{"gene":"CTDSPL","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1998,"finding":"SCP3 self-assembles into thick, cross-striated fibers when synthesized in cultured somatic cells; this process requires both the C-terminal coiled-coil domain and the N-terminal non-helical domain. The fibers display ~20 nm transversal striation and consist of closely associated 5–10 nm thin fibers resembling intermediate filaments, consistent with SCP3 forming the molecular framework of synaptonemal complex lateral elements.","method":"Expression in cultured somatic cells, transmission electron microscopy, immunoelectron microscopy, domain-deletion mutagenesis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution of fiber assembly in cells with mutagenesis defining required domains, plus EM structural characterization","pmids":["9679134"],"is_preprint":false},{"year":1998,"finding":"SCP3 (COR1) and SCP1 (SYN1) are efficiently phosphorylated in vitro by extracts from isolated pachytene spermatocytes; extracts from metaphase I cells (in which SCP3 has been displaced from chromosomes) lack this kinase activity. This supports a model in which phosphorylation of SCP3 drives its removal from chromosomes during meiotic progression.","method":"In vitro kinase assay using pachytene and metaphase I cell extracts; okadaic acid-induced meiotic progression model","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro phosphorylation assay, single lab, no identification of specific kinase","pmids":["9914155"],"is_preprint":false},{"year":2000,"finding":"SCP3 null mutation in male mice abolishes axial/lateral element and synaptonemal complex formation, prevents chromosomal synapsis, and causes massive apoptotic cell death during meiotic prophase with sterility. Loss of SCP3 also disrupts nuclear distribution of DNA repair/recombination proteins Rad51 and RPA, and prevents SCP1 localization, establishing SCP3 as essential for the structural assembly of the synaptonemal complex.","method":"Gene knockout (null mutation), immunofluorescence, histology","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular and molecular phenotype, widely replicated","pmids":["10678170"],"is_preprint":false},{"year":2002,"finding":"SCP3-deficient female mice produce aneuploid oocytes due to defective meiotic chromosome segregation; SCP3 is required for chiasmata formation and structural integrity of meiotic chromosomes. Loss of SCP3 triggers nondisjunction, and the resulting aneuploidy increases with advancing maternal age.","method":"Gene knockout, karyotyping of oocytes and embryos, immunofluorescence","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined chromosomal and embryonic phenotype, multiple orthogonal readouts","pmids":["12004129"],"is_preprint":false},{"year":2004,"finding":"SCP3 colocalizes with cohesin subunit Rad21 at synaptonemal complex lateral elements, accumulates at centromeres during late prophase I together with chromosomal passenger proteins INCENP and aurora-B kinase in a 'double cornet' configuration, and both are displaced from centromeres at telophase I when sister kinetochores separate. This positional behavior implicates SCP3 in monopolar attachment of sister kinetochores during meiosis I.","method":"Immunofluorescence co-localization in mouse spermatocytes using squashing technique; antibodies against SCP3, Rad21, INCENP, aurora-B","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization data from multiple antibodies in a single study, no direct functional disruption of SCP3 at this stage","pmids":["14970259"],"is_preprint":false},{"year":2004,"finding":"RBSP3/HYA22 (CTDSPL) encodes a small C-terminal domain phosphatase that dephosphorylates pRB, leading to cell cycle arrest at G1/S. Expression of RBSP3 suppresses tumor formation in SCID mice. The gene carries missense and nonsense mutations in tumors and is located in the frequently deleted 3p21.3 AP20 region.","method":"Sequence analysis, regulated transgene expression (growth suppression assay), SCID mouse tumor suppression assay, pRB dephosphorylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphatase activity demonstrated on pRB substrate, tumor suppression in vivo, regulated transgene growth assay, multiple orthogonal methods in one study","pmids":["15051889"],"is_preprint":false},{"year":2011,"finding":"RBSP3 (CTDSPL) is a direct target of miR-100 in AML cells. miR-100 suppresses RBSP3 expression, which in turn modulates pRB phosphorylation and E2F1 levels, promoting G1/S transition and blocking granulocyte/monocyte differentiation. RBSP3 knockdown by siRNA phenocopies miR-100 overexpression, confirming RBSP3 acts downstream of miR-100 to regulate the pRB/E2F1 axis.","method":"miRNA target validation, siRNA knockdown, cell cycle analysis (flow cytometry), western blot for pRB/E2F1","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miRNA target validation plus siRNA phenocopy, multiple readouts, single lab","pmids":["21643017"],"is_preprint":false},{"year":2016,"finding":"CTDSPL directly binds RB protein: GST pull-down assay showed CTDSPL precipitates RB from MCF-7 cell extracts, and surface plasmon resonance confirmed the interaction is direct and physical, supporting the mechanism by which CTDSPL dephosphorylates and activates RB to arrest the cell cycle at G1/S.","method":"GST pull-down, surface plasmon resonance (SPR)","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal binding methods (GST pull-down + SPR) confirming direct interaction, single lab","pmids":["27414789"],"is_preprint":false},{"year":2017,"finding":"ALV integration into CTDSPL in chicken B-cell lymphomas drives expression of truncated fusion transcripts. Overexpression of CTDSPL in chick embryo fibroblasts promotes cell migration. Truncated viral fusion transcripts of CTDSPL promote immortalization in primary cell culture, revealing oncogenic properties when the gene is dysregulated.","method":"Deep sequencing of viral integration sites, overexpression in chick embryo fibroblasts, cell migration assay, immortalization assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — insertional mutagenesis combined with functional overexpression assays, multiple cellular readouts, single lab","pmids":["28915671"],"is_preprint":false},{"year":2018,"finding":"SCP3 (CTDSPL) overexpression in immunoedited tumor cells upregulates NANOG by hyperactivating the cyclin D1–CDK4/6 axis. CDK4/6 inhibitor palbociclib reverses SCP3-mediated aggressive phenotypes including cancer stem cell properties and immune refractoriness, placing SCP3 upstream of cyclin D1–CDK4/6–NANOG in this pathway.","method":"Overexpression studies, CDK4/6 inhibitor treatment, genetic epistasis (palbociclib reversal), Western blot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with pathway readouts, single lab, multiple cancer models tested","pmids":["29437706"],"is_preprint":false},{"year":2018,"finding":"CTDSPL is a direct target of miR-181b in uveal melanoma cells. Dual-luciferase reporter assay confirmed miR-181b binds the CTDSPL 3′UTR. miR-181b overexpression inhibits CTDSPL, leading to RB phosphorylation and E2F1 accumulation that drives cell cycle progression. siRNA knockdown of CTDSPL phenocopies miR-181b overexpression.","method":"Dual-luciferase reporter assay, microarray, RT-PCR, siRNA knockdown, flow cytometry","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase plus siRNA phenocopy, multiple readouts, single lab","pmids":["29382357"],"is_preprint":false},{"year":2021,"finding":"SCP3 physically interacts with JAB1 (Jun activation domain-binding protein 1), identified by yeast two-hybrid assay. This SCP3–JAB1 interaction drives transcriptional activation of EGF, which activates the EGFR–AKT signaling pathway. Neutralization of secreted EGF with a monoclonal antibody reverses SCP3-mediated aggressive phenotypes and EGFR–AKT activation, placing SCP3 upstream of the EGF–EGFR–AKT axis.","method":"Yeast two-hybrid assay, EGF neutralization with monoclonal antibody, Western blot for EGFR/AKT activation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus functional rescue experiment, single lab, no reciprocal Co-IP shown in abstract","pmids":["34445562"],"is_preprint":false},{"year":2024,"finding":"CTDSPL overexpression in mesenchymal stem cells induces premature senescence, characterized by enlarged morphology, upregulation of p16, SA-β-gal accumulation, and reduced phosphorylated RB indicating cell cycle arrest. miR-18a-5p targets the CTDSPL 3′UTR (validated by luciferase reporter assay) and its inhibition promotes CTDSPL expression and MSC senescence.","method":"Overexpression, luciferase reporter assay, SA-β-gal staining, Western blot (p16, pRB), flow cytometry","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression phenotype plus direct miRNA target validation, multiple readouts, single lab","pmids":["38460957"],"is_preprint":false},{"year":2025,"finding":"Human CTDSPL (along with CTDSP1 and CTDSP2) can functionally replace yeast Psr1 and Psr2 HAD-type phosphatases in restoring TORC1 inhibition and autophagy activation in response to low leucine conditions, demonstrating conserved phosphatase function across species. Mutation of the active site of Psr1 abolishes its inhibitory effects on TORC1, confirming the phosphatase catalytic activity is essential.","method":"Yeast complementation assay (human CTDSPL replacing yeast Psr1/Psr2), active-site mutagenesis, TORC1 activity assay, autophagy readout","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — functional complementation with active-site mutagenesis establishes catalytic requirement; human gene tested in heterologous system, single lab","pmids":["40103213"],"is_preprint":false},{"year":2013,"finding":"Crystallization of the SCP3 C-terminal coiled-coil domain was achieved with X-ray diffraction data collected to 3.2 Å resolution (space group C2), with three molecules in the asymmetric unit, providing structural groundwork for understanding the coiled-coil domain critical for fiber self-assembly.","method":"Recombinant protein expression in E. coli, purification, X-ray crystallography","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"Low","confidence_rationale":"Tier 1 / Weak — preliminary crystallographic data only (no refined structure reported in abstract), single study","pmids":["24192369"],"is_preprint":false}],"current_model":"CTDSPL (SCP3/RBSP3/HYA22) encodes a small C-terminal domain (HAD-type) phosphatase that, in somatic/cancer contexts, directly binds and dephosphorylates pRB to induce G1/S cell cycle arrest; it is targeted by oncomiRs (miR-100, miR-181b, miR-503-5p) that suppress its expression, relieving pRB phosphorylation and enabling E2F1-driven proliferation. In cancer cells it also activates the EGF–EGFR–AKT axis via physical interaction with JAB1, and upregulates NANOG through hyperactivation of cyclin D1–CDK4/6. In its meiotic role (alias SCP3), the protein self-assembles through its coiled-coil and N-terminal domains into cross-striated intermediate filament-like fibers that form the core of synaptonemal complex lateral elements, is essential for chromosomal synapsis, chiasmata formation, and faithful chromosome segregation in both male and female meiosis, and its removal from chromosomes is triggered by phosphorylation during meiotic progression."},"narrative":{"mechanistic_narrative":"CTDSPL (alias SCP3/RBSP3/HYA22) is a small C-terminal domain HAD-type phosphatase that operates in two distinct biological contexts: structural assembly of the meiotic synaptonemal complex and dephosphorylation-driven cell cycle control [PMID:9679134, PMID:15051889]. In meiosis, the protein self-assembles—via its C-terminal coiled-coil and N-terminal non-helical domains—into cross-striated, intermediate filament-like fibers that constitute the molecular framework of synaptonemal complex lateral elements [PMID:9679134, PMID:24192369]. Null mutation abolishes axial/lateral element and synaptonemal complex formation, prevents chromosomal synapsis, mislocalizes the recombination proteins Rad51 and RPA and the partner SCP1, and causes apoptotic arrest and sterility in males [PMID:10678170]; in females it is required for chiasmata formation and chromosome segregation, with its loss producing age-dependent oocyte aneuploidy [PMID:12004129]. Its removal from chromosomes during meiotic progression is driven by phosphorylation [PMID:9914155], and it co-localizes with the cohesin subunit Rad21 and accumulates at centromeres with INCENP and aurora-B, implicating it in monopolar sister-kinetochore attachment in meiosis I [PMID:14970259]. In somatic and cancer contexts the same gene acts as a tumor suppressor: it directly binds RB and dephosphorylates it to enforce G1/S arrest, suppresses tumor formation in vivo, and is mutated and deleted at the 3p21.3 locus [PMID:15051889, PMID:27414789]. This RB-dephosphorylating activity is suppressed by oncogenic microRNAs—miR-100, miR-181b, and miR-18a-5p target its 3′UTR to relieve RB phosphorylation and drive E2F1-dependent proliferation or, conversely, modulate cellular senescence [PMID:21643017, PMID:29382357, PMID:38460957]. In immunoedited tumor cells the protein conversely promotes aggressive phenotypes by hyperactivating the cyclin D1–CDK4/6–NANOG axis and by interacting with JAB1 to activate EGF–EGFR–AKT signaling [PMID:29437706, PMID:34445562]. Its catalytic HAD phosphatase function is evolutionarily conserved, as human CTDSPL complements yeast Psr1/Psr2 to restore TORC1 inhibition and autophagy [PMID:40103213].","teleology":[{"year":1998,"claim":"Established the structural basis of the protein's meiotic role by showing it intrinsically self-assembles into the fiber framework of synaptonemal complex lateral elements.","evidence":"Expression in cultured somatic cells with TEM/immuno-EM and domain-deletion mutagenesis","pmids":["9679134"],"confidence":"High","gaps":["Atomic-resolution assembly mechanism not resolved","Did not test in vivo requirement of each domain during meiosis"]},{"year":1998,"claim":"Addressed how the protein is cleared from chromosomes, showing phosphorylation accompanies its meiotic displacement.","evidence":"In vitro kinase assays using pachytene vs metaphase I spermatocyte extracts","pmids":["9914155"],"confidence":"Medium","gaps":["Responsible kinase not identified","Phosphosites not mapped","Causality of phosphorylation in removal not directly demonstrated in vivo"]},{"year":2000,"claim":"Demonstrated the protein is genetically essential for synaptonemal complex assembly and male meiotic progression.","evidence":"Null knockout in male mice with immunofluorescence and histology","pmids":["10678170"],"confidence":"High","gaps":["Mechanism linking SC loss to apoptotic checkpoint not defined","Did not address female meiosis"]},{"year":2002,"claim":"Extended the meiotic role to females, establishing requirement for chiasmata and segregation fidelity and linking loss to maternal-age aneuploidy.","evidence":"Knockout female mice with oocyte/embryo karyotyping and immunofluorescence","pmids":["12004129"],"confidence":"High","gaps":["Molecular basis of age-dependent aneuploidy increase unresolved"]},{"year":2004,"claim":"Positioned the protein relative to cohesin and passenger proteins, implicating it in monopolar kinetochore attachment in meiosis I.","evidence":"Immunofluorescence co-localization (Rad21, INCENP, aurora-B) in mouse spermatocytes","pmids":["14970259"],"confidence":"Medium","gaps":["No direct functional disruption to test causal role in monopolar attachment","Co-localization does not establish physical complex"]},{"year":2004,"claim":"Defined a distinct somatic function—an RB-dephosphorylating phosphatase that enforces G1/S arrest and suppresses tumors at the 3p21.3 locus.","evidence":"Sequence analysis, regulated transgene growth suppression, SCID mouse tumor assay, pRB dephosphorylation assay","pmids":["15051889"],"confidence":"High","gaps":["Direct enzyme-substrate kinetics on RB not characterized here","RB phosphosite specificity undefined"]},{"year":2011,"claim":"Placed the gene downstream of an oncomiR, showing miR-100 suppression of the gene relieves the pRB/E2F1 brake on proliferation and differentiation.","evidence":"miRNA target validation, siRNA phenocopy, flow cytometry, western blot in AML cells","pmids":["21643017"],"confidence":"Medium","gaps":["Direct 3′UTR binding site not mapped in this study","Single lineage context"]},{"year":2016,"claim":"Confirmed the RB interaction is direct and physical, supporting the dephosphorylation mechanism.","evidence":"GST pull-down and surface plasmon resonance with MCF-7 extracts","pmids":["27414789"],"confidence":"Medium","gaps":["Interaction interface not mapped","Single lab; no cellular reciprocal validation"]},{"year":2017,"claim":"Revealed context-dependent oncogenic potential, where truncated/dysregulated forms promote migration and immortalization.","evidence":"Viral integration site sequencing in chicken B-cell lymphomas plus overexpression, migration, and immortalization assays","pmids":["28915671"],"confidence":"Medium","gaps":["Mechanism of truncated-transcript oncogenicity unresolved","Avian system; relevance to human tumors not tested"]},{"year":2018,"claim":"Identified pro-tumorigenic signaling outputs, placing the protein upstream of cyclin D1–CDK4/6–NANOG and of a JAB1-driven EGF–EGFR–AKT axis.","evidence":"Overexpression with palbociclib epistasis (NANOG axis) and yeast two-hybrid plus EGF neutralization (JAB1/EGF axis), Western blot","pmids":["29437706","34445562"],"confidence":"Medium","gaps":["Reciprocal Co-IP for JAB1 interaction not shown","Reconciliation of tumor-suppressor vs aggressive phenotypes left unresolved","Phosphatase-dependence of these outputs untested"]},{"year":2018,"claim":"Broadened the oncomiR regulatory network, showing miR-181b directly targets the 3′UTR to drive RB phosphorylation and E2F1-dependent cell cycle progression.","evidence":"Dual-luciferase reporter, microarray, siRNA phenocopy, flow cytometry in uveal melanoma","pmids":["29382357"],"confidence":"Medium","gaps":["Single tumor type","In vivo relevance not established"]},{"year":2024,"claim":"Linked the gene's RB-arrest activity to cellular senescence, showing overexpression drives premature MSC senescence under miR-18a-5p control.","evidence":"Overexpression, luciferase reporter, SA-β-gal, Western blot (p16, pRB), flow cytometry","pmids":["38460957"],"confidence":"Medium","gaps":["Catalytic requirement for senescence not tested","p16 induction mechanism unclear"]},{"year":2025,"claim":"Established that the catalytic HAD phosphatase activity is conserved and functionally relevant to TORC1/autophagy control.","evidence":"Yeast complementation by human CTDSPL with active-site mutagenesis, TORC1 activity and autophagy readouts","pmids":["40103213"],"confidence":"Medium","gaps":["Direct TORC1-pathway substrate of human CTDSPL not identified","Tested only in heterologous yeast system"]},{"year":null,"claim":"How a single gene reconciles its meiotic structural fiber role, its tumor-suppressive RB phosphatase activity, and its pro-tumorigenic JAB1/EGF and CDK4/6–NANOG outputs in a unified mechanistic framework remains unresolved.","evidence":"No single study integrates the structural, phosphatase, and signaling functions","pmids":[],"confidence":"Low","gaps":["No refined high-resolution structure of full-length protein or fiber","Human RB phosphosites and TORC1-relevant substrates unmapped","Determinants switching tumor-suppressor vs oncogenic behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6,10]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11]}],"complexes":["synaptonemal complex lateral element"],"partners":["RB1","SCP1","RAD21","JAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15194","full_name":"CTD small phosphatase-like protein","aliases":["Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 3","NIF-like protein","Nuclear LIM interactor-interacting factor 1","NLI-interacting factor 1","Protein YA22","hYA22","RBSP3","Small C-terminal domain phosphatase 3","SCP3","Small CTD phosphatase 3"],"length_aa":276,"mass_kda":31.1,"function":"Recruited by REST to neuronal genes that contain RE-1 elements, leading to neuronal gene silencing in non-neuronal cells (By similarity). Preferentially catalyzes the dephosphorylation of 'Ser-5' within the tandem 7 residue repeats in the C-terminal domain (CTD) of the largest RNA polymerase II subunit POLR2A. Negatively regulates RNA polymerase II transcription, possibly by controlling the transition from initiation/capping to processive transcript elongation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15194/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTDSPL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTDSPL","total_profiled":1310},"omim":[{"mim_id":"612151","title":"MICRO RNA 26A1; MIR26A1","url":"https://www.omim.org/entry/612151"},{"mim_id":"608711","title":"CTD SMALL PHOSPHATASE 2; CTDSP2","url":"https://www.omim.org/entry/608711"},{"mim_id":"608592","title":"CTD SMALL PHOSPHATASE-LIKE; CTDSPL","url":"https://www.omim.org/entry/608592"},{"mim_id":"605323","title":"C-TERMINAL DOMAIN OF RNA POLYMERASE II POLYPEPTIDE A, SMALL PHOSPHATASE OF, 1; CTDSP1","url":"https://www.omim.org/entry/605323"},{"mim_id":"600571","title":"RE1-SILENCING TRANSCRIPTION FACTOR; REST","url":"https://www.omim.org/entry/600571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CTDSPL"},"hgnc":{"alias_symbol":["HYA22","SCP3","PSR1","RBSP3"],"prev_symbol":["C3orf8"]},"alphafold":{"accession":"O15194","domains":[{"cath_id":"3.40.50.1000","chopping":"105-117_148-276","consensus_level":"medium","plddt":96.2382,"start":105,"end":276}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15194","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15194-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15194-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTDSPL","jax_strain_url":"https://www.jax.org/strain/search?query=CTDSPL"},"sequence":{"accession":"O15194","fasta_url":"https://rest.uniprot.org/uniprotkb/O15194.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15194/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15194"}},"corpus_meta":[{"pmid":"10678170","id":"PMC_10678170","title":"The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10678170","citation_count":583,"is_preprint":false},{"pmid":"12004129","id":"PMC_12004129","title":"Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3.","date":"2002","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12004129","citation_count":273,"is_preprint":false},{"pmid":"10611385","id":"PMC_10611385","title":"Psr1, a nuclear localized protein that regulates phosphorus metabolism in Chlamydomonas.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10611385","citation_count":191,"is_preprint":false},{"pmid":"16400166","id":"PMC_16400166","title":"Genome-based approaches to understanding phosphorus deprivation responses and PSR1 control in 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phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/30963588","citation_count":35,"is_preprint":false},{"pmid":"29437706","id":"PMC_29437706","title":"Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3-NANOG Axis.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29437706","citation_count":33,"is_preprint":false},{"pmid":"18256545","id":"PMC_18256545","title":"Mammalian neo-oogenesis and expression of meiosis-specific protein SCP3 in adult human and monkey ovaries.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18256545","citation_count":31,"is_preprint":false},{"pmid":"19478941","id":"PMC_19478941","title":"High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19478941","citation_count":26,"is_preprint":false},{"pmid":"19140316","id":"PMC_19140316","title":"[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer].","date":"2008","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/19140316","citation_count":25,"is_preprint":false},{"pmid":"31350858","id":"PMC_31350858","title":"Lipid remodeling regulator 1 (LRL1) is differently involved in the phosphorus-depletion response from PSR1 in Chlamydomonas reinhardtii.","date":"2019","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31350858","citation_count":25,"is_preprint":false},{"pmid":"8409918","id":"PMC_8409918","title":"The DNA sequence and minimal replicon of the Corynebacterium glutamicum plasmid pSR1: evidence of a common ancestry with plasmids from C. diphtheriae.","date":"1993","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8409918","citation_count":22,"is_preprint":false},{"pmid":"3280974","id":"PMC_3280974","title":"Gene conversion associated with site-specific recombination in yeast plasmid pSR1.","date":"1988","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3280974","citation_count":19,"is_preprint":false},{"pmid":"28915671","id":"PMC_28915671","title":"Integration of ALV into CTDSPL and CTDSPL2 genes in B-cell lymphomas promotes cell immortalization, migration and survival.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28915671","citation_count":18,"is_preprint":false},{"pmid":"2005867","id":"PMC_2005867","title":"Mutations in a Saccharomyces cerevisiae host showing increased holding stability of the heterologous plasmid pSR1.","date":"1991","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/2005867","citation_count":18,"is_preprint":false},{"pmid":"25977440","id":"PMC_25977440","title":"Draft Genome Sequence of Anaeromyxobacter sp. Strain PSR-1, an Arsenate-Respiring Bacterium Isolated from Arsenic-Contaminated Soil.","date":"2015","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/25977440","citation_count":16,"is_preprint":false},{"pmid":"32978134","id":"PMC_32978134","title":"Possible Involvement of a Tetrathionate Reductase Homolog in Dissimilatory Arsenate Reduction by Anaeromyxobacter sp. Strain PSR-1.","date":"2020","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32978134","citation_count":14,"is_preprint":false},{"pmid":"24631545","id":"PMC_24631545","title":"Responsiveness of four gender-specific genes, figla, foxl2, scp3 and sox9a to 17α-ethinylestradiol in adult rare minnow Gobiocypris rarus.","date":"2014","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24631545","citation_count":12,"is_preprint":false},{"pmid":"39870634","id":"PMC_39870634","title":"GPX modulation promotes regenerative axonal fusion and functional recovery after injury through PSR-1 condensation.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39870634","citation_count":8,"is_preprint":false},{"pmid":"17380895","id":"PMC_17380895","title":"[Tumor suppressor gene RBSP3 in cervical carcinoma: copy number and transcriptional level].","date":"2007","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/17380895","citation_count":7,"is_preprint":false},{"pmid":"24785011","id":"PMC_24785011","title":"Expression of miR-100 and RBSP3 in FTC-133 cells after exposure to 131I.","date":"2014","source":"Nuclear medicine communications","url":"https://pubmed.ncbi.nlm.nih.gov/24785011","citation_count":6,"is_preprint":false},{"pmid":"37341065","id":"PMC_37341065","title":"Hsa-miR-503-5p regulates CTDSPL to accelerate cisplatin resistance and angiogenesis of lung adenocarcinoma cells.","date":"2023","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/37341065","citation_count":6,"is_preprint":false},{"pmid":"37575910","id":"PMC_37575910","title":"Overexpression of PSR1 in Chlamydomonas reinhardtii induces luxury phosphorus uptake.","date":"2023","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/37575910","citation_count":6,"is_preprint":false},{"pmid":"29672635","id":"PMC_29672635","title":"Differential transmission of the molecular signature of RBSP3, LIMD1 and CDC25A in basal/ parabasal versus spinous of normal epithelium during head and neck tumorigenesis: A mechanistic study.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29672635","citation_count":5,"is_preprint":false},{"pmid":"27277446","id":"PMC_27277446","title":"Scp3 expression in relation to the ovarian differentiation in the protogynous hermaphroditic ricefield eel Monopterus albus.","date":"2016","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27277446","citation_count":5,"is_preprint":false},{"pmid":"31253359","id":"PMC_31253359","title":"Effects of body temperature on the expression and localization of meiosis-related proteins STRA8 and SCP3 in boar testes.","date":"2019","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/31253359","citation_count":5,"is_preprint":false},{"pmid":"27414789","id":"PMC_27414789","title":"[Interaction of two tumor suppressors: Phosphatase CTDSPL and Rb protein].","date":"2016","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/27414789","citation_count":4,"is_preprint":false},{"pmid":"27458253","id":"PMC_27458253","title":"Association of P16-RBSP3 inactivation with phosphorylated RB1 overexpression in basal-parabasal layers of normal cervix unchanged during CACX development.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27458253","citation_count":4,"is_preprint":false},{"pmid":"29624473","id":"PMC_29624473","title":"Preferential allelic deletion of RBSP3, LIMD1 and CDC25A in head and neck squamous cell carcinoma: Implication in cancer screening and early detection.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29624473","citation_count":2,"is_preprint":false},{"pmid":"8479419","id":"PMC_8479419","title":"A specific host factor binds at a cis-acting transcriptionally silent locus required for stability control of yeast plasmid pSR1.","date":"1993","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/8479419","citation_count":2,"is_preprint":false},{"pmid":"36308428","id":"PMC_36308428","title":"Expression of scp3 and dazl reveals the meiotic characteristics of the olive flounder Paralichthys olivaceus†.","date":"2023","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/36308428","citation_count":1,"is_preprint":false},{"pmid":"38460957","id":"PMC_38460957","title":"MicroRNA-18a prevents senescence of mesenchymal stem cells by targeting CTDSPL.","date":"2024","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38460957","citation_count":1,"is_preprint":false},{"pmid":"39484844","id":"PMC_39484844","title":"Psr1 phosphatase regulates pre-mRNA splicing through spliceosomal B complex factor Snu66.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/39484844","citation_count":1,"is_preprint":false},{"pmid":"40103213","id":"PMC_40103213","title":"The Whi2-Psr1-Psr2 complex selectively regulates TORC1 and autophagy under low leucine conditions but not nitrogen depletion.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/40103213","citation_count":1,"is_preprint":false},{"pmid":"25767875","id":"PMC_25767875","title":"Fission yeast Scp3 potentially maintains microtubule orientation through bundling.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25767875","citation_count":1,"is_preprint":false},{"pmid":"40384610","id":"PMC_40384610","title":"A histone demethylase is involved in regulating the transcription factor PSR1 for carbon storage in Chlamydomonas.","date":"2025","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40384610","citation_count":1,"is_preprint":false},{"pmid":"34445562","id":"PMC_34445562","title":"Interaction between SCP3 and JAB1 Confers Cancer Therapeutic Resistance and Stem-like Properties through EGF Expression.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34445562","citation_count":0,"is_preprint":false},{"pmid":"24192369","id":"PMC_24192369","title":"Expression, crystallization and preliminary X-ray crystallographic studies of SCP3 coiled-coil domain.","date":"2013","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/24192369","citation_count":0,"is_preprint":false},{"pmid":"41930162","id":"PMC_41930162","title":"miR-100-5p Enhances Cell Cycle-Mediated Chemoresistance by Modulating the CTDSPL/pRB/E2F1 Signaling Pathway in Oxaliplatin-Resistant Colorectal Cancer Cells.","date":"2026","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/41930162","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.30.671211","title":"A plasma membrane Ca  <sup>2+</sup>  -dependent protein kinase PtCDPK2 promotes phosphorus starvation resilience in  <i>Phaeodactylum tricornutum</i>","date":"2025-08-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.30.671211","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28589,"output_tokens":4375,"usd":0.075696,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11724,"output_tokens":4009,"usd":0.079422,"stage2_stop_reason":"end_turn"},"total_usd":0.155118,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian gene CTDSPL (also known as HYA22, RBSP3, C3orf8, and the alias SCP3 which refers to this gene in mammalian/meiotic context).\n\n**Classification notes:**\n- Papers about mammalian/mouse/rat SCP3 (synaptonemal complex protein 3, meiosis) = canonical gene CTDSPL (alias SCP3) → INCLUDE\n- Papers about RBSP3/HYA22/CTDSPL as tumor suppressor → INCLUDE\n- Papers about Chlamydomonas PSR1 (phosphorus starvation response) → EXCLUDE (plant/algal symbol collision)\n- Papers about yeast pSR1 plasmid → EXCLUDE (symbol collision)\n- Papers about Phytophthora PSR1 effector → EXCLUDE (symbol collision)\n- Papers about C. elegans PSR-1 (phosphatidylserine receptor) → EXCLUDE (different protein, JmjC domain)\n- Papers about bacterial PSR-1 (arsenate-reducing) → EXCLUDE\n- Papers about fission yeast Scp3 (microtubule bundling) → EXCLUDE (incompatible function)\n- Paper [47] about yeast Psr1 phosphatase (pre-mRNA splicing via Snu66) → This is S. cerevisiae Psr1, a HAD phosphatase. Paper [48] explicitly states human CTDSPL can functionally replace yeast Psr1 → relevant context\n- Paper [48] about Whi2-Psr1-Psr2 complex in yeast, with human CTDSP1/2/CTDSPL complementing → INCLUDE for functional conservation finding\n- Papers about SCP3 in cancer (Oh et al. 2018, Oh et al. 2021) → INCLUDE (mammalian SCP3/CTDSPL)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SCP3 self-assembles into thick, cross-striated fibers when synthesized in cultured somatic cells; this process requires both the C-terminal coiled-coil domain and the N-terminal non-helical domain. The fibers display ~20 nm transversal striation and consist of closely associated 5–10 nm thin fibers resembling intermediate filaments, consistent with SCP3 forming the molecular framework of synaptonemal complex lateral elements.\",\n      \"method\": \"Expression in cultured somatic cells, transmission electron microscopy, immunoelectron microscopy, domain-deletion mutagenesis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution of fiber assembly in cells with mutagenesis defining required domains, plus EM structural characterization\",\n      \"pmids\": [\"9679134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SCP3 (COR1) and SCP1 (SYN1) are efficiently phosphorylated in vitro by extracts from isolated pachytene spermatocytes; extracts from metaphase I cells (in which SCP3 has been displaced from chromosomes) lack this kinase activity. This supports a model in which phosphorylation of SCP3 drives its removal from chromosomes during meiotic progression.\",\n      \"method\": \"In vitro kinase assay using pachytene and metaphase I cell extracts; okadaic acid-induced meiotic progression model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro phosphorylation assay, single lab, no identification of specific kinase\",\n      \"pmids\": [\"9914155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SCP3 null mutation in male mice abolishes axial/lateral element and synaptonemal complex formation, prevents chromosomal synapsis, and causes massive apoptotic cell death during meiotic prophase with sterility. Loss of SCP3 also disrupts nuclear distribution of DNA repair/recombination proteins Rad51 and RPA, and prevents SCP1 localization, establishing SCP3 as essential for the structural assembly of the synaptonemal complex.\",\n      \"method\": \"Gene knockout (null mutation), immunofluorescence, histology\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular and molecular phenotype, widely replicated\",\n      \"pmids\": [\"10678170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SCP3-deficient female mice produce aneuploid oocytes due to defective meiotic chromosome segregation; SCP3 is required for chiasmata formation and structural integrity of meiotic chromosomes. Loss of SCP3 triggers nondisjunction, and the resulting aneuploidy increases with advancing maternal age.\",\n      \"method\": \"Gene knockout, karyotyping of oocytes and embryos, immunofluorescence\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined chromosomal and embryonic phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"12004129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SCP3 colocalizes with cohesin subunit Rad21 at synaptonemal complex lateral elements, accumulates at centromeres during late prophase I together with chromosomal passenger proteins INCENP and aurora-B kinase in a 'double cornet' configuration, and both are displaced from centromeres at telophase I when sister kinetochores separate. This positional behavior implicates SCP3 in monopolar attachment of sister kinetochores during meiosis I.\",\n      \"method\": \"Immunofluorescence co-localization in mouse spermatocytes using squashing technique; antibodies against SCP3, Rad21, INCENP, aurora-B\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization data from multiple antibodies in a single study, no direct functional disruption of SCP3 at this stage\",\n      \"pmids\": [\"14970259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RBSP3/HYA22 (CTDSPL) encodes a small C-terminal domain phosphatase that dephosphorylates pRB, leading to cell cycle arrest at G1/S. Expression of RBSP3 suppresses tumor formation in SCID mice. The gene carries missense and nonsense mutations in tumors and is located in the frequently deleted 3p21.3 AP20 region.\",\n      \"method\": \"Sequence analysis, regulated transgene expression (growth suppression assay), SCID mouse tumor suppression assay, pRB dephosphorylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphatase activity demonstrated on pRB substrate, tumor suppression in vivo, regulated transgene growth assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15051889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RBSP3 (CTDSPL) is a direct target of miR-100 in AML cells. miR-100 suppresses RBSP3 expression, which in turn modulates pRB phosphorylation and E2F1 levels, promoting G1/S transition and blocking granulocyte/monocyte differentiation. RBSP3 knockdown by siRNA phenocopies miR-100 overexpression, confirming RBSP3 acts downstream of miR-100 to regulate the pRB/E2F1 axis.\",\n      \"method\": \"miRNA target validation, siRNA knockdown, cell cycle analysis (flow cytometry), western blot for pRB/E2F1\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miRNA target validation plus siRNA phenocopy, multiple readouts, single lab\",\n      \"pmids\": [\"21643017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CTDSPL directly binds RB protein: GST pull-down assay showed CTDSPL precipitates RB from MCF-7 cell extracts, and surface plasmon resonance confirmed the interaction is direct and physical, supporting the mechanism by which CTDSPL dephosphorylates and activates RB to arrest the cell cycle at G1/S.\",\n      \"method\": \"GST pull-down, surface plasmon resonance (SPR)\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal binding methods (GST pull-down + SPR) confirming direct interaction, single lab\",\n      \"pmids\": [\"27414789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ALV integration into CTDSPL in chicken B-cell lymphomas drives expression of truncated fusion transcripts. Overexpression of CTDSPL in chick embryo fibroblasts promotes cell migration. Truncated viral fusion transcripts of CTDSPL promote immortalization in primary cell culture, revealing oncogenic properties when the gene is dysregulated.\",\n      \"method\": \"Deep sequencing of viral integration sites, overexpression in chick embryo fibroblasts, cell migration assay, immortalization assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — insertional mutagenesis combined with functional overexpression assays, multiple cellular readouts, single lab\",\n      \"pmids\": [\"28915671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCP3 (CTDSPL) overexpression in immunoedited tumor cells upregulates NANOG by hyperactivating the cyclin D1–CDK4/6 axis. CDK4/6 inhibitor palbociclib reverses SCP3-mediated aggressive phenotypes including cancer stem cell properties and immune refractoriness, placing SCP3 upstream of cyclin D1–CDK4/6–NANOG in this pathway.\",\n      \"method\": \"Overexpression studies, CDK4/6 inhibitor treatment, genetic epistasis (palbociclib reversal), Western blot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with pathway readouts, single lab, multiple cancer models tested\",\n      \"pmids\": [\"29437706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTDSPL is a direct target of miR-181b in uveal melanoma cells. Dual-luciferase reporter assay confirmed miR-181b binds the CTDSPL 3′UTR. miR-181b overexpression inhibits CTDSPL, leading to RB phosphorylation and E2F1 accumulation that drives cell cycle progression. siRNA knockdown of CTDSPL phenocopies miR-181b overexpression.\",\n      \"method\": \"Dual-luciferase reporter assay, microarray, RT-PCR, siRNA knockdown, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase plus siRNA phenocopy, multiple readouts, single lab\",\n      \"pmids\": [\"29382357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SCP3 physically interacts with JAB1 (Jun activation domain-binding protein 1), identified by yeast two-hybrid assay. This SCP3–JAB1 interaction drives transcriptional activation of EGF, which activates the EGFR–AKT signaling pathway. Neutralization of secreted EGF with a monoclonal antibody reverses SCP3-mediated aggressive phenotypes and EGFR–AKT activation, placing SCP3 upstream of the EGF–EGFR–AKT axis.\",\n      \"method\": \"Yeast two-hybrid assay, EGF neutralization with monoclonal antibody, Western blot for EGFR/AKT activation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus functional rescue experiment, single lab, no reciprocal Co-IP shown in abstract\",\n      \"pmids\": [\"34445562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTDSPL overexpression in mesenchymal stem cells induces premature senescence, characterized by enlarged morphology, upregulation of p16, SA-β-gal accumulation, and reduced phosphorylated RB indicating cell cycle arrest. miR-18a-5p targets the CTDSPL 3′UTR (validated by luciferase reporter assay) and its inhibition promotes CTDSPL expression and MSC senescence.\",\n      \"method\": \"Overexpression, luciferase reporter assay, SA-β-gal staining, Western blot (p16, pRB), flow cytometry\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression phenotype plus direct miRNA target validation, multiple readouts, single lab\",\n      \"pmids\": [\"38460957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human CTDSPL (along with CTDSP1 and CTDSP2) can functionally replace yeast Psr1 and Psr2 HAD-type phosphatases in restoring TORC1 inhibition and autophagy activation in response to low leucine conditions, demonstrating conserved phosphatase function across species. Mutation of the active site of Psr1 abolishes its inhibitory effects on TORC1, confirming the phosphatase catalytic activity is essential.\",\n      \"method\": \"Yeast complementation assay (human CTDSPL replacing yeast Psr1/Psr2), active-site mutagenesis, TORC1 activity assay, autophagy readout\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — functional complementation with active-site mutagenesis establishes catalytic requirement; human gene tested in heterologous system, single lab\",\n      \"pmids\": [\"40103213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystallization of the SCP3 C-terminal coiled-coil domain was achieved with X-ray diffraction data collected to 3.2 Å resolution (space group C2), with three molecules in the asymmetric unit, providing structural groundwork for understanding the coiled-coil domain critical for fiber self-assembly.\",\n      \"method\": \"Recombinant protein expression in E. coli, purification, X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — preliminary crystallographic data only (no refined structure reported in abstract), single study\",\n      \"pmids\": [\"24192369\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTDSPL (SCP3/RBSP3/HYA22) encodes a small C-terminal domain (HAD-type) phosphatase that, in somatic/cancer contexts, directly binds and dephosphorylates pRB to induce G1/S cell cycle arrest; it is targeted by oncomiRs (miR-100, miR-181b, miR-503-5p) that suppress its expression, relieving pRB phosphorylation and enabling E2F1-driven proliferation. In cancer cells it also activates the EGF–EGFR–AKT axis via physical interaction with JAB1, and upregulates NANOG through hyperactivation of cyclin D1–CDK4/6. In its meiotic role (alias SCP3), the protein self-assembles through its coiled-coil and N-terminal domains into cross-striated intermediate filament-like fibers that form the core of synaptonemal complex lateral elements, is essential for chromosomal synapsis, chiasmata formation, and faithful chromosome segregation in both male and female meiosis, and its removal from chromosomes is triggered by phosphorylation during meiotic progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTDSPL (alias SCP3/RBSP3/HYA22) is a small C-terminal domain HAD-type phosphatase that operates in two distinct biological contexts: structural assembly of the meiotic synaptonemal complex and dephosphorylation-driven cell cycle control [#0, #5]. In meiosis, the protein self-assembles—via its C-terminal coiled-coil and N-terminal non-helical domains—into cross-striated, intermediate filament-like fibers that constitute the molecular framework of synaptonemal complex lateral elements [#0, #14]. Null mutation abolishes axial/lateral element and synaptonemal complex formation, prevents chromosomal synapsis, mislocalizes the recombination proteins Rad51 and RPA and the partner SCP1, and causes apoptotic arrest and sterility in males [#2]; in females it is required for chiasmata formation and chromosome segregation, with its loss producing age-dependent oocyte aneuploidy [#3]. Its removal from chromosomes during meiotic progression is driven by phosphorylation [#1], and it co-localizes with the cohesin subunit Rad21 and accumulates at centromeres with INCENP and aurora-B, implicating it in monopolar sister-kinetochore attachment in meiosis I [#4]. In somatic and cancer contexts the same gene acts as a tumor suppressor: it directly binds RB and dephosphorylates it to enforce G1/S arrest, suppresses tumor formation in vivo, and is mutated and deleted at the 3p21.3 locus [#5, #7]. This RB-dephosphorylating activity is suppressed by oncogenic microRNAs—miR-100, miR-181b, and miR-18a-5p target its 3′UTR to relieve RB phosphorylation and drive E2F1-dependent proliferation or, conversely, modulate cellular senescence [#6, #10, #12]. In immunoedited tumor cells the protein conversely promotes aggressive phenotypes by hyperactivating the cyclin D1–CDK4/6–NANOG axis and by interacting with JAB1 to activate EGF–EGFR–AKT signaling [#9, #11]. Its catalytic HAD phosphatase function is evolutionarily conserved, as human CTDSPL complements yeast Psr1/Psr2 to restore TORC1 inhibition and autophagy [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the structural basis of the protein's meiotic role by showing it intrinsically self-assembles into the fiber framework of synaptonemal complex lateral elements.\",\n      \"evidence\": \"Expression in cultured somatic cells with TEM/immuno-EM and domain-deletion mutagenesis\",\n      \"pmids\": [\"9679134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution assembly mechanism not resolved\", \"Did not test in vivo requirement of each domain during meiosis\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Addressed how the protein is cleared from chromosomes, showing phosphorylation accompanies its meiotic displacement.\",\n      \"evidence\": \"In vitro kinase assays using pachytene vs metaphase I spermatocyte extracts\",\n      \"pmids\": [\"9914155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinase not identified\", \"Phosphosites not mapped\", \"Causality of phosphorylation in removal not directly demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated the protein is genetically essential for synaptonemal complex assembly and male meiotic progression.\",\n      \"evidence\": \"Null knockout in male mice with immunofluorescence and histology\",\n      \"pmids\": [\"10678170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking SC loss to apoptotic checkpoint not defined\", \"Did not address female meiosis\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the meiotic role to females, establishing requirement for chiasmata and segregation fidelity and linking loss to maternal-age aneuploidy.\",\n      \"evidence\": \"Knockout female mice with oocyte/embryo karyotyping and immunofluorescence\",\n      \"pmids\": [\"12004129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of age-dependent aneuploidy increase unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Positioned the protein relative to cohesin and passenger proteins, implicating it in monopolar kinetochore attachment in meiosis I.\",\n      \"evidence\": \"Immunofluorescence co-localization (Rad21, INCENP, aurora-B) in mouse spermatocytes\",\n      \"pmids\": [\"14970259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional disruption to test causal role in monopolar attachment\", \"Co-localization does not establish physical complex\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a distinct somatic function—an RB-dephosphorylating phosphatase that enforces G1/S arrest and suppresses tumors at the 3p21.3 locus.\",\n      \"evidence\": \"Sequence analysis, regulated transgene growth suppression, SCID mouse tumor assay, pRB dephosphorylation assay\",\n      \"pmids\": [\"15051889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzyme-substrate kinetics on RB not characterized here\", \"RB phosphosite specificity undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed the gene downstream of an oncomiR, showing miR-100 suppression of the gene relieves the pRB/E2F1 brake on proliferation and differentiation.\",\n      \"evidence\": \"miRNA target validation, siRNA phenocopy, flow cytometry, western blot in AML cells\",\n      \"pmids\": [\"21643017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct 3′UTR binding site not mapped in this study\", \"Single lineage context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the RB interaction is direct and physical, supporting the dephosphorylation mechanism.\",\n      \"evidence\": \"GST pull-down and surface plasmon resonance with MCF-7 extracts\",\n      \"pmids\": [\"27414789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interface not mapped\", \"Single lab; no cellular reciprocal validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed context-dependent oncogenic potential, where truncated/dysregulated forms promote migration and immortalization.\",\n      \"evidence\": \"Viral integration site sequencing in chicken B-cell lymphomas plus overexpression, migration, and immortalization assays\",\n      \"pmids\": [\"28915671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of truncated-transcript oncogenicity unresolved\", \"Avian system; relevance to human tumors not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified pro-tumorigenic signaling outputs, placing the protein upstream of cyclin D1–CDK4/6–NANOG and of a JAB1-driven EGF–EGFR–AKT axis.\",\n      \"evidence\": \"Overexpression with palbociclib epistasis (NANOG axis) and yeast two-hybrid plus EGF neutralization (JAB1/EGF axis), Western blot\",\n      \"pmids\": [\"29437706\", \"34445562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal Co-IP for JAB1 interaction not shown\", \"Reconciliation of tumor-suppressor vs aggressive phenotypes left unresolved\", \"Phosphatase-dependence of these outputs untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened the oncomiR regulatory network, showing miR-181b directly targets the 3′UTR to drive RB phosphorylation and E2F1-dependent cell cycle progression.\",\n      \"evidence\": \"Dual-luciferase reporter, microarray, siRNA phenocopy, flow cytometry in uveal melanoma\",\n      \"pmids\": [\"29382357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor type\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked the gene's RB-arrest activity to cellular senescence, showing overexpression drives premature MSC senescence under miR-18a-5p control.\",\n      \"evidence\": \"Overexpression, luciferase reporter, SA-β-gal, Western blot (p16, pRB), flow cytometry\",\n      \"pmids\": [\"38460957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic requirement for senescence not tested\", \"p16 induction mechanism unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that the catalytic HAD phosphatase activity is conserved and functionally relevant to TORC1/autophagy control.\",\n      \"evidence\": \"Yeast complementation by human CTDSPL with active-site mutagenesis, TORC1 activity and autophagy readouts\",\n      \"pmids\": [\"40103213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TORC1-pathway substrate of human CTDSPL not identified\", \"Tested only in heterologous yeast system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single gene reconciles its meiotic structural fiber role, its tumor-suppressive RB phosphatase activity, and its pro-tumorigenic JAB1/EGF and CDK4/6–NANOG outputs in a unified mechanistic framework remains unresolved.\",\n      \"evidence\": \"No single study integrates the structural, phosphatase, and signaling functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No refined high-resolution structure of full-length protein or fiber\", \"Human RB phosphosites and TORC1-relevant substrates unmapped\", \"Determinants switching tumor-suppressor vs oncogenic behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [\n      \"synaptonemal complex lateral element\"\n    ],\n    \"partners\": [\n      \"RB1\",\n      \"SCP1\",\n      \"RAD21\",\n      \"JAB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}