interacting cofactor that enhances Spin1 binding to histone marks) is dispensable for meiotic division but is specifically required for haploid spermatid development in mice, as shown by CRISPR/Cas9 knockout models.","method":"CRISPR/Cas9 Spindoc knockout mice (two independent models), histological and spermatid developmental analysis","journal":"Reproductive biology and endocrinology : RB&E","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with defined cellular phenotype; two independent KO models","pmids":["34526015"],"is_preprint":false},{"year":2023,"finding":"HNRNPK promotes SPIN1 exon 4 inclusion by interacting with an intronic splicing enhancer in intron 4 of SPIN1 pre-mRNA; exon 4 skipping generates a long non-coding RNA isoform that leads to reduced SPIN1 protein. SPIN1 overexpression partially rescues the growth inhibition caused by HNRNPK knockdown, placing SPIN1 downstream of HNRNPK in an epigenetic cancer regulatory pathway.","method":"RNA splicing analysis (RT-PCR), HNRNPK knockdown, SPIN1 overexpression rescue, RNABP–RNA interaction mapping (intronic splicing enhancer), cell growth/cell-cycle assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — splice site mapping, knockdown–rescue epistasis; single lab with two orthogonal methods","pmids":["36736887"],"is_preprint":false},{"year":2024,"finding":"SLXL1 and SLX (X-linked) compete with SLY1 and SLY2 (Y-linked) for binding to the third Tudor domain of SPIN1 in a dose-dependent, protein-family-specific manner; SLY1 and SLY2 form homo- and heterodimers, indicating competition between multimeric complexes. Positive selection maps to the interaction domains.","method":"Yeast-based protein–protein interaction assay, domain-deletion mapping (N-terminal and Tudor domain III of SPIN1), competition binding assay, dimerization assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast interaction system with domain-level mapping and competition assay; preprint, single lab","pmids":["bio_10.1101_2024.10.18.619120"],"is_preprint":true},{"year":2016,"finding":"SPIN1 activates the PI3K-Akt signaling pathway in breast cancer cells; knockdown of SPIN1 suppresses PIK3CA, AKT, CREB1, and BCL2, and inhibiting SPIN1 reduces cell migration, invasion, and resistance to chemotherapy.","method":"miRNA overexpression/inhibition, SPIN1 knockdown/overexpression, Western blot for PI3K-Akt pathway components, in vitro and in vivo (xenograft) functional assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement via knockdown with multiple functional readouts; indirect (miRNA target) approach, single lab","pmids":["27171498"],"is_preprint":false}],"current_model":"SPIN1 (Spindlin1) is a multivalent histone code reader that uses its three Tudor domains to recognize H3K4me3 and H3R8me2a marks on chromatin; it acts as a transcriptional co-activator that directly occupies chromatin to drive expression of oncogenic targets (e.g., GDNF/RET, MDM2, FOXM1, Cyclin D1) via cooperative interactions with partners such as MAZ, MLL1, and SPIN.DOC, while an N-terminal IDR enables phase separation to concentrate chromatin-regulatory machinery; SPIN1 also sequesters the ribosomal protein uL18 in the nucleolus to dampen the uL18–MDM2–p53 tumor-suppressive axis, is recruited to DNA double-strand breaks via PAR-binding to promote H3K9me3/Tip60/ATM-dependent HR repair, and is spatially regulated in oocytes by the SCMC component FILIA, which retains SPIN1 in the cytoplasm to prevent premature H3K4me3 reading during oocyte-to-embryo transition."},"narrative":{"mechanistic_narrative":"SPIN1 (Spindlin1) is a multivalent histone-mark reader that functions as a chromatin-associated transcriptional co-regulator driving expression of proliferative and oncogenic gene programs [PMID:25749382, PMID:29168801]. Its triple Tudor domain architecture recognizes methylated histone epitopes, with Tudor domain II engaging trimethyllysine peptides and the aromatic cage of the triple Tudor domain reading asymmetric dimethylarginine at H3R8 through electrostatically tunable CH3-π/cation-π interactions [PMID:31260300, PMID:38533580, PMID:39023428]. Through these reader activities SPIN1 occupies chromatin to activate oncogenic targets: in cooperation with the transcription factor MAZ it enhances GDNF/RET signaling [PMID:25749382], and it binds H3K4me3 at the MDM2 promoter to activate MDM2 within a SPIN1-MDM2-p21-E2F1 positive feedback loop in gastric cancer [PMID:32767629]. SPIN1 additionally controls the p53 axis post-transcriptionally by sequestering the ribosomal protein uL18 (RPL5) in the nucleolus, preventing uL18 from inhibiting MDM2 and thereby restraining p53 activation [PMID:29547122]. Its N-terminal intrinsically disordered region (IDR) is central to several activities: it drives liquid-like phase separation that recruits the methyltransferase MLL1, enriches H3K4 methylation, and amplifies genome-wide chromatin binding at MAPK pathway genes [PMID:38777743], and it binds Poly-ADP-ribose to recruit SPIN1 to DNA double-strand breaks, where it promotes H3K9me3 accumulation, H3K9me3-Tip60 interaction, ATM activation, and homologous-recombination repair [PMID:39090319]. SPIN1 forms a stable nucleosome-bound complex with WDR76 while recognizing H3K4me3 [PMID:39116123] and is regulated by cofactors including SPIN.DOC, which docks via its C-terminal domain to modulate SPIN1 chromatin localization and Wnt-repressive activity [PMID:30803761]. SPIN1 activity is spatially gated during the oocyte-to-embryo transition by the SCMC component FILIA, which retains SPIN1 in the cytoplasm; loss of FILIA permits nuclear SPIN1 to compete with KDM5B for H3K4me3 and impair zygotic genome activation [PMID:40247146]. Conditional Spin1 ablation in myoblast precursors causes severe sarcomere disorganization, necrosis, and lethality, establishing an essential developmental role through direct chromatin targets [PMID:29168801].","teleology":[{"year":2015,"claim":"Established that SPIN1's oncogenic function depends on direct chromatin association, linking it to a transcription-factor partner and a defined oncogenic target rather than a vague nuclear role.","evidence":"ChIP-seq, transcriptomics, reader-domain mutagenesis, MAZ knockdown, and xenografts in liposarcoma cells","pmids":["25749382"],"confidence":"High","gaps":["Did not resolve which histone mark drives MAZ-dependent recruitment","Generality of the GDNF/RET program beyond liposarcoma untested"]},{"year":2016,"claim":"Placed SPIN1 upstream of a canonical proliferation/survival pathway, broadening its functional output beyond direct transcription.","evidence":"SPIN1 knockdown/overexpression with Western blots of PI3K-Akt components and migration/invasion/chemoresistance assays in breast cancer cells and xenografts","pmids":["27171498"],"confidence":"Medium","gaps":["Pathway placement via indirect miRNA-target approach","No demonstration of direct chromatin occupancy at PI3K-Akt genes"]},{"year":2017,"claim":"Demonstrated an essential in vivo developmental requirement and identified genome-wide direct targets in a non-cancer tissue.","evidence":"Conditional Spin1 knockout mice (Myf5-Cre), ChIP-seq in primary myoblasts, staged transcriptomics, and histology","pmids":["29168801"],"confidence":"High","gaps":["Which reader activity drives myoblast target selection not dissected","Mechanistic link between chromatin targets and sarcomere phenotype incomplete"]},{"year":2018,"claim":"Revealed a transcription-independent route by which SPIN1 controls p53, through nucleolar sequestration of a ribosomal protein that otherwise inhibits MDM2.","evidence":"Reciprocal Co-IP, nucleolar fractionation, SPIN1 ablation, and genetic epistasis with uL18/uL5 depletion","pmids":["29547122"],"confidence":"High","gaps":["Structural basis of SPIN1-uL18 binding unresolved","How nucleolar SPIN1 pool is partitioned from chromatin pool unclear"]},{"year":2019,"claim":"Defined SPIN1 as a druggable methyllysine reader by mapping inhibitor binding to a specific Tudor domain.","evidence":"Trimethyllysine peptide displacement assay, SPIN1-MS31 co-crystal structure, and cellular target engagement","pmids":["31260300"],"confidence":"High","gaps":["Tudor domain II selectivity did not yet block all three reader pockets","Cellular phenotypic consequences of inhibition not fully characterized"]},{"year":2019,"claim":"Identified SPIN.DOC as a direct cofactor that tunes SPIN1 stability, chromatin localization, and a Wnt-repressive output.","evidence":"Co-IP, chromatin fractionation, TOPflash reporter assays, and C-terminal deletion mutagenesis","pmids":["30803761"],"confidence":"Medium","gaps":["Single lab; no structural model of the SPIN.DOC-SPIN1 interface","Mechanism switching SPIN1 between activation and repression unresolved"]},{"year":2020,"claim":"Connected SPIN1 H3K4me3 reading to direct MDM2 promoter activation within a self-reinforcing transcriptional feedback loop.","evidence":"ChIP at the MDM2 promoter, E2F1-SPIN1 promoter luciferase reporter, and proliferation/cell-cycle assays in gastric cancer cells","pmids":["32767629"],"confidence":"Medium","gaps":["Single lab; loop dynamics not quantitatively modeled","Relationship to the nucleolar uL18-MDM2 mechanism not integrated"]},{"year":2021,"claim":"Showed the SPIN1 cofactor Spindoc has a stage-specific essential role in spermatid development, distinguishing it from meiotic function.","evidence":"Two independent CRISPR/Cas9 Spindoc knockout mouse models with histological spermatid analysis","pmids":["34526015"],"confidence":"Medium","gaps":["Whether the phenotype requires SPIN1 binding not directly tested","Molecular targets of the Spindoc-SPIN1 complex in spermatids unknown"]},{"year":2023,"claim":"Identified an upstream RNA-level control of SPIN1 abundance via alternative splicing, placing SPIN1 downstream of an RNA-binding regulator in cancer growth.","evidence":"RT-PCR splicing analysis, HNRNPK knockdown, intronic splicing enhancer mapping, and SPIN1 overexpression rescue","pmids":["36736887"],"confidence":"Medium","gaps":["Single lab; in vivo relevance of the lncRNA isoform untested","How splicing choice is regulated across tissues unknown"]},{"year":2024,"claim":"Established that SPIN1's N-terminal IDR drives phase separation that recruits MLL1, locally enriches H3K4 methylation, and amplifies genome-wide chromatin binding.","evidence":"In vitro and cellular phase-separation assays with FRAP, SPIN1-MLL1 co-condensate assays, and IDR-dependent ChIP-seq","pmids":["38777743"],"confidence":"Medium","gaps":["Single lab; physiological condensate concentration thresholds unclear","Whether condensation is required in vivo not tested"]},{"year":2024,"claim":"Defined a DNA-damage role: the same IDR binds PAR to recruit SPIN1 to double-strand breaks where it promotes H3K9me3-Tip60-ATM-driven homologous recombination.","evidence":"Laser micro-irradiation imaging, PAR binding assay, Co-IP, HR reporter, and ATM activation assays","pmids":["39090319"],"confidence":"High","gaps":["How SPIN1 promotes H3K9me3 accumulation mechanistically unclear","Relationship between PAR-recruited and transcription-associated SPIN1 pools unresolved"]},{"year":2024,"claim":"Provided a structural model of SPIN1 in a stable complex by mapping the WDR76:SPIN1 nucleosome assembly and linking it to the DNA damage response.","evidence":"Serial capture affinity purification, cross-linking mass spectrometry, and Bayesian integrative structural modeling with H3K4me3 co-purification","pmids":["39116123"],"confidence":"High","gaps":["Functional consequence of WDR76 binding for SPIN1 reader activity not dissected","Whether this complex overlaps with the PAR/HR pathway untested"]},{"year":2024,"claim":"Advanced selective chemical probes occupying a Tudor pocket and disrupting SPIN1-H3 binding in cells with oral bioavailability, enabling in vivo interrogation.","evidence":"SPIN1-compound 11 co-crystal, 38-target selectivity panel, NanoBRET cellular engagement, and mouse pharmacokinetics","pmids":["38533580"],"confidence":"High","gaps":["In vivo efficacy against SPIN1-driven tumors not yet shown","Probe occupies a single Tudor domain, leaving other reader functions intact"]},{"year":2024,"claim":"Provided the physico-chemical basis for arginine-methyl recognition, explaining how H3R8me2a creates a new SPIN1 binding epitope.","evidence":"Quantitative binding with Tudor mutants, computational electrostatic (cation-π) analysis, and model peptide experiments","pmids":["39023428"],"confidence":"Medium","gaps":["Single lab in vitro study","Cellular consequence of tuned H3R8me2a reading not tested"]},{"year":2024,"claim":"Mapped a competitive, X/Y-linked protein interaction network on SPIN1's third Tudor domain, implicating SPIN1 in genetic conflict between paralog families.","evidence":"Yeast protein-interaction assays, domain-deletion mapping, competition binding, and dimerization assays (preprint)","pmids":["bio_10.1101_2024.10.18.619120"],"confidence":"Medium","gaps":["Preprint; interactions not validated in mammalian cells","Functional consequence of SLX/SLY competition unknown"]},{"year":2025,"claim":"Showed SPIN1 reader activity must be spatially restrained during the oocyte-to-embryo transition, identifying FILIA-mediated cytoplasmic retention as the gating mechanism.","evidence":"Co-IP, subcellular fractionation/immunofluorescence, FILIA knockout mice, embryo H3K4me3 ChIP, and KDM5B-competition rescue","pmids":["40247146"],"confidence":"High","gaps":["Molecular basis of FILIA-SPIN1 cytoplasmic anchoring unresolved","Whether other SPIN1 nuclear functions are similarly gated unknown"]},{"year":null,"claim":"How SPIN1's distinct functional pools — chromatin reader, nucleolar uL18 sequestration, PAR-recruited DSB repair factor, and phase-separated condensate hub — are coordinated and partitioned within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling the nucleolar, chromatin, and DNA-damage pools","Post-translational or partner-driven switching between these functions uncharacterized","Integration of cytoplasmic gating (FILIA) with somatic-cell functions untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2,3,4,8,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,10,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,9,10]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,10,11]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,16]}],"complexes":["WDR76:SPIN1 nucleosome complex","SPIN.DOC-SPIN1 complex"],"partners":["MAZ","RPL5","MLL1","WDR76","SPIN.DOC","FILIA","KAT5","HNRNPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2V7","full_name":"Protein spinster homolog 1","aliases":["HSpin1","SPNS1","Spinster-like protein 1"],"length_aa":528,"mass_kda":56.6,"function":"Plays a critical role in the phospholipid salvage pathway from lysosomes to the cytosol (PubMed:36161949, PubMed:37075117). Mediates the rate-limiting, proton-dependent, lysosomal efflux of lysophospholipids, which can then be reacylated by acyltransferases in the endoplasmic reticulum to form phospholipids (PubMed:36161949, PubMed:37075117). Selective for zwitterionic headgroups such as lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), can also transport lysophosphatidylglycerol (LPG), but not other anionic lysophospholipids, sphingosine, nor sphingomyelin (PubMed:36161949). Transports lysophospholipids with saturated, monounsaturated, and polyunsaturated fatty acids, such as 1-hexadecanoyl-sn-glycero-3-phosphocholine, 1-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine and 1-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, respectively (PubMed:36161949, PubMed:37075117). Can also transport lysoplasmalogen (LPC with a fatty alcohol) such as 1-(1Z-hexadecenyl)-sn-glycero-3-phosphocholine (PubMed:36161949). Lysosomal LPC could function as intracellular signaling messenger (PubMed:37075117). Essential player in lysosomal homeostasis (PubMed:36161949). Crucial for cell survival under conditions of nutrient limitation (PubMed:37075117). May be involved in necrotic or autophagic cell death (PubMed:12815463)","subcellular_location":"Lysosome membrane; Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9H2V7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPIN1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPIN1","total_profiled":1310},"omim":[{"mim_id":"621257","title":"SPINDLIN INTERACTOR AND REPRESSOR OF CHROMATIN BINDING; SPINDOC","url":"https://www.omim.org/entry/621257"},{"mim_id":"619038","title":"SPOC DOMAIN-CONTAINING PROTEIN 1; SPOCD1","url":"https://www.omim.org/entry/619038"},{"mim_id":"612583","title":"SPHINGOLIPID TRANSPORTER 1; SPNS1","url":"https://www.omim.org/entry/612583"},{"mim_id":"610363","title":"PEPTIDYLARGININE DEIMINASE, TYPE VI; PADI6","url":"https://www.omim.org/entry/610363"},{"mim_id":"609936","title":"SPINDLIN 1; SPIN1","url":"https://www.omim.org/entry/609936"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPIN1"},"hgnc":{"alias_symbol":["TDRD24"],"prev_symbol":["SPIN"]},"alphafold":{"accession":"Q9H2V7","domains":[{"cath_id":"1.20.1250.20","chopping":"46-244","consensus_level":"medium","plddt":91.9333,"start":46,"end":244},{"cath_id":"1.20.1250.20","chopping":"261-498","consensus_level":"medium","plddt":93.0765,"start":261,"end":498}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2V7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2V7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2V7-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPIN1","jax_strain_url":"https://www.jax.org/strain/search?query=SPIN1"},"sequence":{"accession":"Q9H2V7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2V7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2V7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2V7"}},"corpus_meta":[{"pmid":"27171498","id":"PMC_27171498","title":"Suppression of SPIN1-mediated PI3K-Akt pathway by miR-489 increases chemosensitivity in breast cancer.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27171498","citation_count":103,"is_preprint":false},{"pmid":"18586868","id":"PMC_18586868","title":"SPIN1, a K homology domain protein negatively regulated and ubiquitinated by the E3 ubiquitin ligase SPL11, is involved in flowering time control in rice.","date":"2008","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/18586868","citation_count":73,"is_preprint":false},{"pmid":"28423652","id":"PMC_28423652","title":"Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28423652","citation_count":55,"is_preprint":false},{"pmid":"25749382","id":"PMC_25749382","title":"The histone code reader SPIN1 controls RET signaling in liposarcoma.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25749382","citation_count":51,"is_preprint":false},{"pmid":"29547122","id":"PMC_29547122","title":"SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29547122","citation_count":51,"is_preprint":false},{"pmid":"29743122","id":"PMC_29743122","title":"SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29743122","citation_count":50,"is_preprint":false},{"pmid":"28666210","id":"PMC_28666210","title":"miR-489 inhibits proliferation, cell cycle progression and induces apoptosis of glioma cells via targeting SPIN1-mediated PI3K/AKT pathway.","date":"2017","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/28666210","citation_count":49,"is_preprint":false},{"pmid":"31017716","id":"PMC_31017716","title":"LINC00473/miR-374a-5p regulates esophageal squamous cell carcinoma via targeting SPIN1 to weaken the effect of radiotherapy.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31017716","citation_count":39,"is_preprint":false},{"pmid":"30290307","id":"PMC_30290307","title":"miR-409 Inhibits Human Non-Small-Cell Lung Cancer Progression by Directly Targeting SPIN1.","date":"2018","source":"Molecular therapy. 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nucleosome.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39116123","citation_count":8,"is_preprint":false},{"pmid":"40247146","id":"PMC_40247146","title":"The subcortical maternal complex safeguards mouse oocyte-to-embryo transition by preventing nuclear entry of SPIN1.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40247146","citation_count":8,"is_preprint":false},{"pmid":"39548064","id":"PMC_39548064","title":"SPIN1 accelerates tumorigenesis and confers radioresistance in non-small cell lung cancer by orchestrating the FOXO3a/FOXM1 axis.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39548064","citation_count":6,"is_preprint":false},{"pmid":"36459832","id":"PMC_36459832","title":"Circ_0001686 knockdown suppresses tumorigenesis and enhances radiosensitivity in esophagus cancer through regulating miR-876-5p/SPIN1 axis.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/36459832","citation_count":6,"is_preprint":false},{"pmid":"38348706","id":"PMC_38348706","title":"Exosome-transported of circ_0081069 induces SPIN1 production by binding to miR-195-5p to inhibit radiosensitivity in esophageal squamous cell carcinoma.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38348706","citation_count":6,"is_preprint":false},{"pmid":"34526015","id":"PMC_34526015","title":"The Spin1 interactor, Spindoc, is dispensable for meiotic division, but essential for haploid spermatid development in mice.","date":"2021","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/34526015","citation_count":6,"is_preprint":false},{"pmid":"39023428","id":"PMC_39023428","title":"Contribution of Electrostatic CH3-π Interactions to Recognition of 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SPIN1 depletion increases free uL18 and uL5, which are required for SPIN1-depletion-induced p53 activation.\",\n      \"method\": \"Co-immunoprecipitation (SPIN1–uL18 binding), nucleolar fractionation, knockdown/ablation of SPIN1, epistasis with uL18/uL5 depletion, cell growth/apoptosis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, fractionation, genetic epistasis, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"29547122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPIN1 is a methyllysine reader protein; a potent and selective fragment-like inhibitor (MS31/compound 3) was developed that binds specifically to tudor domain II of SPIN1, blocking binding of trimethyllysine-containing peptides. Crystal structure of the SPIN1–MS31 complex confirmed tudor domain II selectivity.\",\n      \"method\": \"Biochemical binding assay (trimethyllysine peptide displacement), crystal structure determination (SPIN1–inhibitor complex), cellular target engagement assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, confirmed in cells, rigorous selectivity profiling\",\n      \"pmids\": [\"31260300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPIN1 co-crystal structure with compound 11 confirmed that inhibitors occupy one of the three Tudor domains of SPIN1. A SPIN1-selective inhibitor (MS8535/compound 18) disrupts SPIN1–H3 interactions in cells in a concentration-dependent manner and shows oral bioavailability in mice.\",\n      \"method\": \"Co-crystal structure (SPIN1–compound 11), selectivity panel (38 epigenetic targets), cellular NanoBRET/proximity assay, pharmacokinetic assessment in mice\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure confirmed mechanism, orthogonal selectivity and cellular engagement data\",\n      \"pmids\": [\"38533580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CH3–π interactions between methyl groups of asymmetric dimethylarginine (H3R8me2a) and aromatic cage residues in the SPIN1 triple Tudor domain are electrostatically tunable (cation-π character), providing a mechanistic explanation for how arginine methylation creates a new binding epitope recognized by SPIN1.\",\n      \"method\": \"Quantitative binding assays with Tudor domain mutants, computational electrostatic analysis (cation-π), model peptide experiments (NMR/fluorescence)\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic in vitro study with mutagenesis and computation, single lab\",\n      \"pmids\": [\"39023428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPIN1 is recruited to DNA double-strand break lesions via its N-terminal intrinsically disordered region (IDR) that binds Poly-ADP-ribose (PAR). At damage sites, SPIN1 promotes H3K9me3 accumulation and enhances the interaction between H3K9me3 and Tip60, thereby activating ATM and homologous recombination (HR) repair.\",\n      \"method\": \"Laser micro-irradiation/live-cell imaging (recruitment assay), PAR binding assay, Co-IP (SPIN1–Tip60–H3K9me3), knockdown with DSB repair readouts (γH2AX, HR reporter), ATM activation assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, PAR binding, Co-IP, functional HR assay) in a single study establishing mechanism\",\n      \"pmids\": [\"39090319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPIN1's N-terminal IDR drives formation of liquid-like phase-separated condensates that recruit the histone methyltransferase MLL1, enrich H3K4 methylation marks, facilitate SPIN1 binding to H3K4me3, and enhance SPIN1 genome-wide chromatin binding at MAPK pathway genes.\",\n      \"method\": \"Phase separation assay in vitro and in cells (fluorescence microscopy, FRAP), Co-condensate assay (SPIN1–MLL1), ChIP-seq (genome-wide chromatin occupancy with and without IDR), H3K4me3 ChIP\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (FRAP, Co-IP, ChIP-seq), single lab\",\n      \"pmids\": [\"38777743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPIN1 facilitates MDM2-mediated ubiquitination and degradation of FOXO3a, leading to upregulation of FOXM1, which in turn promotes DNA double-strand break repair and NSCLC radioresistance.\",\n      \"method\": \"Knockdown/overexpression with cell proliferation, cell-cycle (G2/M), clonogenic, and DSB-repair assays; rescue experiments with FOXM1 restoration; ubiquitination assay for FOXO3a\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown-rescue epistasis with multiple functional readouts; single lab\",\n      \"pmids\": [\"39548064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPIN1 forms a stable complex with WDR76 while recognizing H3K4me3; cross-linking mass spectrometry and integrative structural modeling (Bayesian IMP) built a model of WDR76:SPIN1 bound to the nucleosome. Interaction network analysis of co-purifying proteins implicated this complex in the DNA damage response.\",\n      \"method\": \"Serial capture affinity purification (SCAP), cross-linking mass spectrometry, Bayesian Integrative Modeling Platform (IMP), co-purification of H3K4me3, fluorescence microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — SCAP isolation of specific complex, XL-MS, integrated structural modeling with experimental validation\",\n      \"pmids\": [\"39116123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The SCMC component FILIA directly interacts with SPIN1 and retains it in the cytoplasm. Loss of FILIA causes residual SPIN1 to translocate to the nucleus, where it impairs H3K4me3 reprogramming and zygotic genome activation by competing with KDM5B for binding to H3K4me3.\",\n      \"method\": \"Co-immunoprecipitation (FILIA–SPIN1), subcellular fractionation/immunofluorescence (cytoplasmic vs. nuclear SPIN1), embryo live imaging, H3K4me3 ChIP in embryos, FILIA knockout mice, H3K4me3–SPIN1 interaction inhibition rescue experiment\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo fractionation, genetic KO, epistasis with KDM5B competition, functional embryo phenotype rescue\",\n      \"pmids\": [\"40247146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPIN1 sustains gastric cancer cell proliferation by binding to H3K4me3 at the MDM2 promoter region, activating MDM2 expression. E2F1 directly binds the SPIN1 promoter and activates SPIN1 transcription, forming a SPIN1–MDM2–p21–E2F1 positive feedback loop.\",\n      \"method\": \"ChIP (SPIN1 on MDM2 promoter H3K4me3), luciferase reporter (E2F1 on SPIN1 promoter), knockdown/overexpression with cell-cycle and proliferation assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay establish direct binding; single lab with two orthogonal methods\",\n      \"pmids\": [\"32767629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional ablation of Spin1 in murine myoblast precursors (Myf5-Cre) causes severe sarcomere disorganization, necrosis, and lethality, with genome-wide Spin1 chromatin occupancy revealing direct target genes including deregulated bHLH transcription factor networks, aberrant titin-associated proteins, and abnormal glycogen metabolism.\",\n      \"method\": \"Conditional Spin1 knockout mice (Myf5-Cre), ChIP-seq (primary myoblasts), transcriptome analysis at multiple embryonic stages, histology\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic KO with defined phenotypic readouts and genome-wide mechanistic data\",\n      \"pmids\": [\"29168801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPIN.DOC (Spindlin docking protein) directly interacts with SPIN1 via its C-terminal domain; SPIN.DOC overexpression increases SPIN1 expression and chromatin localization. SPIN.DOC knockdown slightly destabilizes SPIN1 without altering its chromatin localization. The SPIN.DOC–SPIN1 complex acts as a transcriptional repressor of Wnt signaling; a C-terminal deletion mutant of SPIN.DOC that cannot bind SPIN1 instead activates Wnt signaling.\",\n      \"method\": \"shRNA knockdown, Co-IP (SPIN.DOC–SPIN1), chromatin fractionation, TOPflash Wnt reporter assay, C-terminal deletion mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, chromatin fractionation, reporter assay with mutagenesis; single lab\",\n      \"pmids\": [\"30803761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Spindoc (the Spin1-interacting cofactor that enhances Spin1 binding to histone marks) is dispensable for meiotic division but is specifically required for haploid spermatid development in mice, as shown by CRISPR/Cas9 knockout models.\",\n      \"method\": \"CRISPR/Cas9 Spindoc knockout mice (two independent models), histological and spermatid developmental analysis\",\n      \"journal\": \"Reproductive biology and endocrinology : RB&E\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with defined cellular phenotype; two independent KO models\",\n      \"pmids\": [\"34526015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNRNPK promotes SPIN1 exon 4 inclusion by interacting with an intronic splicing enhancer in intron 4 of SPIN1 pre-mRNA; exon 4 skipping generates a long non-coding RNA isoform that leads to reduced SPIN1 protein. SPIN1 overexpression partially rescues the growth inhibition caused by HNRNPK knockdown, placing SPIN1 downstream of HNRNPK in an epigenetic cancer regulatory pathway.\",\n      \"method\": \"RNA splicing analysis (RT-PCR), HNRNPK knockdown, SPIN1 overexpression rescue, RNABP–RNA interaction mapping (intronic splicing enhancer), cell growth/cell-cycle assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — splice site mapping, knockdown–rescue epistasis; single lab with two orthogonal methods\",\n      \"pmids\": [\"36736887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLXL1 and SLX (X-linked) compete with SLY1 and SLY2 (Y-linked) for binding to the third Tudor domain of SPIN1 in a dose-dependent, protein-family-specific manner; SLY1 and SLY2 form homo- and heterodimers, indicating competition between multimeric complexes. Positive selection maps to the interaction domains.\",\n      \"method\": \"Yeast-based protein–protein interaction assay, domain-deletion mapping (N-terminal and Tudor domain III of SPIN1), competition binding assay, dimerization assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast interaction system with domain-level mapping and competition assay; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.18.619120\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPIN1 activates the PI3K-Akt signaling pathway in breast cancer cells; knockdown of SPIN1 suppresses PIK3CA, AKT, CREB1, and BCL2, and inhibiting SPIN1 reduces cell migration, invasion, and resistance to chemotherapy.\",\n      \"method\": \"miRNA overexpression/inhibition, SPIN1 knockdown/overexpression, Western blot for PI3K-Akt pathway components, in vitro and in vivo (xenograft) functional assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement via knockdown with multiple functional readouts; indirect (miRNA target) approach, single lab\",\n      \"pmids\": [\"27171498\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPIN1 (Spindlin1) is a multivalent histone code reader that uses its three Tudor domains to recognize H3K4me3 and H3R8me2a marks on chromatin; it acts as a transcriptional co-activator that directly occupies chromatin to drive expression of oncogenic targets (e.g., GDNF/RET, MDM2, FOXM1, Cyclin D1) via cooperative interactions with partners such as MAZ, MLL1, and SPIN.DOC, while an N-terminal IDR enables phase separation to concentrate chromatin-regulatory machinery; SPIN1 also sequesters the ribosomal protein uL18 in the nucleolus to dampen the uL18–MDM2–p53 tumor-suppressive axis, is recruited to DNA double-strand breaks via PAR-binding to promote H3K9me3/Tip60/ATM-dependent HR repair, and is spatially regulated in oocytes by the SCMC component FILIA, which retains SPIN1 in the cytoplasm to prevent premature H3K4me3 reading during oocyte-to-embryo transition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPIN1 (Spindlin1) is a multivalent histone-mark reader that functions as a chromatin-associated transcriptional co-regulator driving expression of proliferative and oncogenic gene programs [#0, #11]. Its triple Tudor domain architecture recognizes methylated histone epitopes, with Tudor domain II engaging trimethyllysine peptides and the aromatic cage of the triple Tudor domain reading asymmetric dimethylarginine at H3R8 through electrostatically tunable CH3-\\u03c0/cation-\\u03c0 interactions [#2, #3, #4]. Through these reader activities SPIN1 occupies chromatin to activate oncogenic targets: in cooperation with the transcription factor MAZ it enhances GDNF/RET signaling [#0], and it binds H3K4me3 at the MDM2 promoter to activate MDM2 within a SPIN1-MDM2-p21-E2F1 positive feedback loop in gastric cancer [#10]. SPIN1 additionally controls the p53 axis post-transcriptionally by sequestering the ribosomal protein uL18 (RPL5) in the nucleolus, preventing uL18 from inhibiting MDM2 and thereby restraining p53 activation [#1]. Its N-terminal intrinsically disordered region (IDR) is central to several activities: it drives liquid-like phase separation that recruits the methyltransferase MLL1, enriches H3K4 methylation, and amplifies genome-wide chromatin binding at MAPK pathway genes [#6], and it binds Poly-ADP-ribose to recruit SPIN1 to DNA double-strand breaks, where it promotes H3K9me3 accumulation, H3K9me3-Tip60 interaction, ATM activation, and homologous-recombination repair [#5]. SPIN1 forms a stable nucleosome-bound complex with WDR76 while recognizing H3K4me3 [#8] and is regulated by cofactors including SPIN.DOC, which docks via its C-terminal domain to modulate SPIN1 chromatin localization and Wnt-repressive activity [#12]. SPIN1 activity is spatially gated during the oocyte-to-embryo transition by the SCMC component FILIA, which retains SPIN1 in the cytoplasm; loss of FILIA permits nuclear SPIN1 to compete with KDM5B for H3K4me3 and impair zygotic genome activation [#9]. Conditional Spin1 ablation in myoblast precursors causes severe sarcomere disorganization, necrosis, and lethality, establishing an essential developmental role through direct chromatin targets [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that SPIN1's oncogenic function depends on direct chromatin association, linking it to a transcription-factor partner and a defined oncogenic target rather than a vague nuclear role.\",\n      \"evidence\": \"ChIP-seq, transcriptomics, reader-domain mutagenesis, MAZ knockdown, and xenografts in liposarcoma cells\",\n      \"pmids\": [\"25749382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which histone mark drives MAZ-dependent recruitment\", \"Generality of the GDNF/RET program beyond liposarcoma untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SPIN1 upstream of a canonical proliferation/survival pathway, broadening its functional output beyond direct transcription.\",\n      \"evidence\": \"SPIN1 knockdown/overexpression with Western blots of PI3K-Akt components and migration/invasion/chemoresistance assays in breast cancer cells and xenografts\",\n      \"pmids\": [\"27171498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement via indirect miRNA-target approach\", \"No demonstration of direct chromatin occupancy at PI3K-Akt genes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an essential in vivo developmental requirement and identified genome-wide direct targets in a non-cancer tissue.\",\n      \"evidence\": \"Conditional Spin1 knockout mice (Myf5-Cre), ChIP-seq in primary myoblasts, staged transcriptomics, and histology\",\n      \"pmids\": [\"29168801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which reader activity drives myoblast target selection not dissected\", \"Mechanistic link between chromatin targets and sarcomere phenotype incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a transcription-independent route by which SPIN1 controls p53, through nucleolar sequestration of a ribosomal protein that otherwise inhibits MDM2.\",\n      \"evidence\": \"Reciprocal Co-IP, nucleolar fractionation, SPIN1 ablation, and genetic epistasis with uL18/uL5 depletion\",\n      \"pmids\": [\"29547122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SPIN1-uL18 binding unresolved\", \"How nucleolar SPIN1 pool is partitioned from chromatin pool unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined SPIN1 as a druggable methyllysine reader by mapping inhibitor binding to a specific Tudor domain.\",\n      \"evidence\": \"Trimethyllysine peptide displacement assay, SPIN1-MS31 co-crystal structure, and cellular target engagement\",\n      \"pmids\": [\"31260300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tudor domain II selectivity did not yet block all three reader pockets\", \"Cellular phenotypic consequences of inhibition not fully characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SPIN.DOC as a direct cofactor that tunes SPIN1 stability, chromatin localization, and a Wnt-repressive output.\",\n      \"evidence\": \"Co-IP, chromatin fractionation, TOPflash reporter assays, and C-terminal deletion mutagenesis\",\n      \"pmids\": [\"30803761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; no structural model of the SPIN.DOC-SPIN1 interface\", \"Mechanism switching SPIN1 between activation and repression unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SPIN1 H3K4me3 reading to direct MDM2 promoter activation within a self-reinforcing transcriptional feedback loop.\",\n      \"evidence\": \"ChIP at the MDM2 promoter, E2F1-SPIN1 promoter luciferase reporter, and proliferation/cell-cycle assays in gastric cancer cells\",\n      \"pmids\": [\"32767629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; loop dynamics not quantitatively modeled\", \"Relationship to the nucleolar uL18-MDM2 mechanism not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the SPIN1 cofactor Spindoc has a stage-specific essential role in spermatid development, distinguishing it from meiotic function.\",\n      \"evidence\": \"Two independent CRISPR/Cas9 Spindoc knockout mouse models with histological spermatid analysis\",\n      \"pmids\": [\"34526015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the phenotype requires SPIN1 binding not directly tested\", \"Molecular targets of the Spindoc-SPIN1 complex in spermatids unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an upstream RNA-level control of SPIN1 abundance via alternative splicing, placing SPIN1 downstream of an RNA-binding regulator in cancer growth.\",\n      \"evidence\": \"RT-PCR splicing analysis, HNRNPK knockdown, intronic splicing enhancer mapping, and SPIN1 overexpression rescue\",\n      \"pmids\": [\"36736887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo relevance of the lncRNA isoform untested\", \"How splicing choice is regulated across tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that SPIN1's N-terminal IDR drives phase separation that recruits MLL1, locally enriches H3K4 methylation, and amplifies genome-wide chromatin binding.\",\n      \"evidence\": \"In vitro and cellular phase-separation assays with FRAP, SPIN1-MLL1 co-condensate assays, and IDR-dependent ChIP-seq\",\n      \"pmids\": [\"38777743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; physiological condensate concentration thresholds unclear\", \"Whether condensation is required in vivo not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a DNA-damage role: the same IDR binds PAR to recruit SPIN1 to double-strand breaks where it promotes H3K9me3-Tip60-ATM-driven homologous recombination.\",\n      \"evidence\": \"Laser micro-irradiation imaging, PAR binding assay, Co-IP, HR reporter, and ATM activation assays\",\n      \"pmids\": [\"39090319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPIN1 promotes H3K9me3 accumulation mechanistically unclear\", \"Relationship between PAR-recruited and transcription-associated SPIN1 pools unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided a structural model of SPIN1 in a stable complex by mapping the WDR76:SPIN1 nucleosome assembly and linking it to the DNA damage response.\",\n      \"evidence\": \"Serial capture affinity purification, cross-linking mass spectrometry, and Bayesian integrative structural modeling with H3K4me3 co-purification\",\n      \"pmids\": [\"39116123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of WDR76 binding for SPIN1 reader activity not dissected\", \"Whether this complex overlaps with the PAR/HR pathway untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Advanced selective chemical probes occupying a Tudor pocket and disrupting SPIN1-H3 binding in cells with oral bioavailability, enabling in vivo interrogation.\",\n      \"evidence\": \"SPIN1-compound 11 co-crystal, 38-target selectivity panel, NanoBRET cellular engagement, and mouse pharmacokinetics\",\n      \"pmids\": [\"38533580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy against SPIN1-driven tumors not yet shown\", \"Probe occupies a single Tudor domain, leaving other reader functions intact\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the physico-chemical basis for arginine-methyl recognition, explaining how H3R8me2a creates a new SPIN1 binding epitope.\",\n      \"evidence\": \"Quantitative binding with Tudor mutants, computational electrostatic (cation-\\u03c0) analysis, and model peptide experiments\",\n      \"pmids\": [\"39023428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab in vitro study\", \"Cellular consequence of tuned H3R8me2a reading not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a competitive, X/Y-linked protein interaction network on SPIN1's third Tudor domain, implicating SPIN1 in genetic conflict between paralog families.\",\n      \"evidence\": \"Yeast protein-interaction assays, domain-deletion mapping, competition binding, and dimerization assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.18.619120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; interactions not validated in mammalian cells\", \"Functional consequence of SLX/SLY competition unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed SPIN1 reader activity must be spatially restrained during the oocyte-to-embryo transition, identifying FILIA-mediated cytoplasmic retention as the gating mechanism.\",\n      \"evidence\": \"Co-IP, subcellular fractionation/immunofluorescence, FILIA knockout mice, embryo H3K4me3 ChIP, and KDM5B-competition rescue\",\n      \"pmids\": [\"40247146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of FILIA-SPIN1 cytoplasmic anchoring unresolved\", \"Whether other SPIN1 nuclear functions are similarly gated unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPIN1's distinct functional pools — chromatin reader, nucleolar uL18 sequestration, PAR-recruited DSB repair factor, and phase-separated condensate hub — are coordinated and partitioned within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling the nucleolar, chromatin, and DNA-damage pools\", \"Post-translational or partner-driven switching between these functions uncharacterized\", \"Integration of cytoplasmic gating (FILIA) with somatic-cell functions untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2, 3, 4, 8, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 10, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 9, 10]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 10, 11]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 16]}\n    ],\n    \"complexes\": [\n      \"WDR76:SPIN1 nucleosome complex\",\n      \"SPIN.DOC-SPIN1 complex\"\n    ],\n    \"partners\": [\n      \"MAZ\",\n      \"RPL5\",\n      \"MLL1\",\n      \"WDR76\",\n      \"SPIN.DOC\",\n      \"FILIA\",\n      \"KAT5\",\n      \"HNRNPK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}