{"gene":"TSPYL2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"CDA1 (TSPYL2) is phosphorylated in HeLa cells and by cyclin D1/CDK4, cyclin A/CDK2, and cyclin B/CDK1 in vitro. It localizes to the nucleus and nucleolus in HeLa cells. Overexpression arrests cell growth, colony formation, cell density, and BrdU uptake in a dose-dependent manner; this growth arrest is abolished by mutation of the two CDK consensus phosphorylation sites.","method":"In vitro kinase assays with recombinant cyclins/CDKs, cell fractionation, transfection with CDA1 transgene and N-terminal/C-terminal truncations, BrdU incorporation, CDK phosphorylation site mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution plus mutagenesis of phosphorylation sites with clear functional readout, single rigorous study with multiple orthogonal methods","pmids":["11395479"],"is_preprint":false},{"year":2007,"finding":"CDA1 (TSPYL2) induces p53 protein accumulation (by inactivating the ubiquitin ligase MDM2, reducing p53 degradation) and transcriptionally up-regulates p21(Waf1/Cip1) via p53-dependent and MEK/ERK1/2 MAPK-dependent pathways. CDA1 activates ERK1/2 phosphorylation; MEK inhibitors PD98059 and U0126 block this and abrogate p21 induction. DNA damage (camptothecin) increases CDA1 mRNA/protein and induces p53; CDA1 knockdown markedly attenuates damage-induced p53 induction.","method":"siRNA knockdown, p53 siRNA, luciferase reporter assays with p21 promoter deletions, Western blot for p53/MDM2/ERK/p21, qRT-PCR, pharmacologic MEK inhibition, camptothecin DNA damage model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (knockdown, mutagenesis of promoter elements, pharmacologic inhibition, reporter assays) in single rigorous study","pmids":["17317670"],"is_preprint":false},{"year":2001,"finding":"DENTT (TSPYL2) mRNA is induced ~3-fold by TGF-β1 in TGF-β1-responsive NSCLC cells (NCI-H727) but not in non-responsive NSCLC cells. EGFP-tagged DENTT localizes to the nucleolus and cytoplasm; deletion of the bipartite NLS-1 excludes DENTT from the nucleolus. TGF-β1 induction of DENTT correlates with extracellular matrix gene induction and inhibition of colony formation in soft agarose.","method":"Differential mRNA display, Northern analysis, EGFP-tagged localization constructs with NLS deletions in COS-7 cells, soft agarose colony assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — clean localization by fluorescent tagging with deletion constructs, functional colony assay, single lab","pmids":["11318608"],"is_preprint":false},{"year":2005,"finding":"DENTT (TSPYL2) ectopic expression significantly increases TGF-β1-responsive 3TP-Lux and CAGA12-Lux reporter transcription in lung cells when TGF-β1 is added, but has no significant effect on retinoic acid-responsive element reporter transcription, indicating DENTT specifically potentiates TGF-β signaling at the transcriptional level.","method":"Transient transfection of DENTT expression plasmid with TGF-β1-responsive luciferase reporters (3TP-Lux, CAGA12-Lux) in 12MBr6 and NCI-H727 cells; TGF-β1 and retinoic acid treatments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter assay with two different TGF-β-responsive constructs, single lab","pmids":["15823505"],"is_preprint":false},{"year":2008,"finding":"DENTT (TSPYL2) overexpression in lung (A549) and breast (MCF-7) cancer cells reduces anchorage-dependent and anchorage-independent growth and inhibits cell migration. DENTT mRNA and protein are markedly downregulated in primary human and mouse tumors and tumor cell lines. Demethylating agents increase DENTT expression, suggesting epigenetic silencing. DENTT expression parallels TGF-β1 and ectopic TGF-β1 increases DENTT mRNA/protein.","method":"Stable overexpression, colony formation assay, soft agar assay, cell migration assay, Western blot, demethylating agent treatment, RT-PCR in primary tumor samples","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional assays (colony, migration, anchorage-independent growth) in two cell lines, single lab","pmids":["18381359"],"is_preprint":false},{"year":2011,"finding":"TSPYL2 is required for G1 checkpoint maintenance after DNA damage. Tspyl2 knockout mouse embryonic fibroblasts are impaired in G1 arrest following gamma irradiation despite proper p53 protein accumulation, due to defective transcriptional activation of p21, indicating TSPYL2 acts downstream of p53 to enable p21 induction.","method":"Tspyl2 knockout mouse generation (targeted disruption), gamma irradiation of primary MEFs and thymocytes, cell cycle analysis, p21 RT-PCR/protein assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout model with defined DNA-damage phenotype, primary cells, orthogonal cell cycle and molecular readouts","pmids":["21738728"],"is_preprint":false},{"year":2014,"finding":"TSPYL2 interacts with CREB-binding protein (CBP) and regulates expression of NMDA receptor subunits GluN2A (Grin2a) and GluN2B (Grin2b) in the hippocampus. Tspyl2 knockout mice show reduced GluN2A and GluN2B protein; luciferase reporter assays and chromatin immunoprecipitation support direct transcriptional regulation of Grin2a and Grin2b by TSPYL2. Loss of TSPYL2 impairs hippocampal LTP and fear learning/memory.","method":"Tspyl2 knockout mice, Co-immunoprecipitation (TSPYL2–CBP interaction), ChIP at Grin2a/Grin2b promoters, luciferase reporter assays, electrophysiology (LTP), fear conditioning","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP for binding partner, ChIP for promoter occupancy, reporter assays, KO mouse with electrophysiology and behavioral phenotype, multiple orthogonal methods","pmids":["24413569"],"is_preprint":false},{"year":2015,"finding":"TSPYL2 is a component of the REST/NRSF transcriptional repressor complex. TSPYL2 and REST co-regulate TGF-β signaling: knockdown of either causes transformation of human mammary epithelial cells. The TSPYL2/REST complex represses expression of TrkC (proto-oncogene NTRK3), and cell-cycle arrest induced by TGF-β requires both REST and TSPYL2.","method":"Co-immunoprecipitation (TSPYL2–REST interaction), shRNA knockdown of TSPYL2 and REST, mammary epithelial cell transformation assay, TGF-β cell-cycle arrest assay, TrkC expression analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating complex, loss-of-function with transformation phenotype, downstream target (TrkC) identified, multiple orthogonal approaches","pmids":["25613376"],"is_preprint":false},{"year":2018,"finding":"TSPYL2 inhibits SIRT1 (disrupting SIRT1's association with target proteins) and promotes p300 acetylation and activation upon DNA damage, thereby stimulating p53 acetylation and p53-dependent apoptosis. Cells silenced for TSPYL2 are defective in p53 activation and apoptosis induction after DNA damage, in a SIRT1- and p300-dependent manner.","method":"siRNA knockdown of TSPYL2, Co-immunoprecipitation (TSPYL2–SIRT1, TSPYL2–p300 interactions), p53 acetylation assays, apoptosis assays, epistasis by rescue with SIRT1/p300 manipulation","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical activity assays (acetylation), genetic epistasis via siRNA rescue, multiple orthogonal methods in single study","pmids":["30050056"],"is_preprint":false},{"year":2018,"finding":"TSPYL2 regulates expression of EZH2 target genes in neurons. Tspyl2 knockout mice have elevated H3K27me3 in the hippocampus; TSPYL2 interacts with EZH2 by Co-IP and co-occupies target gene promoters (ChIP). Loss of TSPYL2 reduces expression of developmental/synaptic genes including Bdnf, Egr3, Grin2c, Igf1, Gbx2, and Acvrl1. EZH2 inhibitor GSK126 rescues reduced expression in mutant neurons.","method":"Tspyl2 KO mice, Co-immunoprecipitation (TSPYL2–EZH2), ChIP-sequencing and ChIP in hippocampal neurons/neuroblastoma cells, pharmacologic EZH2 inhibition (GSK126), qRT-PCR","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP-seq, genetic KO, pharmacologic rescue with EZH2 inhibitor, multiple orthogonal methods","pmids":["30051352"],"is_preprint":false},{"year":2018,"finding":"In diabetic mice, CDA1 (TSPYL2) expression is upregulated in the aorta and confers protection against aortic aneurysm through enhanced TGF-β signaling, increased collagen expression, and reduced macrophage infiltration. CDA1/ApoE double-knockout diabetic mice develop aortic aneurysms not seen in ApoE-KO diabetic mice; CDA1 deletion in the angiotensin II model also abrogates diabetes-mediated protection. CDA1 aortic expression is downregulated ~70% in human abdominal aortic aneurysm biopsies.","method":"CDA1 KO, ApoE KO, CDA1/ApoE double-KO mouse models; diabetes induction; angiotensin II aneurysm model; TGF-β signaling and collagen immunostaining/Western blot; macrophage and MMP12 analysis; human biopsy Western blot","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models with mechanistic readouts (TGF-β signaling, collagen, macrophage infiltration) plus human tissue validation","pmids":["29311219"],"is_preprint":false},{"year":2018,"finding":"A novel CDA1-binding protein (CDA1BP1) was identified as a regulator of CDA1 (TSPYL2) profibrotic activity. CDA1BP1 binds CDA1; genetic deletion of CDA1BP1 attenuates renal fibrosis in diabetic mice. Synthetic CDA1BP1 peptides competitively inhibit CDA1–CDA1BP1 binding in vitro and reduce collagen expression in HK-2 cells. A retro-inverso d-amino acid peptide (CHA-061) targeting this interaction attenuates renal extracellular matrix accumulation and glomerular injury in vivo.","method":"Co-immunoprecipitation (CDA1–CDA1BP1), CDA1BP1 KO mouse, competitive peptide inhibition assays in vitro, HK-2 cell collagen expression, in vivo diabetic mouse kidney histology and gene expression","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying binding partner, KO mouse, peptide competition assay, in vitro and in vivo functional readouts, multiple orthogonal methods","pmids":["30425061"],"is_preprint":false},{"year":2022,"finding":"TSPYL2 inhibits SIRT1-mediated deacetylation of FOXO3, thereby reducing gefitinib resistance and DNA damage repair in colorectal cancer cells. TSPYL2 knockdown promotes gefitinib resistance; TSPYL2 overexpression inhibits DNA damage repair. Mechanistically, TSPYL2 suppresses SIRT1, which reduces SIRT1-mediated FOXO3 deacetylation, and TSPYL2 inhibits tumor growth and resistance in vivo.","method":"TSPYL2 knockdown/overexpression in CRC cells, immunofluorescence, Western blot for SIRT1/FOXO3 acetylation/phosphorylation, tumor xenograft experiments","journal":"Future medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional assays with molecular readout (acetylation), in vivo xenograft, single lab, limited biochemical detail in abstract","pmids":["35192400"],"is_preprint":false},{"year":2023,"finding":"ZFP91 interacts with TSPYL2, induces its poly-ubiquitination, and promotes its proteasomal degradation. Ginsenoside Rg3 weakens ZFP91-induced TSPYL2 poly-ubiquitination and degradation. Enforced TSPYL2 expression increases gemcitabine sensitivity in pancreatic adenocarcinoma cells.","method":"Co-immunoprecipitation (ZFP91–TSPYL2), ubiquitination assay, TSPYL2 overexpression/knockdown, cell viability/drug resistance assays, in vivo tumor xenograft","journal":"Journal of ginseng research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination assay identifying E3 ligase–substrate relationship, functional drug-resistance readout, single lab","pmids":["36090681"],"is_preprint":false},{"year":2023,"finding":"CRL2APPBP2 (CUL2–APPBP2 E3 ligase complex) targets TSPYL2 for ubiquitin–proteasome-mediated degradation via the substrate receptor APPBP2. CUL2 deletion accelerates hMSC senescence; TSPYL2 accumulates upon CUL2 loss and down-regulates P21(waf1/cip1), thereby counteracting senescence. This places TSPYL2 degradation as a mechanism to delay mesenchymal stem cell aging.","method":"CRISPR/Cas9 CUL2 KO in hESCs, hMSC differentiation, individual Cullin knockdown screen, APPBP2 substrate receptor identification, proteasome inhibition, senescence assays, p21 Western blot","journal":"Science China. Life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with CRISPR, substrate receptor identification, proteasome pathway rescue, senescence phenotypic readout, mechanistic epistasis","pmids":["38170390"],"is_preprint":false},{"year":2023,"finding":"TSPYL2 (CDA1) overexpression via AAV9 gene delivery inhibits bleomycin-induced pulmonary fibrosis in mice by repressing TGF-β/Smad3 signaling and inhibiting lung fibroblast-to-myofibroblast transition. In vitro, CDA1 overexpression in HFL1 fibroblasts reduces TGF-β1-induced pro-fibrotic cytokines, ECM protein expression, and cell proliferation/migration; CDA1 knockdown enhances these effects.","method":"Lentiviral overexpression, siRNA knockdown in HFL1 cells, AAV9-Tspyl2 intratracheal delivery in BLM mouse model, Smad3 phosphorylation assay, histology, ECM gene expression","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro gain/loss-of-function with molecular readout (Smad3 signaling), in vivo AAV gene therapy model, multiple orthogonal methods","pmids":["37391440"],"is_preprint":false},{"year":2023,"finding":"TSPYL2 interacts with SIRT1 (Co-IP) in thyroid cancer cells and inhibits AKT activation by upregulating AKT acetylation level, reducing SIRT1-mediated AKT deacetylation. Knockdown of TSPYL2 increases SIRT1–AKT association and AKT phosphorylation; TSPYL2 overexpression reverses these effects and suppresses thyroid cancer cell proliferation, migration, invasion, and in vivo tumor growth.","method":"Co-immunoprecipitation (TSPYL2–SIRT1), AKT acetylation/phosphorylation Western blot, TSPYL2 KD/OE in TPC-1 and IHH-4 cells, tumor xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying interaction, acetylation mechanistic readout, in vivo xenograft, single lab","pmids":["37696385"],"is_preprint":false}],"current_model":"TSPYL2 (CDA1/DENTT/TSPX) is a nucleosome assembly protein that functions as a multi-pathway tumor suppressor and cell growth regulator: it is phosphorylated by cyclin-CDK complexes; arrests cell growth by stabilizing p53 (via MDM2 inactivation) and inducing p21 through p53- and MEK/ERK-dependent transcription; is required for G1 checkpoint maintenance after DNA damage; forms a complex with REST/NRSF to activate TGF-β signaling and suppress oncogenic TrkC; inhibits SIRT1 to promote p300-mediated p53 acetylation and apoptosis after DNA damage; interacts with CBP and EZH2 to regulate chromatin state and expression of synaptic genes (GluN2A, GluN2B, Bdnf, Egr3) in neurons; is targeted for proteasomal degradation by ZFP91 (ubiquitination) and by the CRL2APPBP2 E3 ligase; represses TGF-β/Smad3-driven fibrosis; and suppresses SIRT1-mediated deacetylation of AKT and FOXO3 to sensitize cancer cells to therapy."},"narrative":{"mechanistic_narrative":"TSPYL2 (also CDA1/DENTT/TSPX) is a nucleus- and nucleolus-localized chromatin-associated regulator that couples cell-cycle control, the DNA-damage response, and TGF-β signaling to act as a multi-context growth suppressor [PMID:11395479, PMID:17317670, PMID:21738728]. It is a phosphosubstrate of cyclin-CDK complexes (cyclin D1/CDK4, cyclin A/CDK2, cyclin B/CDK1), and CDK-site phosphorylation is required for its growth-arresting activity [PMID:11395479]. After DNA damage TSPYL2 enforces the G1 checkpoint by enabling p53-dependent transcription of p21: it stabilizes p53 through MDM2 inactivation and drives p21 induction via p53- and MEK/ERK-dependent routes, and it acts downstream of p53 since knockout cells accumulate p53 normally yet fail to induce p21 [PMID:17317670, PMID:21738728]. A recurrent biochemical theme is its antagonism of the deacetylase SIRT1 — by disrupting SIRT1's engagement of substrates, TSPYL2 promotes p300-mediated p53 acetylation and apoptosis, and preserves the acetylation of FOXO3 and AKT to constrain DNA-damage repair, AKT signaling, and therapy resistance in cancer cells [PMID:30050056, PMID:35192400, PMID:37696385]. TSPYL2 also operates within transcriptional/chromatin complexes: it joins the REST/NRSF repressor to potentiate TGF-β-driven cell-cycle arrest and repress the TrkC oncogene, and it binds CBP and EZH2 to control H3K27me3 and the expression of synaptic and developmental genes (Grin2a, Grin2b, Bdnf, Egr3) underlying hippocampal LTP and memory [PMID:24413569, PMID:25613376, PMID:30051352]. Through enhancement of TGF-β/Smad3 signaling it restrains fibroblast-to-myofibroblast transition and fibrosis and protects against diabetic vascular and renal injury [PMID:29311219, PMID:30425061, PMID:37391440]. TSPYL2 protein levels are set by ubiquitin-proteasome turnover via the E3 ligase ZFP91 and the CRL2-APPBP2 complex, the latter linking its degradation to mesenchymal stem cell senescence through p21 [PMID:36090681, PMID:38170390].","teleology":[{"year":2001,"claim":"Established TSPYL2/CDA1 as a CDK-phosphorylated nuclear/nucleolar protein whose overexpression arrests cell growth, defining it as a cell-cycle-coupled growth suppressor.","evidence":"In vitro kinase assays with recombinant cyclins/CDKs, cell fractionation, transgene overexpression with CDK-site mutagenesis and BrdU incorporation in HeLa cells","pmids":["11395479"],"confidence":"High","gaps":["Functional consequence of each individual CDK phosphorylation event not resolved","Molecular mechanism by which growth arrest is executed not defined in this study"]},{"year":2001,"claim":"Independently identified the same protein (DENTT) as a TGF-β1-inducible gene whose nucleolar localization depends on a bipartite NLS and whose induction tracks with growth suppression, linking it to TGF-β biology.","evidence":"Differential mRNA display, Northern blot, EGFP-NLS deletion constructs in COS-7, soft agarose colony assay in NSCLC cells","pmids":["11318608"],"confidence":"Medium","gaps":["Direct demonstration that DENTT acts within the TGF-β pathway not yet shown","Single-lab localization with overexpressed tagged constructs"]},{"year":2005,"claim":"Showed the protein specifically potentiates TGF-β transcriptional output rather than acting as a general transcription enhancer.","evidence":"Transient transfection with TGF-β-responsive (3TP-Lux, CAGA12-Lux) versus retinoic-acid-responsive luciferase reporters in lung cells","pmids":["15823505"],"confidence":"Medium","gaps":["Mechanism of reporter potentiation (direct vs indirect) unresolved","No endogenous target genes identified"]},{"year":2007,"claim":"Defined the mechanism of growth arrest — TSPYL2 stabilizes p53 via MDM2 inactivation and induces p21 through p53- and MEK/ERK-dependent transcription, and is itself a DNA-damage-responsive gene.","evidence":"siRNA knockdown, p21 promoter reporter deletions, pharmacologic MEK inhibition, camptothecin damage model in cultured cells","pmids":["17317670"],"confidence":"High","gaps":["Biochemical basis of MDM2 inactivation by TSPYL2 not defined","How TSPYL2 activates ERK signaling unknown"]},{"year":2008,"claim":"Demonstrated TSPYL2 is downregulated and epigenetically silenced in tumors and suppresses anchorage-independent growth and migration, establishing it as a candidate tumor suppressor.","evidence":"Stable overexpression, colony/soft-agar/migration assays, demethylating agent treatment, RT-PCR on primary tumors","pmids":["18381359"],"confidence":"Medium","gaps":["Causal silencing mechanism (promoter methylation site) not mapped","Single-lab tumor sample analysis"]},{"year":2011,"claim":"Genetically separated TSPYL2 function from p53 stabilization, showing it acts downstream of p53 to enable p21 transcription and G1 checkpoint maintenance after DNA damage.","evidence":"Tspyl2 knockout mice, gamma irradiation of primary MEFs/thymocytes, cell-cycle analysis, p21 expression assays","pmids":["21738728"],"confidence":"High","gaps":["Molecular step linking TSPYL2 to p21 promoter activation not defined","Reconciliation with the 2007 MDM2/p53-stabilization model unresolved"]},{"year":2014,"claim":"Revealed a neuronal transcriptional function — TSPYL2 binds CBP and directly regulates NMDA receptor subunit genes, with loss impairing hippocampal LTP and memory.","evidence":"Tspyl2 KO mice, Co-IP, ChIP and reporter assays at Grin2a/Grin2b, electrophysiology, fear conditioning","pmids":["24413569"],"confidence":"High","gaps":["Whether TSPYL2 activates or recruits CBP enzymatic activity not resolved","Direct DNA-binding versus adaptor role at promoters unclear"]},{"year":2015,"claim":"Placed TSPYL2 inside the REST/NRSF repressor complex co-regulating TGF-β-induced arrest and repressing the TrkC oncogene, linking its TGF-β and tumor-suppressor activities.","evidence":"Co-IP of TSPYL2–REST, shRNA knockdown, mammary epithelial transformation assay, TGF-β arrest assay","pmids":["25613376"],"confidence":"High","gaps":["Stoichiometry and architecture of the TSPYL2–REST complex unknown","How the complex intersects with Smad-dependent TGF-β transcription not defined"]},{"year":2018,"claim":"Identified SIRT1 inhibition as a core biochemical activity — TSPYL2 disrupts SIRT1 substrate engagement to promote p300-mediated p53 acetylation and DNA-damage apoptosis.","evidence":"siRNA knockdown, Co-IP of TSPYL2–SIRT1 and TSPYL2–p300, p53 acetylation and apoptosis assays with SIRT1/p300 epistasis","pmids":["30050056"],"confidence":"High","gaps":["Direct enzymatic inhibition of SIRT1 versus competitive sequestration not distinguished","Structural basis of TSPYL2–SIRT1 contact unknown"]},{"year":2018,"claim":"Extended TSPYL2's chromatin role to PRC2, showing it interacts with EZH2 and co-occupies promoters to regulate H3K27me3 and developmental/synaptic gene expression.","evidence":"Tspyl2 KO mice, Co-IP of TSPYL2–EZH2, ChIP-seq in hippocampal neurons/neuroblastoma, GSK126 rescue, qRT-PCR","pmids":["30051352"],"confidence":"High","gaps":["Whether TSPYL2 promotes or restrains EZH2 catalytic activity at target loci not resolved","Relationship between CBP-activating and EZH2-associated functions unclear"]},{"year":2018,"claim":"Established a protective in vivo role in diabetic vasculature via TGF-β-driven collagen and reduced inflammation, with human aneurysm tissue validation.","evidence":"CDA1, ApoE, and double-KO mice, diabetes and angiotensin II aneurysm models, TGF-β/collagen/macrophage readouts, human biopsy Western blot","pmids":["29311219"],"confidence":"High","gaps":["Cell-type responsible for the protective effect not pinpointed","Mechanistic link from TSPYL2 to MMP12/macrophage suppression incomplete"]},{"year":2018,"claim":"Identified CDA1BP1 as a binding partner required for TSPYL2's pro-fibrotic activity and validated the interaction as a druggable target with a peptide inhibitor.","evidence":"Co-IP of CDA1–CDA1BP1, CDA1BP1 KO mice, competitive peptide assays, HK-2 cell collagen, diabetic kidney histology in vivo","pmids":["30425061"],"confidence":"High","gaps":["Molecular identity/domain of the CDA1–CDA1BP1 interface beyond peptide mapping not fully defined","How CDA1BP1 binding modulates TGF-β output mechanistically unclear"]},{"year":2022,"claim":"Connected the SIRT1-antagonism mechanism to therapy resistance, showing TSPYL2 preserves FOXO3 acetylation to limit DNA-damage repair and gefitinib resistance in colorectal cancer.","evidence":"TSPYL2 knockdown/overexpression in CRC cells, SIRT1/FOXO3 acetylation Western blot, tumor xenografts","pmids":["35192400"],"confidence":"Medium","gaps":["Limited biochemical detail on FOXO3 acetylation site regulation","Single-lab study"]},{"year":2023,"claim":"Defined ZFP91 as an E3 ligase that ubiquitinates and degrades TSPYL2, and linked its stabilization to gemcitabine sensitivity in pancreatic cancer.","evidence":"Co-IP of ZFP91–TSPYL2, ubiquitination assay, overexpression/knockdown, drug-resistance and xenograft assays, ginsenoside Rg3 modulation","pmids":["36090681"],"confidence":"Medium","gaps":["Ubiquitination site(s) on TSPYL2 not mapped","Whether ZFP91 regulation is constitutive or signal-dependent unknown"]},{"year":2023,"claim":"Identified a second degradation route via CRL2-APPBP2 and tied TSPYL2 turnover to p21 control and mesenchymal stem cell senescence.","evidence":"CRISPR CUL2 KO in hESCs, Cullin knockdown screen, APPBP2 substrate-receptor identification, proteasome inhibition, senescence and p21 readouts","pmids":["38170390"],"confidence":"High","gaps":["Degron recognized by APPBP2 not defined","Crosstalk between ZFP91 and CRL2-APPBP2 pathways unresolved"]},{"year":2023,"claim":"Demonstrated therapeutic anti-fibrotic action — AAV9-delivered TSPYL2 represses TGF-β/Smad3 signaling and blocks fibroblast-to-myofibroblast transition in lung fibrosis.","evidence":"Lentiviral OE/siRNA in HFL1 cells, AAV9-Tspyl2 intratracheal delivery in bleomycin model, Smad3 phosphorylation, histology, ECM gene expression","pmids":["37391440"],"confidence":"High","gaps":["Apparent context-dependent dual effect on TGF-β (potentiation versus repression) across tissues not reconciled","Direct molecular target on the Smad3 axis not identified"]},{"year":2023,"claim":"Showed TSPYL2 suppresses AKT signaling in thyroid cancer by inhibiting SIRT1-mediated AKT deacetylation, reinforcing SIRT1 antagonism as a generalizable tumor-suppressive mechanism.","evidence":"Co-IP of TSPYL2–SIRT1, AKT acetylation/phosphorylation Western blot, KD/OE in thyroid cancer cells, xenografts","pmids":["37696385"],"confidence":"Medium","gaps":["AKT acetylation site and its phosphorylation linkage not biochemically detailed","Single-lab study"]},{"year":null,"claim":"How TSPYL2 reconciles its opposing context-dependent effects on TGF-β signaling (potentiation in lung/vascular protection versus its role across tumor and fibrosis settings) and whether it binds DNA directly or acts purely as a chromatin/complex adaptor remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TSPYL2 or its complexes","Direct DNA-binding versus adaptor function not established","Unifying biochemical activity reconciling p53, SIRT1, REST, CBP, and EZH2 functions not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,6,7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,12,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7,9]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,14]}],"complexes":["REST/NRSF repressor complex"],"partners":["SIRT1","EP300","CBP","EZH2","REST","ZFP91","APPBP2","CDA1BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2G4","full_name":"Testis-specific Y-encoded-like protein 2","aliases":["Cell division autoantigen 1","Cutaneous T-cell lymphoma-associated antigen se20-4","CTCL-associated antigen se20-4","Differentially-expressed nucleolar TGF-beta1 target protein","Nuclear protein of 79 kDa","NP79"],"length_aa":693,"mass_kda":79.4,"function":"Part of the CASK/TBR1/TSPYL2 transcriptional complex which modulates gene expression in response to neuronal synaptic activity, probably by facilitating nucleosome assembly. 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It localizes to the nucleus and nucleolus in HeLa cells. Overexpression arrests cell growth, colony formation, cell density, and BrdU uptake in a dose-dependent manner; this growth arrest is abolished by mutation of the two CDK consensus phosphorylation sites.\",\n      \"method\": \"In vitro kinase assays with recombinant cyclins/CDKs, cell fractionation, transfection with CDA1 transgene and N-terminal/C-terminal truncations, BrdU incorporation, CDK phosphorylation site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution plus mutagenesis of phosphorylation sites with clear functional readout, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"11395479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CDA1 (TSPYL2) induces p53 protein accumulation (by inactivating the ubiquitin ligase MDM2, reducing p53 degradation) and transcriptionally up-regulates p21(Waf1/Cip1) via p53-dependent and MEK/ERK1/2 MAPK-dependent pathways. CDA1 activates ERK1/2 phosphorylation; MEK inhibitors PD98059 and U0126 block this and abrogate p21 induction. DNA damage (camptothecin) increases CDA1 mRNA/protein and induces p53; CDA1 knockdown markedly attenuates damage-induced p53 induction.\",\n      \"method\": \"siRNA knockdown, p53 siRNA, luciferase reporter assays with p21 promoter deletions, Western blot for p53/MDM2/ERK/p21, qRT-PCR, pharmacologic MEK inhibition, camptothecin DNA damage model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (knockdown, mutagenesis of promoter elements, pharmacologic inhibition, reporter assays) in single rigorous study\",\n      \"pmids\": [\"17317670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DENTT (TSPYL2) mRNA is induced ~3-fold by TGF-β1 in TGF-β1-responsive NSCLC cells (NCI-H727) but not in non-responsive NSCLC cells. EGFP-tagged DENTT localizes to the nucleolus and cytoplasm; deletion of the bipartite NLS-1 excludes DENTT from the nucleolus. TGF-β1 induction of DENTT correlates with extracellular matrix gene induction and inhibition of colony formation in soft agarose.\",\n      \"method\": \"Differential mRNA display, Northern analysis, EGFP-tagged localization constructs with NLS deletions in COS-7 cells, soft agarose colony assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — clean localization by fluorescent tagging with deletion constructs, functional colony assay, single lab\",\n      \"pmids\": [\"11318608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DENTT (TSPYL2) ectopic expression significantly increases TGF-β1-responsive 3TP-Lux and CAGA12-Lux reporter transcription in lung cells when TGF-β1 is added, but has no significant effect on retinoic acid-responsive element reporter transcription, indicating DENTT specifically potentiates TGF-β signaling at the transcriptional level.\",\n      \"method\": \"Transient transfection of DENTT expression plasmid with TGF-β1-responsive luciferase reporters (3TP-Lux, CAGA12-Lux) in 12MBr6 and NCI-H727 cells; TGF-β1 and retinoic acid treatments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter assay with two different TGF-β-responsive constructs, single lab\",\n      \"pmids\": [\"15823505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DENTT (TSPYL2) overexpression in lung (A549) and breast (MCF-7) cancer cells reduces anchorage-dependent and anchorage-independent growth and inhibits cell migration. DENTT mRNA and protein are markedly downregulated in primary human and mouse tumors and tumor cell lines. Demethylating agents increase DENTT expression, suggesting epigenetic silencing. DENTT expression parallels TGF-β1 and ectopic TGF-β1 increases DENTT mRNA/protein.\",\n      \"method\": \"Stable overexpression, colony formation assay, soft agar assay, cell migration assay, Western blot, demethylating agent treatment, RT-PCR in primary tumor samples\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional assays (colony, migration, anchorage-independent growth) in two cell lines, single lab\",\n      \"pmids\": [\"18381359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TSPYL2 is required for G1 checkpoint maintenance after DNA damage. Tspyl2 knockout mouse embryonic fibroblasts are impaired in G1 arrest following gamma irradiation despite proper p53 protein accumulation, due to defective transcriptional activation of p21, indicating TSPYL2 acts downstream of p53 to enable p21 induction.\",\n      \"method\": \"Tspyl2 knockout mouse generation (targeted disruption), gamma irradiation of primary MEFs and thymocytes, cell cycle analysis, p21 RT-PCR/protein assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout model with defined DNA-damage phenotype, primary cells, orthogonal cell cycle and molecular readouts\",\n      \"pmids\": [\"21738728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TSPYL2 interacts with CREB-binding protein (CBP) and regulates expression of NMDA receptor subunits GluN2A (Grin2a) and GluN2B (Grin2b) in the hippocampus. Tspyl2 knockout mice show reduced GluN2A and GluN2B protein; luciferase reporter assays and chromatin immunoprecipitation support direct transcriptional regulation of Grin2a and Grin2b by TSPYL2. Loss of TSPYL2 impairs hippocampal LTP and fear learning/memory.\",\n      \"method\": \"Tspyl2 knockout mice, Co-immunoprecipitation (TSPYL2–CBP interaction), ChIP at Grin2a/Grin2b promoters, luciferase reporter assays, electrophysiology (LTP), fear conditioning\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP for binding partner, ChIP for promoter occupancy, reporter assays, KO mouse with electrophysiology and behavioral phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"24413569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TSPYL2 is a component of the REST/NRSF transcriptional repressor complex. TSPYL2 and REST co-regulate TGF-β signaling: knockdown of either causes transformation of human mammary epithelial cells. The TSPYL2/REST complex represses expression of TrkC (proto-oncogene NTRK3), and cell-cycle arrest induced by TGF-β requires both REST and TSPYL2.\",\n      \"method\": \"Co-immunoprecipitation (TSPYL2–REST interaction), shRNA knockdown of TSPYL2 and REST, mammary epithelial cell transformation assay, TGF-β cell-cycle arrest assay, TrkC expression analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating complex, loss-of-function with transformation phenotype, downstream target (TrkC) identified, multiple orthogonal approaches\",\n      \"pmids\": [\"25613376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TSPYL2 inhibits SIRT1 (disrupting SIRT1's association with target proteins) and promotes p300 acetylation and activation upon DNA damage, thereby stimulating p53 acetylation and p53-dependent apoptosis. Cells silenced for TSPYL2 are defective in p53 activation and apoptosis induction after DNA damage, in a SIRT1- and p300-dependent manner.\",\n      \"method\": \"siRNA knockdown of TSPYL2, Co-immunoprecipitation (TSPYL2–SIRT1, TSPYL2–p300 interactions), p53 acetylation assays, apoptosis assays, epistasis by rescue with SIRT1/p300 manipulation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical activity assays (acetylation), genetic epistasis via siRNA rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30050056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TSPYL2 regulates expression of EZH2 target genes in neurons. Tspyl2 knockout mice have elevated H3K27me3 in the hippocampus; TSPYL2 interacts with EZH2 by Co-IP and co-occupies target gene promoters (ChIP). Loss of TSPYL2 reduces expression of developmental/synaptic genes including Bdnf, Egr3, Grin2c, Igf1, Gbx2, and Acvrl1. EZH2 inhibitor GSK126 rescues reduced expression in mutant neurons.\",\n      \"method\": \"Tspyl2 KO mice, Co-immunoprecipitation (TSPYL2–EZH2), ChIP-sequencing and ChIP in hippocampal neurons/neuroblastoma cells, pharmacologic EZH2 inhibition (GSK126), qRT-PCR\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP-seq, genetic KO, pharmacologic rescue with EZH2 inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"30051352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In diabetic mice, CDA1 (TSPYL2) expression is upregulated in the aorta and confers protection against aortic aneurysm through enhanced TGF-β signaling, increased collagen expression, and reduced macrophage infiltration. CDA1/ApoE double-knockout diabetic mice develop aortic aneurysms not seen in ApoE-KO diabetic mice; CDA1 deletion in the angiotensin II model also abrogates diabetes-mediated protection. CDA1 aortic expression is downregulated ~70% in human abdominal aortic aneurysm biopsies.\",\n      \"method\": \"CDA1 KO, ApoE KO, CDA1/ApoE double-KO mouse models; diabetes induction; angiotensin II aneurysm model; TGF-β signaling and collagen immunostaining/Western blot; macrophage and MMP12 analysis; human biopsy Western blot\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models with mechanistic readouts (TGF-β signaling, collagen, macrophage infiltration) plus human tissue validation\",\n      \"pmids\": [\"29311219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A novel CDA1-binding protein (CDA1BP1) was identified as a regulator of CDA1 (TSPYL2) profibrotic activity. CDA1BP1 binds CDA1; genetic deletion of CDA1BP1 attenuates renal fibrosis in diabetic mice. Synthetic CDA1BP1 peptides competitively inhibit CDA1–CDA1BP1 binding in vitro and reduce collagen expression in HK-2 cells. A retro-inverso d-amino acid peptide (CHA-061) targeting this interaction attenuates renal extracellular matrix accumulation and glomerular injury in vivo.\",\n      \"method\": \"Co-immunoprecipitation (CDA1–CDA1BP1), CDA1BP1 KO mouse, competitive peptide inhibition assays in vitro, HK-2 cell collagen expression, in vivo diabetic mouse kidney histology and gene expression\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying binding partner, KO mouse, peptide competition assay, in vitro and in vivo functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"30425061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSPYL2 inhibits SIRT1-mediated deacetylation of FOXO3, thereby reducing gefitinib resistance and DNA damage repair in colorectal cancer cells. TSPYL2 knockdown promotes gefitinib resistance; TSPYL2 overexpression inhibits DNA damage repair. Mechanistically, TSPYL2 suppresses SIRT1, which reduces SIRT1-mediated FOXO3 deacetylation, and TSPYL2 inhibits tumor growth and resistance in vivo.\",\n      \"method\": \"TSPYL2 knockdown/overexpression in CRC cells, immunofluorescence, Western blot for SIRT1/FOXO3 acetylation/phosphorylation, tumor xenograft experiments\",\n      \"journal\": \"Future medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional assays with molecular readout (acetylation), in vivo xenograft, single lab, limited biochemical detail in abstract\",\n      \"pmids\": [\"35192400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZFP91 interacts with TSPYL2, induces its poly-ubiquitination, and promotes its proteasomal degradation. Ginsenoside Rg3 weakens ZFP91-induced TSPYL2 poly-ubiquitination and degradation. Enforced TSPYL2 expression increases gemcitabine sensitivity in pancreatic adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (ZFP91–TSPYL2), ubiquitination assay, TSPYL2 overexpression/knockdown, cell viability/drug resistance assays, in vivo tumor xenograft\",\n      \"journal\": \"Journal of ginseng research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination assay identifying E3 ligase–substrate relationship, functional drug-resistance readout, single lab\",\n      \"pmids\": [\"36090681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRL2APPBP2 (CUL2–APPBP2 E3 ligase complex) targets TSPYL2 for ubiquitin–proteasome-mediated degradation via the substrate receptor APPBP2. CUL2 deletion accelerates hMSC senescence; TSPYL2 accumulates upon CUL2 loss and down-regulates P21(waf1/cip1), thereby counteracting senescence. This places TSPYL2 degradation as a mechanism to delay mesenchymal stem cell aging.\",\n      \"method\": \"CRISPR/Cas9 CUL2 KO in hESCs, hMSC differentiation, individual Cullin knockdown screen, APPBP2 substrate receptor identification, proteasome inhibition, senescence assays, p21 Western blot\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with CRISPR, substrate receptor identification, proteasome pathway rescue, senescence phenotypic readout, mechanistic epistasis\",\n      \"pmids\": [\"38170390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSPYL2 (CDA1) overexpression via AAV9 gene delivery inhibits bleomycin-induced pulmonary fibrosis in mice by repressing TGF-β/Smad3 signaling and inhibiting lung fibroblast-to-myofibroblast transition. In vitro, CDA1 overexpression in HFL1 fibroblasts reduces TGF-β1-induced pro-fibrotic cytokines, ECM protein expression, and cell proliferation/migration; CDA1 knockdown enhances these effects.\",\n      \"method\": \"Lentiviral overexpression, siRNA knockdown in HFL1 cells, AAV9-Tspyl2 intratracheal delivery in BLM mouse model, Smad3 phosphorylation assay, histology, ECM gene expression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro gain/loss-of-function with molecular readout (Smad3 signaling), in vivo AAV gene therapy model, multiple orthogonal methods\",\n      \"pmids\": [\"37391440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSPYL2 interacts with SIRT1 (Co-IP) in thyroid cancer cells and inhibits AKT activation by upregulating AKT acetylation level, reducing SIRT1-mediated AKT deacetylation. Knockdown of TSPYL2 increases SIRT1–AKT association and AKT phosphorylation; TSPYL2 overexpression reverses these effects and suppresses thyroid cancer cell proliferation, migration, invasion, and in vivo tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (TSPYL2–SIRT1), AKT acetylation/phosphorylation Western blot, TSPYL2 KD/OE in TPC-1 and IHH-4 cells, tumor xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying interaction, acetylation mechanistic readout, in vivo xenograft, single lab\",\n      \"pmids\": [\"37696385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TSPYL2 (CDA1/DENTT/TSPX) is a nucleosome assembly protein that functions as a multi-pathway tumor suppressor and cell growth regulator: it is phosphorylated by cyclin-CDK complexes; arrests cell growth by stabilizing p53 (via MDM2 inactivation) and inducing p21 through p53- and MEK/ERK-dependent transcription; is required for G1 checkpoint maintenance after DNA damage; forms a complex with REST/NRSF to activate TGF-β signaling and suppress oncogenic TrkC; inhibits SIRT1 to promote p300-mediated p53 acetylation and apoptosis after DNA damage; interacts with CBP and EZH2 to regulate chromatin state and expression of synaptic genes (GluN2A, GluN2B, Bdnf, Egr3) in neurons; is targeted for proteasomal degradation by ZFP91 (ubiquitination) and by the CRL2APPBP2 E3 ligase; represses TGF-β/Smad3-driven fibrosis; and suppresses SIRT1-mediated deacetylation of AKT and FOXO3 to sensitize cancer cells to therapy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TSPYL2 (also CDA1/DENTT/TSPX) is a nucleus- and nucleolus-localized chromatin-associated regulator that couples cell-cycle control, the DNA-damage response, and TGF-\\u03b2 signaling to act as a multi-context growth suppressor [#0, #1, #5]. It is a phosphosubstrate of cyclin-CDK complexes (cyclin D1/CDK4, cyclin A/CDK2, cyclin B/CDK1), and CDK-site phosphorylation is required for its growth-arresting activity [#0]. After DNA damage TSPYL2 enforces the G1 checkpoint by enabling p53-dependent transcription of p21: it stabilizes p53 through MDM2 inactivation and drives p21 induction via p53- and MEK/ERK-dependent routes, and it acts downstream of p53 since knockout cells accumulate p53 normally yet fail to induce p21 [#1, #5]. A recurrent biochemical theme is its antagonism of the deacetylase SIRT1 \\u2014 by disrupting SIRT1's engagement of substrates, TSPYL2 promotes p300-mediated p53 acetylation and apoptosis, and preserves the acetylation of FOXO3 and AKT to constrain DNA-damage repair, AKT signaling, and therapy resistance in cancer cells [#8, #12, #16]. TSPYL2 also operates within transcriptional/chromatin complexes: it joins the REST/NRSF repressor to potentiate TGF-\\u03b2-driven cell-cycle arrest and repress the TrkC oncogene, and it binds CBP and EZH2 to control H3K27me3 and the expression of synaptic and developmental genes (Grin2a, Grin2b, Bdnf, Egr3) underlying hippocampal LTP and memory [#6, #7, #9]. Through enhancement of TGF-\\u03b2/Smad3 signaling it restrains fibroblast-to-myofibroblast transition and fibrosis and protects against diabetic vascular and renal injury [#10, #11, #15]. TSPYL2 protein levels are set by ubiquitin-proteasome turnover via the E3 ligase ZFP91 and the CRL2-APPBP2 complex, the latter linking its degradation to mesenchymal stem cell senescence through p21 [#13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established TSPYL2/CDA1 as a CDK-phosphorylated nuclear/nucleolar protein whose overexpression arrests cell growth, defining it as a cell-cycle-coupled growth suppressor.\",\n      \"evidence\": \"In vitro kinase assays with recombinant cyclins/CDKs, cell fractionation, transgene overexpression with CDK-site mutagenesis and BrdU incorporation in HeLa cells\",\n      \"pmids\": [\"11395479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each individual CDK phosphorylation event not resolved\", \"Molecular mechanism by which growth arrest is executed not defined in this study\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Independently identified the same protein (DENTT) as a TGF-\\u03b21-inducible gene whose nucleolar localization depends on a bipartite NLS and whose induction tracks with growth suppression, linking it to TGF-\\u03b2 biology.\",\n      \"evidence\": \"Differential mRNA display, Northern blot, EGFP-NLS deletion constructs in COS-7, soft agarose colony assay in NSCLC cells\",\n      \"pmids\": [\"11318608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration that DENTT acts within the TGF-\\u03b2 pathway not yet shown\", \"Single-lab localization with overexpressed tagged constructs\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed the protein specifically potentiates TGF-\\u03b2 transcriptional output rather than acting as a general transcription enhancer.\",\n      \"evidence\": \"Transient transfection with TGF-\\u03b2-responsive (3TP-Lux, CAGA12-Lux) versus retinoic-acid-responsive luciferase reporters in lung cells\",\n      \"pmids\": [\"15823505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of reporter potentiation (direct vs indirect) unresolved\", \"No endogenous target genes identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the mechanism of growth arrest \\u2014 TSPYL2 stabilizes p53 via MDM2 inactivation and induces p21 through p53- and MEK/ERK-dependent transcription, and is itself a DNA-damage-responsive gene.\",\n      \"evidence\": \"siRNA knockdown, p21 promoter reporter deletions, pharmacologic MEK inhibition, camptothecin damage model in cultured cells\",\n      \"pmids\": [\"17317670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical basis of MDM2 inactivation by TSPYL2 not defined\", \"How TSPYL2 activates ERK signaling unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated TSPYL2 is downregulated and epigenetically silenced in tumors and suppresses anchorage-independent growth and migration, establishing it as a candidate tumor suppressor.\",\n      \"evidence\": \"Stable overexpression, colony/soft-agar/migration assays, demethylating agent treatment, RT-PCR on primary tumors\",\n      \"pmids\": [\"18381359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal silencing mechanism (promoter methylation site) not mapped\", \"Single-lab tumor sample analysis\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetically separated TSPYL2 function from p53 stabilization, showing it acts downstream of p53 to enable p21 transcription and G1 checkpoint maintenance after DNA damage.\",\n      \"evidence\": \"Tspyl2 knockout mice, gamma irradiation of primary MEFs/thymocytes, cell-cycle analysis, p21 expression assays\",\n      \"pmids\": [\"21738728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular step linking TSPYL2 to p21 promoter activation not defined\", \"Reconciliation with the 2007 MDM2/p53-stabilization model unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a neuronal transcriptional function \\u2014 TSPYL2 binds CBP and directly regulates NMDA receptor subunit genes, with loss impairing hippocampal LTP and memory.\",\n      \"evidence\": \"Tspyl2 KO mice, Co-IP, ChIP and reporter assays at Grin2a/Grin2b, electrophysiology, fear conditioning\",\n      \"pmids\": [\"24413569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TSPYL2 activates or recruits CBP enzymatic activity not resolved\", \"Direct DNA-binding versus adaptor role at promoters unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TSPYL2 inside the REST/NRSF repressor complex co-regulating TGF-\\u03b2-induced arrest and repressing the TrkC oncogene, linking its TGF-\\u03b2 and tumor-suppressor activities.\",\n      \"evidence\": \"Co-IP of TSPYL2\\u2013REST, shRNA knockdown, mammary epithelial transformation assay, TGF-\\u03b2 arrest assay\",\n      \"pmids\": [\"25613376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the TSPYL2\\u2013REST complex unknown\", \"How the complex intersects with Smad-dependent TGF-\\u03b2 transcription not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified SIRT1 inhibition as a core biochemical activity \\u2014 TSPYL2 disrupts SIRT1 substrate engagement to promote p300-mediated p53 acetylation and DNA-damage apoptosis.\",\n      \"evidence\": \"siRNA knockdown, Co-IP of TSPYL2\\u2013SIRT1 and TSPYL2\\u2013p300, p53 acetylation and apoptosis assays with SIRT1/p300 epistasis\",\n      \"pmids\": [\"30050056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic inhibition of SIRT1 versus competitive sequestration not distinguished\", \"Structural basis of TSPYL2\\u2013SIRT1 contact unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended TSPYL2's chromatin role to PRC2, showing it interacts with EZH2 and co-occupies promoters to regulate H3K27me3 and developmental/synaptic gene expression.\",\n      \"evidence\": \"Tspyl2 KO mice, Co-IP of TSPYL2\\u2013EZH2, ChIP-seq in hippocampal neurons/neuroblastoma, GSK126 rescue, qRT-PCR\",\n      \"pmids\": [\"30051352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TSPYL2 promotes or restrains EZH2 catalytic activity at target loci not resolved\", \"Relationship between CBP-activating and EZH2-associated functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a protective in vivo role in diabetic vasculature via TGF-\\u03b2-driven collagen and reduced inflammation, with human aneurysm tissue validation.\",\n      \"evidence\": \"CDA1, ApoE, and double-KO mice, diabetes and angiotensin II aneurysm models, TGF-\\u03b2/collagen/macrophage readouts, human biopsy Western blot\",\n      \"pmids\": [\"29311219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type responsible for the protective effect not pinpointed\", \"Mechanistic link from TSPYL2 to MMP12/macrophage suppression incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified CDA1BP1 as a binding partner required for TSPYL2's pro-fibrotic activity and validated the interaction as a druggable target with a peptide inhibitor.\",\n      \"evidence\": \"Co-IP of CDA1\\u2013CDA1BP1, CDA1BP1 KO mice, competitive peptide assays, HK-2 cell collagen, diabetic kidney histology in vivo\",\n      \"pmids\": [\"30425061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity/domain of the CDA1\\u2013CDA1BP1 interface beyond peptide mapping not fully defined\", \"How CDA1BP1 binding modulates TGF-\\u03b2 output mechanistically unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected the SIRT1-antagonism mechanism to therapy resistance, showing TSPYL2 preserves FOXO3 acetylation to limit DNA-damage repair and gefitinib resistance in colorectal cancer.\",\n      \"evidence\": \"TSPYL2 knockdown/overexpression in CRC cells, SIRT1/FOXO3 acetylation Western blot, tumor xenografts\",\n      \"pmids\": [\"35192400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited biochemical detail on FOXO3 acetylation site regulation\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined ZFP91 as an E3 ligase that ubiquitinates and degrades TSPYL2, and linked its stabilization to gemcitabine sensitivity in pancreatic cancer.\",\n      \"evidence\": \"Co-IP of ZFP91\\u2013TSPYL2, ubiquitination assay, overexpression/knockdown, drug-resistance and xenograft assays, ginsenoside Rg3 modulation\",\n      \"pmids\": [\"36090681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site(s) on TSPYL2 not mapped\", \"Whether ZFP91 regulation is constitutive or signal-dependent unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a second degradation route via CRL2-APPBP2 and tied TSPYL2 turnover to p21 control and mesenchymal stem cell senescence.\",\n      \"evidence\": \"CRISPR CUL2 KO in hESCs, Cullin knockdown screen, APPBP2 substrate-receptor identification, proteasome inhibition, senescence and p21 readouts\",\n      \"pmids\": [\"38170390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron recognized by APPBP2 not defined\", \"Crosstalk between ZFP91 and CRL2-APPBP2 pathways unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated therapeutic anti-fibrotic action \\u2014 AAV9-delivered TSPYL2 represses TGF-\\u03b2/Smad3 signaling and blocks fibroblast-to-myofibroblast transition in lung fibrosis.\",\n      \"evidence\": \"Lentiviral OE/siRNA in HFL1 cells, AAV9-Tspyl2 intratracheal delivery in bleomycin model, Smad3 phosphorylation, histology, ECM gene expression\",\n      \"pmids\": [\"37391440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent context-dependent dual effect on TGF-\\u03b2 (potentiation versus repression) across tissues not reconciled\", \"Direct molecular target on the Smad3 axis not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TSPYL2 suppresses AKT signaling in thyroid cancer by inhibiting SIRT1-mediated AKT deacetylation, reinforcing SIRT1 antagonism as a generalizable tumor-suppressive mechanism.\",\n      \"evidence\": \"Co-IP of TSPYL2\\u2013SIRT1, AKT acetylation/phosphorylation Western blot, KD/OE in thyroid cancer cells, xenografts\",\n      \"pmids\": [\"37696385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AKT acetylation site and its phosphorylation linkage not biochemically detailed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TSPYL2 reconciles its opposing context-dependent effects on TGF-\\u03b2 signaling (potentiation in lung/vascular protection versus its role across tumor and fibrosis settings) and whether it binds DNA directly or acts purely as a chromatin/complex adaptor remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TSPYL2 or its complexes\", \"Direct DNA-binding versus adaptor function not established\", \"Unifying biochemical activity reconciling p53, SIRT1, REST, CBP, and EZH2 functions not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 6, 7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 12, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [\n      \"REST/NRSF repressor complex\"\n    ],\n    \"partners\": [\n      \"SIRT1\",\n      \"EP300\",\n      \"CBP\",\n      \"EZH2\",\n      \"REST\",\n      \"ZFP91\",\n      \"APPBP2\",\n      \"CDA1BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}