{"gene":"PSPC1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"PSPC1 (PSP1) forms a heterodimer with p54nrb (NONO) in vivo; the DBHS domain of PSPC1 mediates this interaction. This interaction is necessary but not sufficient for paraspeckle targeting, which also requires an RNA-binding-competent RRM domain. Paraspeckle formation itself is dependent on RNA Polymerase II transcription.","method":"Co-immunoprecipitation, domain-mapping experiments, DRB-mediated transcription inhibition assay, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain-mapping and functional rescue, replicated in multiple conditions in the same study","pmids":["16148043"],"is_preprint":false},{"year":2006,"finding":"PSPC1 interacts with androgen receptor (AR) and with NONO and SFPQ in Sertoli cells, forming complexes that coactivate AR-mediated transcription; PSPC1 is the most effective coactivator among the three DBHS proteins in this context.","method":"Co-immunoprecipitation, luciferase reporter assay with androgen-responsive elements, immunohistochemistry of mouse testis sections","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods","pmids":["16641145"],"is_preprint":false},{"year":2011,"finding":"The PSPC1–NONO heterodimer was crystallized, confirming that the conserved DBHS domain (comprising two tandem RRMs, a NOPS domain, and part of a coiled-coil) provides the dimerization interface for these two paraspeckle proteins.","method":"Protein crystallography (crystal diffraction to 1.9 Å, space group C2)","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure obtained but functional validation of interface not reported in this crystallization paper alone","pmids":["22102035"],"is_preprint":false},{"year":2013,"finding":"PSPC1 is part of a transcriptional complex with LMX1B and PSF (SFPQ) in dopaminergic cells; PSPC1 was identified as a binding partner of LMX1B by affinity purification/mass spectrometry and confirmed by co-immunoprecipitation in vitro and in vivo.","method":"Affinity purification of LMX1B-HIS followed by mass spectrometry; co-immunoprecipitation in vitro and in vivo","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification followed by reciprocal Co-IP, single lab, two orthogonal methods","pmids":["23308148"],"is_preprint":false},{"year":2014,"finding":"PSPC1 is required for the G1/S DNA damage checkpoint: knockdown of PSPC1 in HeLa cells caused cells to escape cisplatin-induced G1/S arrest and enter mitosis, leading to increased cell death. PSPC1 did not co-localize with γH2AX, 53BP1, or Rad51, indicating it does not directly participate in those DNA repair pathways.","method":"siRNA knockdown, cell cycle analysis by flow cytometry, γH2AX/53BP1/Rad51 co-localization by immunofluorescence, cisplatin treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cell cycle phenotype plus negative co-localization controls, single lab","pmids":["24819514"],"is_preprint":false},{"year":2014,"finding":"PSPC1 functionally compensates for NONO in DNA double-strand break (DSB) repair: in NONO-knockout MEFs, PSPC1 is upregulated and replaces NONO in a stable complex with SFPQ. Dual knockdown of NONO and PSPC1 causes severe radiosensitivity and delayed DSB repair focus resolution. Epistasis with DNA-PK inhibitor NU7741 places NONO/PSPC1 in the same DSB repair pathway as DNA-PK.","method":"Knockout mouse-derived MEFs, siRNA knockdown, clonogenic radiosensitivity assay, γH2AX foci resolution, DNA-PK inhibitor epistasis, co-immunoprecipitation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with siRNA, functional repair assays, and pharmacological epistasis across multiple orthogonal methods","pmids":["25100870"],"is_preprint":false},{"year":2017,"finding":"PSPC1 binds intronic and 3'-UTR regions of adipocyte RNAs (including EBF1 mRNA) via CLIP-seq; it associates with the RNA export factor DDX3X in a differentiation-dependent manner. During adipogenesis, PSPC1 relocates from the nucleus to the cytoplasm, coinciding with enhanced nuclear export of adipogenic RNAs. PSPC1 knockout in fat reduces lipid storage and confers resistance to diet-induced obesity.","method":"CLIP-seq, paraspeckle complex purification from adipocytes, co-immunoprecipitation with DDX3X, subcellular fractionation/live imaging, adipose-specific knockout mouse","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP-seq, Co-IP, fractionation, and in vivo KO with defined metabolic phenotype, multiple orthogonal methods in one study","pmids":["28192372"],"is_preprint":false},{"year":2017,"finding":"NONO and PSPC1 synergistically activate transcription of Aldh1a1 in Sertoli cells by binding to a specific CCGGAGTC sequence in the Aldh1a1 promoter, protecting cells against MEHP-induced oxidative stress.","method":"siRNA knockdown of NONO and PSPC1, promoter-binding assay, gene expression analysis, oxidative stress assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding plus functional knockdown phenotype, single lab, two orthogonal methods","pmids":["28117896"],"is_preprint":false},{"year":2018,"finding":"PSPC1 interacts with phosphorylated nuclear Smad2/3 to potentiate TGF-β1 autocrine signalling, increasing TGF-β1 secretion. PSPC1 acts as a contextual determinant of Smad2/3 binding preference, switching Smad2/3 from tumour-suppressor to pro-metastatic target genes, thereby driving EMT, stemness, and metastasis.","method":"Co-immunoprecipitation of PSPC1 with pSmad2/3, TGF-β1 ELISA, ChIP-seq for Smad2/3 binding, spontaneous mouse cancer models, multiple cancer cell lines","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, in vivo mouse models, multiple cancer cell types, orthogonal mechanistic methods in one study","pmids":["29593326"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of the SFPQ/PSPC1 heterodimer resolved to 2.3 Å reveals that SFPQ-containing heterodimers dissociate at low micromolar concentrations and that SFPQ/PSPC1 heterodimer has >6-fold higher affinity than SFPQ/NONO heterodimer, providing a structural mechanism for preferential PSPC1–SFPQ heterodimerization over SFPQ homodimerization.","method":"X-ray crystallography (2.3 Å resolution), analytical ultracentrifugation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biophysical affinity measurements providing mechanistic explanation for dimerization preference","pmids":["29530979"],"is_preprint":false},{"year":2018,"finding":"PSPC1 (PSP1/p54nrb) is required for HDV replication in HEK-293 cells; HDV replication induces delocalization of PSP1 from paraspeckles to cytoplasmic foci containing PABP and increases NEAT1 levels, causing paraspeckle enlargement.","method":"RNAi-mediated knockdown in HDV-replicating HEK-293 cells, immunofluorescence for PSP1 localization, NEAT1 level quantification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with virology functional readout plus localization assay, single lab","pmids":["29662142"],"is_preprint":false},{"year":2019,"finding":"PSPC1 is a nuclear substrate of PTK6; when PSPC1 sequesters PTK6 in the nucleus, PTK6 acts as a tumour suppressor. PSPC1 overexpression or Y523F mutation promotes cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signalling and drive EMT and metastasis. Expression of PSPC1-CT131 (C-terminal 131 aa) reverses these translocations and suppresses metastasis.","method":"Co-immunoprecipitation, subcellular fractionation, site-directed mutagenesis (Y523F), HCC orthotopic mouse model, PSPC1-CT131 peptide expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, subcellular fractionation, and in vivo orthotopic model with survival endpoint, multiple orthogonal methods","pmids":["31844057"],"is_preprint":false},{"year":2020,"finding":"PSPC1 overexpression induces focal adhesion formation and activates FAK/Src signalling to enhance cell adhesion and motility. PSPC1 transcriptionally upregulates IGF1R, which mediates focal adhesion pathway activation. Knockdown of paraspeckle components NONO, FUS, and NEAT1 lncRNA abolishes PSPC1-activated IGF1R expression.","method":"Phospho-kinase antibody array, RNA-seq transcriptome analysis, protein pulldown proteomics, IGF1R siRNA/inhibitor treatment, NONO/FUS/NEAT1 siRNA knockdown","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple omics plus functional knockdown assays, single lab","pmids":["32570949"],"is_preprint":false},{"year":2021,"finding":"PSPC1 interacts with phosphatase PPP5C (PP5), and through this interaction regulates CHK1 phosphorylation. PSPC1 undergoes liquid-liquid phase separation via its prion-like domain (PrLD); deletion of PrLD abolishes phase separation and abrogates PSPC1's ability to regulate CHK1 phosphorylation, impairing mouse oocyte maturation.","method":"Co-immunoprecipitation (PSPC1–PPP5C), Western blot for CHK1 phosphorylation, PrLD deletion mutant analysis, in vitro phase separation assay, mouse oocyte maturation assay with knockdown","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional oocyte assay, single lab","pmids":["34490876"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of the human NONO and PSPC1 homodimers were determined, revealing conserved contacts and structural plasticity at the dimerization interface that explain dimer selectivity among DBHS paralogs. Solution X-ray scattering showed that nucleic acid binding is reliant on RRM1 of NONO, and a newly identified 'β-clasp' structure influences RRM1 orientation for cooperative RNA recognition.","method":"X-ray crystallography (NONO and PSPC1 homodimers), small-angle X-ray scattering (SAXS), biochemical nucleic acid binding experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both homodimers plus SAXS and biochemical validation of RNA-binding mechanism","pmids":["34904671"],"is_preprint":false},{"year":2022,"finding":"PSPC1 interacts with TET1 in embryonic stem cells and functionally associates with Polycomb repressive complex-2 (PRC2) at bivalent gene promoters; PSPC1 and TET1 repress bivalent gene expression, and during ESC-to-EpiLC transition they maintain PRC2 chromatin occupancy at bivalent promoters.","method":"Proteomics-based TET1 interactome mapping, genome-wide ChIP-seq for PSPC1, TET1, and PRC2, loss-of-function experiments in ESCs","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interactome plus ChIP-seq genome-wide location analysis plus KO, single lab","pmids":["35675764"],"is_preprint":false},{"year":2023,"finding":"PSPC1 is a regulatory subunit of the m6A demethylase ALKBH5, preferentially interacting with K235-acetylated ALKBH5 (acetylated by KAT8, deacetylated by HDAC7) to recruit m6A-modified mRNA and facilitate m6A erasure, thereby promoting tumorigenesis.","method":"Co-immunoprecipitation of PSPC1 with acetylated ALKBH5, m6A demethylation activity assays, site-directed mutagenesis at K235, KAT8/HDAC7 writer/eraser identification","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic activity assay combined with mutagenesis, Co-IP, and identification of writer/eraser enzymes in one study","pmids":["37369679"],"is_preprint":false},{"year":2024,"finding":"SKP2 stabilizes PSPC1 by preventing TRIM21-mediated polyubiquitination and proteasomal degradation of PSPC1; SKP2 depletion results in PSPC1 polyubiquitination and degradation, and the SKP2/PSPC1 axis promotes PDAC cell migration.","method":"Co-immunoprecipitation, ubiquitination assays, SKP2 depletion by siRNA, SMIP004 (SKP2 inhibitor) treatment, migration assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus pharmacological inhibitor, single lab","pmids":["38360141"],"is_preprint":false},{"year":2024,"finding":"PSPC1 binds directly to the SLIV region of the HCV IRES upon HCV infection, competing with ribosomal protein RPS5 for IRES binding; PSPC1 binding prevents ribosomal loading and inhibits HCV RNA translation. Partial silencing of PSPC1 increases HCV RNA in polysomes and enhances viral replication.","method":"Competition UV-crosslinking experiments, PSPC1 partial silencing (siRNA), polysome profiling, immunoprecipitation assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — UV-crosslinking competition assay plus functional siRNA with polysome profiling, single lab","pmids":["38793620"],"is_preprint":false},{"year":2025,"finding":"PSPC1 co-occupies chromatin with the transcription factor PU.1 in AML cells, activating a unique leukemic transcription program including NDC1. PSPC1 loss induces myeloid differentiation and abolishes leukemogenesis; PSPC1 is not required for normal hematopoiesis.","method":"ChIP-seq for cooperative chromatin binding of PSPC1 and PU.1, PSPC1 knockout/knockdown in human AML cells and mouse models, differentiation and proliferation assays","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus genetic KO in human cells and mouse models with defined functional readout, multiple orthogonal methods","pmids":["39954676"],"is_preprint":false},{"year":2025,"finding":"PSPC1 interacts with SMAD3 and promotes its phosphorylation; iron-induced downregulation of PSPC1 alleviates SMAD3-mediated repression of thermogenic genes, thereby inducing beiging of white adipocytes. Overexpression of PSPC1 in subcutaneous adipose tissue reverses iron-induced beiging.","method":"Co-immunoprecipitation of PSPC1 with SMAD3, RNA-seq and ATAC-seq in adipocytes, PSPC1 overexpression in vivo (subcutaneous adipose tissue), Western blot for SMAD3 phosphorylation","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus multi-omics plus in vivo overexpression, single lab","pmids":["41345872"],"is_preprint":false},{"year":2025,"finding":"NONO, SFPQ, and PSPC1 associate with catalytically active telomerase through the hTR RNA component. Depletion of PSPC1 (and NONO) causes telomerase retention in Cajal bodies, impairs telomerase recruitment to telomeres, and leads to progressive telomere shortening.","method":"Co-immunoprecipitation of DBHS proteins with telomerase/hTR, immunofluorescence for Cajal body retention, telomere length measurement upon PSPC1/NONO depletion in multiple cell lines","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, localization imaging, and telomere length functional assay replicated across multiple cell lines","pmids":["40593584"],"is_preprint":false},{"year":2025,"finding":"PSPC1 interacts with PARP1, competitively inhibiting PARP1-mediated PARylation and dephosphorylation of STAT3, thereby sustaining STAT3 activation and promoting CCL2 transcription and M2 macrophage polarization.","method":"Co-immunoprecipitation of PSPC1 with PARP1, STAT3 phosphorylation assays, CCL2 secretion measurement, macrophage polarization co-culture assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphorylation and functional assays, single lab","pmids":["41986651"],"is_preprint":false},{"year":2025,"finding":"Etoposide-induced DNA double-strand breaks do not substantially alter the NONO–SFPQ or NONO–PSPC1 protein-protein interactions, indicating that DBHS family members promote genome stability as constitutively stable dimers rather than dynamically assembling upon DNA damage.","method":"Label-free mass spectrometry interactome profiling of NONO in U2OS cells ± etoposide, orthogonal co-immunoprecipitation, co-localization assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus Co-IP orthogonal validation, preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"PSPC1 is a multifunctional nuclear scaffold protein of the DBHS family that forms homo- and heterodimers (with NONO and SFPQ) through its conserved DBHS domain; it localizes to paraspeckles in an RNA Pol II- and RRM-dependent manner, participates in DNA double-strand break repair in the same pathway as DNA-PK, acts as a regulatory subunit of the m6A demethylase ALKBH5 (preferring K235-acetylated ALKBH5), sequesters or contextually shuttles signalling proteins (PTK6, β-catenin) between nucleus and cytoplasm, interacts with phospho-Smad2/3 to switch TGF-β1 signalling from tumour-suppressive to pro-metastatic, co-occupies chromatin with PU.1 to drive leukemic transcription, promotes telomerase recruitment to telomeres via hTR, and regulates cell fate in adipocytes and stem cells through associations with DDX3X, TET1, PRC2, SMAD3, and PARP1."},"narrative":{"mechanistic_narrative":"PSPC1 is a multifunctional nuclear DBHS-family scaffold protein that dimerizes through its conserved DBHS domain — comprising tandem RRMs, a NOPS motif, and a coiled-coil — with the related paralogs NONO and SFPQ, and these dimers underlie its roles in paraspeckle biology, genome maintenance, transcriptional control, and RNA metabolism [PMID:16148043, PMID:22102035, PMID:29530979, PMID:34904671]. Heterodimerization with NONO is required, together with an RNA-binding-competent RRM and ongoing RNA Pol II transcription, for targeting to paraspeckles [PMID:16148043], and biophysical analyses show PSPC1 preferentially partners SFPQ over SFPQ self-association and that RRM1 with an adjacent β-clasp mediates cooperative nucleic-acid recognition [PMID:29530979, PMID:34904671]. In genome maintenance, PSPC1 functionally substitutes for NONO in a stable SFPQ-containing complex that promotes DNA double-strand break repair within the DNA-PK pathway and enforces the G1/S DNA damage checkpoint [PMID:24819514, PMID:25100870]. PSPC1 acts as a contextual signalling switch in cancer: it binds phospho-Smad2/3 to redirect TGF-β1 signalling toward pro-metastatic gene programs [PMID:29593326], sequesters the kinase PTK6 and shuttles β-catenin to drive Wnt autocrine signalling and EMT [PMID:31844057], and co-occupies chromatin with PU.1 to sustain a leukemic transcription program whose loss triggers myeloid differentiation without affecting normal hematopoiesis [PMID:39954676]. It additionally serves as a regulatory subunit of the m6A demethylase ALKBH5, preferentially engaging K235-acetylated ALKBH5 to recruit m6A-modified mRNA for demethylation [PMID:37369679], and recruits catalytically active telomerase to telomeres via the hTR RNA component [PMID:40593584]. Beyond malignancy, PSPC1 governs adipocyte and stem-cell fate through differentiation-dependent nucleocytoplasmic shuttling, association with the RNA export factor DDX3X, and interactions with TET1/PRC2 and SMAD3 [PMID:28192372, PMID:35675764, PMID:41345872]. PSPC1 protein levels are controlled by an SKP2–TRIM21 ubiquitination axis, and the protein can undergo prion-like-domain-dependent liquid–liquid phase separation [PMID:34490876, PMID:38360141].","teleology":[{"year":2005,"claim":"Established the molecular basis for paraspeckle assembly by defining how PSPC1 is recruited there, answering whether dimerization alone suffices.","evidence":"Co-IP and domain mapping with DRB transcription inhibition and fluorescence microscopy","pmids":["16148043"],"confidence":"High","gaps":["Did not resolve which RNAs nucleate paraspeckle targeting","Functional consequence of paraspeckle residence not addressed"]},{"year":2006,"claim":"First showed PSPC1 acts as a transcriptional coactivator, extending DBHS function beyond paraspeckle structure to gene regulation.","evidence":"Co-IP and androgen-responsive luciferase reporter assays in Sertoli cells with testis immunohistochemistry","pmids":["16641145"],"confidence":"Medium","gaps":["Direct DNA binding versus scaffold role at AR target genes unresolved","No genome-wide occupancy data"]},{"year":2011,"claim":"Provided the first atomic view of how PSPC1 and NONO dimerize, defining the DBHS interface structurally.","evidence":"X-ray crystallography of the PSPC1–NONO heterodimer to 1.9 Å","pmids":["22102035"],"confidence":"Medium","gaps":["Functional validation of the interface not in this study","No insight into RNA engagement"]},{"year":2014,"claim":"Defined PSPC1's role in genome maintenance, showing it enforces the G1/S checkpoint yet acts outside canonical γH2AX/53BP1/Rad51 foci, and functionally substitutes for NONO in DNA-PK-dependent DSB repair.","evidence":"siRNA/KO MEFs, flow-cytometry cell-cycle analysis, clonogenic radiosensitivity, foci resolution, and DNA-PK inhibitor epistasis","pmids":["24819514","25100870"],"confidence":"High","gaps":["Biochemical step in DSB repair where PSPC1 acts not defined","Redundancy logic between PSPC1 and NONO not fully mapped"]},{"year":2017,"claim":"Revealed PSPC1 as a nucleocytoplasmic regulator of RNA fate in differentiation, coupling RNA binding to DDX3X-dependent export and metabolic phenotype.","evidence":"CLIP-seq, DDX3X Co-IP, subcellular fractionation/live imaging, and adipose-specific knockout mouse","pmids":["28192372","28117896"],"confidence":"High","gaps":["Signal triggering nuclear-to-cytoplasm relocation unknown","Direct RNA export mechanism vs. indirect not fully resolved"]},{"year":2018,"claim":"Demonstrated PSPC1 as a contextual signalling switch in cancer, redirecting TGF-β/Smad2/3 toward pro-metastatic programs, and structurally explained why PSPC1 preferentially partners SFPQ.","evidence":"Reciprocal Co-IP with pSmad2/3, ChIP-seq, mouse cancer models, plus SFPQ/PSPC1 crystal structure and analytical ultracentrifugation","pmids":["29593326","29530979"],"confidence":"High","gaps":["How PSPC1 mechanically alters Smad2/3 promoter preference not detailed","Stoichiometry of signalling complexes in vivo unknown"]},{"year":2019,"claim":"Showed PSPC1 controls oncogenic signalling by spatially partitioning PTK6 and β-catenin, and identified a peptide (CT131) that reverses the metastatic phenotype.","evidence":"Co-IP, subcellular fractionation, Y523F mutagenesis, and HCC orthotopic mouse model with CT131 expression","pmids":["31844057"],"confidence":"High","gaps":["Determinants of context-dependent nuclear vs. cytoplasmic shuttling unresolved","Generality across tumor types beyond HCC limited"]},{"year":2020,"claim":"Linked PSPC1 to focal adhesion/FAK-Src signalling via transcriptional upregulation of IGF1R in a paraspeckle-component-dependent manner.","evidence":"Phospho-kinase array, RNA-seq, proteomics, and NONO/FUS/NEAT1 knockdown","pmids":["32570949"],"confidence":"Medium","gaps":["Direct vs. indirect transcriptional control of IGF1R unclear","Single-lab observation"]},{"year":2021,"claim":"Connected PSPC1 phase separation to checkpoint signalling, showing its prion-like domain is required to regulate CHK1 phosphorylation via PPP5C.","evidence":"Co-IP, PrLD deletion mutants, in vitro phase separation, and mouse oocyte maturation assays","pmids":["34490876"],"confidence":"Medium","gaps":["Physiological scope of phase separation beyond oocytes unknown","Mechanistic link between condensates and PP5 activity not defined"]},{"year":2022,"claim":"Defined PSPC1's epigenetic role in stem-cell fate through TET1 and PRC2 occupancy at bivalent promoters, and refined the structural mechanism of RNA recognition by DBHS homodimers.","evidence":"TET1 interactome proteomics, genome-wide ChIP-seq, ESC loss-of-function, plus NONO/PSPC1 homodimer crystal structures and SAXS","pmids":["35675764","34904671"],"confidence":"High","gaps":["Whether PSPC1 directly recruits PRC2 or acts via RNA scaffolding unclear","RRM1/β-clasp RNA specificity for endogenous targets not mapped"]},{"year":2023,"claim":"Identified PSPC1 as a regulatory subunit of the m6A eraser ALKBH5 sensitive to acetylation state, linking it to epitranscriptomic control of tumorigenesis.","evidence":"Co-IP with acetylated ALKBH5, m6A demethylation assays, K235 mutagenesis, and KAT8/HDAC7 identification","pmids":["37369679"],"confidence":"High","gaps":["mRNA target repertoire of the PSPC1–ALKBH5 axis not enumerated","Acetylation dynamics in physiological contexts unknown"]},{"year":2024,"claim":"Established post-translational control of PSPC1 abundance through an SKP2–TRIM21 ubiquitination axis, and a non-DBHS RNA function in restricting HCV IRES translation.","evidence":"Co-IP and ubiquitination assays with SKP2 depletion; UV-crosslinking competition with RPS5 and polysome profiling","pmids":["38360141","38793620"],"confidence":"Medium","gaps":["Signals governing SKP2 vs. TRIM21 balance not defined","Whether IRES competition reflects a broader antiviral role unknown"]},{"year":2025,"claim":"Expanded PSPC1's regulatory reach to leukemic transcription with PU.1, telomere maintenance via hTR, adipocyte beiging via SMAD3, and immune modulation via PARP1/STAT3.","evidence":"ChIP-seq with PU.1 and AML KO models; telomerase/hTR Co-IP with telomere-length assays; SMAD3 Co-IP with multi-omics and in vivo overexpression; PARP1 Co-IP with STAT3 and macrophage co-culture","pmids":["39954676","40593584","41345872","41986651"],"confidence":"High","gaps":["Unifying logic across these context-specific partnerships unclear","Therapeutic window for targeting PSPC1 in AML versus normal cells not defined"]},{"year":null,"claim":"It remains unresolved whether PSPC1's diverse partner-specific functions reflect distinct molecular states (dimer composition, acetylation, phase separation, localization) and how a single scaffold is partitioned among them in a given cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking dimer identity to functional outcome","Determinants of nucleocytoplasmic vs. condensate partitioning unknown","Endogenous RNA/protein interactome under defined states not catalogued"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,14,18,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,7,8,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,11,15]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,11]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,7,15,19]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,11,16,19]}],"complexes":["paraspeckle","DBHS dimer (PSPC1–NONO / PSPC1–SFPQ)","SFPQ–PSPC1 DSB repair complex","PRC2-associated bivalent promoter complex"],"partners":["NONO","SFPQ","ALKBH5","PTK6","SMAD3","PARP1","TET1","DDX3X"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXF1","full_name":"Paraspeckle component 1","aliases":["Paraspeckle protein 1"],"length_aa":523,"mass_kda":58.7,"function":"RNA-binding protein required for the formation of nuclear paraspeckles (PubMed:22416126). Binds to poly(A), poly(G) and poly(U) RNA homopolymers (PubMed:22416126). Regulates, cooperatively with NONO and SFPQ, androgen receptor-mediated gene transcription activity in Sertoli cell line (By similarity). Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-BMAL1 heterodimer (By similarity). Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS-STING pathway (PubMed:28712728)","subcellular_location":"Nucleus speckle; Nucleus, nucleolus; Nucleus matrix; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8WXF1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSPC1","classification":"Not Classified","n_dependent_lines":237,"n_total_lines":1208,"dependency_fraction":0.19619205298013245},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000121390","cell_line_id":"CID001002","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"EIF4B","stoichiometry":10.0},{"gene":"FAU","stoichiometry":10.0},{"gene":"SERBP1","stoichiometry":10.0},{"gene":"EIF3G","stoichiometry":4.0},{"gene":"CCDC124","stoichiometry":4.0},{"gene":"RPL38","stoichiometry":4.0},{"gene":"RPL19","stoichiometry":4.0},{"gene":"YTHDF3","stoichiometry":0.2},{"gene":"SRP72","stoichiometry":0.2},{"gene":"EIF3J","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001002","total_profiled":1310},"omim":[{"mim_id":"619357","title":"ADENYLATE KINASE 6; AK6","url":"https://www.omim.org/entry/619357"},{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"612769","title":"NONCODING NUCLEAR-ENRICHED ABUNDANT TRANSCRIPT 1; NEAT1","url":"https://www.omim.org/entry/612769"},{"mim_id":"612409","title":"RNA-BINDING MOTIF PROTEIN 14; RBM14","url":"https://www.omim.org/entry/612409"},{"mim_id":"612408","title":"PARASPECKLE COMPONENT 1; PSPC1","url":"https://www.omim.org/entry/612408"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli fibrillar center","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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This interaction is necessary but not sufficient for paraspeckle targeting, which also requires an RNA-binding-competent RRM domain. Paraspeckle formation itself is dependent on RNA Polymerase II transcription.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, DRB-mediated transcription inhibition assay, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain-mapping and functional rescue, replicated in multiple conditions in the same study\",\n      \"pmids\": [\"16148043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PSPC1 interacts with androgen receptor (AR) and with NONO and SFPQ in Sertoli cells, forming complexes that coactivate AR-mediated transcription; PSPC1 is the most effective coactivator among the three DBHS proteins in this context.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay with androgen-responsive elements, immunohistochemistry of mouse testis sections\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"16641145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PSPC1–NONO heterodimer was crystallized, confirming that the conserved DBHS domain (comprising two tandem RRMs, a NOPS domain, and part of a coiled-coil) provides the dimerization interface for these two paraspeckle proteins.\",\n      \"method\": \"Protein crystallography (crystal diffraction to 1.9 Å, space group C2)\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure obtained but functional validation of interface not reported in this crystallization paper alone\",\n      \"pmids\": [\"22102035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PSPC1 is part of a transcriptional complex with LMX1B and PSF (SFPQ) in dopaminergic cells; PSPC1 was identified as a binding partner of LMX1B by affinity purification/mass spectrometry and confirmed by co-immunoprecipitation in vitro and in vivo.\",\n      \"method\": \"Affinity purification of LMX1B-HIS followed by mass spectrometry; co-immunoprecipitation in vitro and in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification followed by reciprocal Co-IP, single lab, two orthogonal methods\",\n      \"pmids\": [\"23308148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSPC1 is required for the G1/S DNA damage checkpoint: knockdown of PSPC1 in HeLa cells caused cells to escape cisplatin-induced G1/S arrest and enter mitosis, leading to increased cell death. PSPC1 did not co-localize with γH2AX, 53BP1, or Rad51, indicating it does not directly participate in those DNA repair pathways.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis by flow cytometry, γH2AX/53BP1/Rad51 co-localization by immunofluorescence, cisplatin treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cell cycle phenotype plus negative co-localization controls, single lab\",\n      \"pmids\": [\"24819514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSPC1 functionally compensates for NONO in DNA double-strand break (DSB) repair: in NONO-knockout MEFs, PSPC1 is upregulated and replaces NONO in a stable complex with SFPQ. Dual knockdown of NONO and PSPC1 causes severe radiosensitivity and delayed DSB repair focus resolution. Epistasis with DNA-PK inhibitor NU7741 places NONO/PSPC1 in the same DSB repair pathway as DNA-PK.\",\n      \"method\": \"Knockout mouse-derived MEFs, siRNA knockdown, clonogenic radiosensitivity assay, γH2AX foci resolution, DNA-PK inhibitor epistasis, co-immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with siRNA, functional repair assays, and pharmacological epistasis across multiple orthogonal methods\",\n      \"pmids\": [\"25100870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSPC1 binds intronic and 3'-UTR regions of adipocyte RNAs (including EBF1 mRNA) via CLIP-seq; it associates with the RNA export factor DDX3X in a differentiation-dependent manner. During adipogenesis, PSPC1 relocates from the nucleus to the cytoplasm, coinciding with enhanced nuclear export of adipogenic RNAs. PSPC1 knockout in fat reduces lipid storage and confers resistance to diet-induced obesity.\",\n      \"method\": \"CLIP-seq, paraspeckle complex purification from adipocytes, co-immunoprecipitation with DDX3X, subcellular fractionation/live imaging, adipose-specific knockout mouse\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP-seq, Co-IP, fractionation, and in vivo KO with defined metabolic phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28192372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NONO and PSPC1 synergistically activate transcription of Aldh1a1 in Sertoli cells by binding to a specific CCGGAGTC sequence in the Aldh1a1 promoter, protecting cells against MEHP-induced oxidative stress.\",\n      \"method\": \"siRNA knockdown of NONO and PSPC1, promoter-binding assay, gene expression analysis, oxidative stress assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding plus functional knockdown phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"28117896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSPC1 interacts with phosphorylated nuclear Smad2/3 to potentiate TGF-β1 autocrine signalling, increasing TGF-β1 secretion. PSPC1 acts as a contextual determinant of Smad2/3 binding preference, switching Smad2/3 from tumour-suppressor to pro-metastatic target genes, thereby driving EMT, stemness, and metastasis.\",\n      \"method\": \"Co-immunoprecipitation of PSPC1 with pSmad2/3, TGF-β1 ELISA, ChIP-seq for Smad2/3 binding, spontaneous mouse cancer models, multiple cancer cell lines\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP-seq, in vivo mouse models, multiple cancer cell types, orthogonal mechanistic methods in one study\",\n      \"pmids\": [\"29593326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of the SFPQ/PSPC1 heterodimer resolved to 2.3 Å reveals that SFPQ-containing heterodimers dissociate at low micromolar concentrations and that SFPQ/PSPC1 heterodimer has >6-fold higher affinity than SFPQ/NONO heterodimer, providing a structural mechanism for preferential PSPC1–SFPQ heterodimerization over SFPQ homodimerization.\",\n      \"method\": \"X-ray crystallography (2.3 Å resolution), analytical ultracentrifugation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biophysical affinity measurements providing mechanistic explanation for dimerization preference\",\n      \"pmids\": [\"29530979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSPC1 (PSP1/p54nrb) is required for HDV replication in HEK-293 cells; HDV replication induces delocalization of PSP1 from paraspeckles to cytoplasmic foci containing PABP and increases NEAT1 levels, causing paraspeckle enlargement.\",\n      \"method\": \"RNAi-mediated knockdown in HDV-replicating HEK-293 cells, immunofluorescence for PSP1 localization, NEAT1 level quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with virology functional readout plus localization assay, single lab\",\n      \"pmids\": [\"29662142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSPC1 is a nuclear substrate of PTK6; when PSPC1 sequesters PTK6 in the nucleus, PTK6 acts as a tumour suppressor. PSPC1 overexpression or Y523F mutation promotes cytoplasmic translocation of active PTK6 and nuclear translocation of β-catenin, which interacts with PSPC1 to augment Wnt3a autocrine signalling and drive EMT and metastasis. Expression of PSPC1-CT131 (C-terminal 131 aa) reverses these translocations and suppresses metastasis.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, site-directed mutagenesis (Y523F), HCC orthotopic mouse model, PSPC1-CT131 peptide expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, subcellular fractionation, and in vivo orthotopic model with survival endpoint, multiple orthogonal methods\",\n      \"pmids\": [\"31844057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSPC1 overexpression induces focal adhesion formation and activates FAK/Src signalling to enhance cell adhesion and motility. PSPC1 transcriptionally upregulates IGF1R, which mediates focal adhesion pathway activation. Knockdown of paraspeckle components NONO, FUS, and NEAT1 lncRNA abolishes PSPC1-activated IGF1R expression.\",\n      \"method\": \"Phospho-kinase antibody array, RNA-seq transcriptome analysis, protein pulldown proteomics, IGF1R siRNA/inhibitor treatment, NONO/FUS/NEAT1 siRNA knockdown\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple omics plus functional knockdown assays, single lab\",\n      \"pmids\": [\"32570949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSPC1 interacts with phosphatase PPP5C (PP5), and through this interaction regulates CHK1 phosphorylation. PSPC1 undergoes liquid-liquid phase separation via its prion-like domain (PrLD); deletion of PrLD abolishes phase separation and abrogates PSPC1's ability to regulate CHK1 phosphorylation, impairing mouse oocyte maturation.\",\n      \"method\": \"Co-immunoprecipitation (PSPC1–PPP5C), Western blot for CHK1 phosphorylation, PrLD deletion mutant analysis, in vitro phase separation assay, mouse oocyte maturation assay with knockdown\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional oocyte assay, single lab\",\n      \"pmids\": [\"34490876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of the human NONO and PSPC1 homodimers were determined, revealing conserved contacts and structural plasticity at the dimerization interface that explain dimer selectivity among DBHS paralogs. Solution X-ray scattering showed that nucleic acid binding is reliant on RRM1 of NONO, and a newly identified 'β-clasp' structure influences RRM1 orientation for cooperative RNA recognition.\",\n      \"method\": \"X-ray crystallography (NONO and PSPC1 homodimers), small-angle X-ray scattering (SAXS), biochemical nucleic acid binding experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both homodimers plus SAXS and biochemical validation of RNA-binding mechanism\",\n      \"pmids\": [\"34904671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSPC1 interacts with TET1 in embryonic stem cells and functionally associates with Polycomb repressive complex-2 (PRC2) at bivalent gene promoters; PSPC1 and TET1 repress bivalent gene expression, and during ESC-to-EpiLC transition they maintain PRC2 chromatin occupancy at bivalent promoters.\",\n      \"method\": \"Proteomics-based TET1 interactome mapping, genome-wide ChIP-seq for PSPC1, TET1, and PRC2, loss-of-function experiments in ESCs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interactome plus ChIP-seq genome-wide location analysis plus KO, single lab\",\n      \"pmids\": [\"35675764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSPC1 is a regulatory subunit of the m6A demethylase ALKBH5, preferentially interacting with K235-acetylated ALKBH5 (acetylated by KAT8, deacetylated by HDAC7) to recruit m6A-modified mRNA and facilitate m6A erasure, thereby promoting tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation of PSPC1 with acetylated ALKBH5, m6A demethylation activity assays, site-directed mutagenesis at K235, KAT8/HDAC7 writer/eraser identification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic activity assay combined with mutagenesis, Co-IP, and identification of writer/eraser enzymes in one study\",\n      \"pmids\": [\"37369679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKP2 stabilizes PSPC1 by preventing TRIM21-mediated polyubiquitination and proteasomal degradation of PSPC1; SKP2 depletion results in PSPC1 polyubiquitination and degradation, and the SKP2/PSPC1 axis promotes PDAC cell migration.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, SKP2 depletion by siRNA, SMIP004 (SKP2 inhibitor) treatment, migration assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus pharmacological inhibitor, single lab\",\n      \"pmids\": [\"38360141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSPC1 binds directly to the SLIV region of the HCV IRES upon HCV infection, competing with ribosomal protein RPS5 for IRES binding; PSPC1 binding prevents ribosomal loading and inhibits HCV RNA translation. Partial silencing of PSPC1 increases HCV RNA in polysomes and enhances viral replication.\",\n      \"method\": \"Competition UV-crosslinking experiments, PSPC1 partial silencing (siRNA), polysome profiling, immunoprecipitation assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — UV-crosslinking competition assay plus functional siRNA with polysome profiling, single lab\",\n      \"pmids\": [\"38793620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSPC1 co-occupies chromatin with the transcription factor PU.1 in AML cells, activating a unique leukemic transcription program including NDC1. PSPC1 loss induces myeloid differentiation and abolishes leukemogenesis; PSPC1 is not required for normal hematopoiesis.\",\n      \"method\": \"ChIP-seq for cooperative chromatin binding of PSPC1 and PU.1, PSPC1 knockout/knockdown in human AML cells and mouse models, differentiation and proliferation assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus genetic KO in human cells and mouse models with defined functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"39954676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSPC1 interacts with SMAD3 and promotes its phosphorylation; iron-induced downregulation of PSPC1 alleviates SMAD3-mediated repression of thermogenic genes, thereby inducing beiging of white adipocytes. Overexpression of PSPC1 in subcutaneous adipose tissue reverses iron-induced beiging.\",\n      \"method\": \"Co-immunoprecipitation of PSPC1 with SMAD3, RNA-seq and ATAC-seq in adipocytes, PSPC1 overexpression in vivo (subcutaneous adipose tissue), Western blot for SMAD3 phosphorylation\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus multi-omics plus in vivo overexpression, single lab\",\n      \"pmids\": [\"41345872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NONO, SFPQ, and PSPC1 associate with catalytically active telomerase through the hTR RNA component. Depletion of PSPC1 (and NONO) causes telomerase retention in Cajal bodies, impairs telomerase recruitment to telomeres, and leads to progressive telomere shortening.\",\n      \"method\": \"Co-immunoprecipitation of DBHS proteins with telomerase/hTR, immunofluorescence for Cajal body retention, telomere length measurement upon PSPC1/NONO depletion in multiple cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, localization imaging, and telomere length functional assay replicated across multiple cell lines\",\n      \"pmids\": [\"40593584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PSPC1 interacts with PARP1, competitively inhibiting PARP1-mediated PARylation and dephosphorylation of STAT3, thereby sustaining STAT3 activation and promoting CCL2 transcription and M2 macrophage polarization.\",\n      \"method\": \"Co-immunoprecipitation of PSPC1 with PARP1, STAT3 phosphorylation assays, CCL2 secretion measurement, macrophage polarization co-culture assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphorylation and functional assays, single lab\",\n      \"pmids\": [\"41986651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Etoposide-induced DNA double-strand breaks do not substantially alter the NONO–SFPQ or NONO–PSPC1 protein-protein interactions, indicating that DBHS family members promote genome stability as constitutively stable dimers rather than dynamically assembling upon DNA damage.\",\n      \"method\": \"Label-free mass spectrometry interactome profiling of NONO in U2OS cells ± etoposide, orthogonal co-immunoprecipitation, co-localization assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus Co-IP orthogonal validation, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PSPC1 is a multifunctional nuclear scaffold protein of the DBHS family that forms homo- and heterodimers (with NONO and SFPQ) through its conserved DBHS domain; it localizes to paraspeckles in an RNA Pol II- and RRM-dependent manner, participates in DNA double-strand break repair in the same pathway as DNA-PK, acts as a regulatory subunit of the m6A demethylase ALKBH5 (preferring K235-acetylated ALKBH5), sequesters or contextually shuttles signalling proteins (PTK6, β-catenin) between nucleus and cytoplasm, interacts with phospho-Smad2/3 to switch TGF-β1 signalling from tumour-suppressive to pro-metastatic, co-occupies chromatin with PU.1 to drive leukemic transcription, promotes telomerase recruitment to telomeres via hTR, and regulates cell fate in adipocytes and stem cells through associations with DDX3X, TET1, PRC2, SMAD3, and PARP1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSPC1 is a multifunctional nuclear DBHS-family scaffold protein that dimerizes through its conserved DBHS domain — comprising tandem RRMs, a NOPS motif, and a coiled-coil — with the related paralogs NONO and SFPQ, and these dimers underlie its roles in paraspeckle biology, genome maintenance, transcriptional control, and RNA metabolism [#0, #2, #9, #14]. Heterodimerization with NONO is required, together with an RNA-binding-competent RRM and ongoing RNA Pol II transcription, for targeting to paraspeckles [#0], and biophysical analyses show PSPC1 preferentially partners SFPQ over SFPQ self-association and that RRM1 with an adjacent β-clasp mediates cooperative nucleic-acid recognition [#9, #14]. In genome maintenance, PSPC1 functionally substitutes for NONO in a stable SFPQ-containing complex that promotes DNA double-strand break repair within the DNA-PK pathway and enforces the G1/S DNA damage checkpoint [#4, #5]. PSPC1 acts as a contextual signalling switch in cancer: it binds phospho-Smad2/3 to redirect TGF-β1 signalling toward pro-metastatic gene programs [#8], sequesters the kinase PTK6 and shuttles β-catenin to drive Wnt autocrine signalling and EMT [#11], and co-occupies chromatin with PU.1 to sustain a leukemic transcription program whose loss triggers myeloid differentiation without affecting normal hematopoiesis [#19]. It additionally serves as a regulatory subunit of the m6A demethylase ALKBH5, preferentially engaging K235-acetylated ALKBH5 to recruit m6A-modified mRNA for demethylation [#16], and recruits catalytically active telomerase to telomeres via the hTR RNA component [#21]. Beyond malignancy, PSPC1 governs adipocyte and stem-cell fate through differentiation-dependent nucleocytoplasmic shuttling, association with the RNA export factor DDX3X, and interactions with TET1/PRC2 and SMAD3 [#6, #15, #20]. PSPC1 protein levels are controlled by an SKP2–TRIM21 ubiquitination axis, and the protein can undergo prion-like-domain-dependent liquid–liquid phase separation [#13, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the molecular basis for paraspeckle assembly by defining how PSPC1 is recruited there, answering whether dimerization alone suffices.\",\n      \"evidence\": \"Co-IP and domain mapping with DRB transcription inhibition and fluorescence microscopy\",\n      \"pmids\": [\"16148043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which RNAs nucleate paraspeckle targeting\", \"Functional consequence of paraspeckle residence not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"First showed PSPC1 acts as a transcriptional coactivator, extending DBHS function beyond paraspeckle structure to gene regulation.\",\n      \"evidence\": \"Co-IP and androgen-responsive luciferase reporter assays in Sertoli cells with testis immunohistochemistry\",\n      \"pmids\": [\"16641145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA binding versus scaffold role at AR target genes unresolved\", \"No genome-wide occupancy data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the first atomic view of how PSPC1 and NONO dimerize, defining the DBHS interface structurally.\",\n      \"evidence\": \"X-ray crystallography of the PSPC1–NONO heterodimer to 1.9 Å\",\n      \"pmids\": [\"22102035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation of the interface not in this study\", \"No insight into RNA engagement\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PSPC1's role in genome maintenance, showing it enforces the G1/S checkpoint yet acts outside canonical γH2AX/53BP1/Rad51 foci, and functionally substitutes for NONO in DNA-PK-dependent DSB repair.\",\n      \"evidence\": \"siRNA/KO MEFs, flow-cytometry cell-cycle analysis, clonogenic radiosensitivity, foci resolution, and DNA-PK inhibitor epistasis\",\n      \"pmids\": [\"24819514\", \"25100870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical step in DSB repair where PSPC1 acts not defined\", \"Redundancy logic between PSPC1 and NONO not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed PSPC1 as a nucleocytoplasmic regulator of RNA fate in differentiation, coupling RNA binding to DDX3X-dependent export and metabolic phenotype.\",\n      \"evidence\": \"CLIP-seq, DDX3X Co-IP, subcellular fractionation/live imaging, and adipose-specific knockout mouse\",\n      \"pmids\": [\"28192372\", \"28117896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering nuclear-to-cytoplasm relocation unknown\", \"Direct RNA export mechanism vs. indirect not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated PSPC1 as a contextual signalling switch in cancer, redirecting TGF-β/Smad2/3 toward pro-metastatic programs, and structurally explained why PSPC1 preferentially partners SFPQ.\",\n      \"evidence\": \"Reciprocal Co-IP with pSmad2/3, ChIP-seq, mouse cancer models, plus SFPQ/PSPC1 crystal structure and analytical ultracentrifugation\",\n      \"pmids\": [\"29593326\", \"29530979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSPC1 mechanically alters Smad2/3 promoter preference not detailed\", \"Stoichiometry of signalling complexes in vivo unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed PSPC1 controls oncogenic signalling by spatially partitioning PTK6 and β-catenin, and identified a peptide (CT131) that reverses the metastatic phenotype.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, Y523F mutagenesis, and HCC orthotopic mouse model with CT131 expression\",\n      \"pmids\": [\"31844057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of context-dependent nuclear vs. cytoplasmic shuttling unresolved\", \"Generality across tumor types beyond HCC limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked PSPC1 to focal adhesion/FAK-Src signalling via transcriptional upregulation of IGF1R in a paraspeckle-component-dependent manner.\",\n      \"evidence\": \"Phospho-kinase array, RNA-seq, proteomics, and NONO/FUS/NEAT1 knockdown\",\n      \"pmids\": [\"32570949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect transcriptional control of IGF1R unclear\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PSPC1 phase separation to checkpoint signalling, showing its prion-like domain is required to regulate CHK1 phosphorylation via PPP5C.\",\n      \"evidence\": \"Co-IP, PrLD deletion mutants, in vitro phase separation, and mouse oocyte maturation assays\",\n      \"pmids\": [\"34490876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological scope of phase separation beyond oocytes unknown\", \"Mechanistic link between condensates and PP5 activity not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined PSPC1's epigenetic role in stem-cell fate through TET1 and PRC2 occupancy at bivalent promoters, and refined the structural mechanism of RNA recognition by DBHS homodimers.\",\n      \"evidence\": \"TET1 interactome proteomics, genome-wide ChIP-seq, ESC loss-of-function, plus NONO/PSPC1 homodimer crystal structures and SAXS\",\n      \"pmids\": [\"35675764\", \"34904671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSPC1 directly recruits PRC2 or acts via RNA scaffolding unclear\", \"RRM1/β-clasp RNA specificity for endogenous targets not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PSPC1 as a regulatory subunit of the m6A eraser ALKBH5 sensitive to acetylation state, linking it to epitranscriptomic control of tumorigenesis.\",\n      \"evidence\": \"Co-IP with acetylated ALKBH5, m6A demethylation assays, K235 mutagenesis, and KAT8/HDAC7 identification\",\n      \"pmids\": [\"37369679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mRNA target repertoire of the PSPC1–ALKBH5 axis not enumerated\", \"Acetylation dynamics in physiological contexts unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established post-translational control of PSPC1 abundance through an SKP2–TRIM21 ubiquitination axis, and a non-DBHS RNA function in restricting HCV IRES translation.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with SKP2 depletion; UV-crosslinking competition with RPS5 and polysome profiling\",\n      \"pmids\": [\"38360141\", \"38793620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals governing SKP2 vs. TRIM21 balance not defined\", \"Whether IRES competition reflects a broader antiviral role unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded PSPC1's regulatory reach to leukemic transcription with PU.1, telomere maintenance via hTR, adipocyte beiging via SMAD3, and immune modulation via PARP1/STAT3.\",\n      \"evidence\": \"ChIP-seq with PU.1 and AML KO models; telomerase/hTR Co-IP with telomere-length assays; SMAD3 Co-IP with multi-omics and in vivo overexpression; PARP1 Co-IP with STAT3 and macrophage co-culture\",\n      \"pmids\": [\"39954676\", \"40593584\", \"41345872\", \"41986651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Unifying logic across these context-specific partnerships unclear\", \"Therapeutic window for targeting PSPC1 in AML versus normal cells not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether PSPC1's diverse partner-specific functions reflect distinct molecular states (dimer composition, acetylation, phase separation, localization) and how a single scaffold is partitioned among them in a given cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking dimer identity to functional outcome\", \"Determinants of nucleocytoplasmic vs. condensate partitioning unknown\", \"Endogenous RNA/protein interactome under defined states not catalogued\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 14, 18, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 7, 8, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 11, 15]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 7, 15, 19]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 11, 16, 19]}\n    ],\n    \"complexes\": [\"paraspeckle\", \"DBHS dimer (PSPC1–NONO / PSPC1–SFPQ)\", \"SFPQ–PSPC1 DSB repair complex\", \"PRC2-associated bivalent promoter complex\"],\n    \"partners\": [\"NONO\", \"SFPQ\", \"ALKBH5\", \"PTK6\", \"SMAD3\", \"PARP1\", \"TET1\", \"DDX3X\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}