{"gene":"DDIAS","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2007,"finding":"Noxin (mouse ortholog of DDIAS) accumulates in the nucleus in response to stress signals (gamma/UV irradiation, hydrogen peroxide, adriamycin, cytokines), and ectopic expression arrests the cell cycle at G1 independently of p53 activity. Loss of Noxin leads to increased cell death, suggesting it opposes apoptosis downstream of stress-induced p53.","method":"Knockout mouse model, ectopic overexpression, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype and nuclear localization by direct experiment, single lab but multiple orthogonal methods","pmids":["17515607"],"is_preprint":false},{"year":2013,"finding":"Human Noxin (hNoxin/DDIAS) contains a DNA-binding C-domain in RPA1 and functions as an anti-apoptotic protein in response to DNA damage; knockdown activates p38 MAPK/p53-mediated apoptosis in A549 NSCLC cells, while overexpression rescues cells from DNA damage-induced apoptosis.","method":"siRNA knockdown, comet assay, western blot (p38/p53 activation), adenoviral shRNA xenograft","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (p38 MAPK/p53), in vivo xenograft validation, single lab","pmids":["24214091"],"is_preprint":false},{"year":2015,"finding":"NFATc1 transcriptionally activates DDIAS by binding to NFAT consensus sequences in the DDIAS promoter, and DDIAS expression contributes to cisplatin resistance in lung cancer cells; DDIAS overexpression rescues cells from cisplatin-mediated death and caspase-3/7 activation.","method":"DDIAS promoter analysis, NFATc1 ChIP/binding assay, siRNA knockdown, overexpression rescue, caspase-3/7 assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding established, functional rescue experiment, single lab","pmids":["26493727"],"is_preprint":false},{"year":2015,"finding":"NOXIN/DDIAS interacts with DNA polymerase α, functioning as a cofactor of the DNA polymerase-primase complex to promote DNA synthesis and accelerate G1-S phase transition in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (NOXIN–DNA polymerase α interaction), cell cycle analysis, overexpression/knockdown proliferation assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP identifying binding partner with supporting functional data (G1-S acceleration), single lab","pmids":["25612832"],"is_preprint":false},{"year":2016,"finding":"EGF activates the ERK5/MEF2B pathway to induce DDIAS transcription; MEF2B binds a MEF2 site in the DDIAS promoter (by ChIP), and DDIAS in turn promotes invasion by increasing β-catenin expression at the post-translational level.","method":"Chromatin immunoprecipitation (MEF2B at DDIAS promoter), CA-MEK5 overexpression, pharmacological ERK5 inhibition, MEF2B siRNA, invasion assay, western blot (β-catenin)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes promoter binding, multiple orthogonal methods, single lab","pmids":["27412911"],"is_preprint":false},{"year":2017,"finding":"DDIAS stability is regulated by the E3 U-box ubiquitin ligase CHIP (carboxyl terminus of HSP70-interacting protein) via proteasomal degradation; CHIP physically associates with both the N- and C-terminal regions of DDIAS, and HSP70-bound DDIAS is recruited to CHIP via its TPR domain. The CHIP U-box domain is required for DDIAS ubiquitination.","method":"Yeast two-hybrid screening (CHIP isolation), Co-IP (CHIP–DDIAS), ubiquitination assay, domain mutant analysis (TPR, U-box), half-life measurement","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — yeast two-hybrid identification confirmed by Co-IP, domain mutagenesis, and ubiquitination assay; multiple orthogonal methods in single study","pmids":["28079882"],"is_preprint":false},{"year":2017,"finding":"DDIAS suppresses TRAIL-induced apoptosis by two mechanisms: (1) the N-terminus of DDIAS binds the death effector domain of FADD and prevents FADD recruitment to the DISC, blocking caspase-8 activation; (2) DDIAS promotes EGF-induced RSK2 phosphorylation, which leads to caspase-8 ubiquitination and proteasomal degradation.","method":"Co-IP (DDIAS N-terminus–FADD DED), DISC assembly assay, caspase-8 ubiquitination/proteasome assay, RSK2 overexpression rescue, siRNA knockdown","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining binding domain, two orthogonal mechanistic pathways established with genetic rescue experiments, single lab","pmids":["29242605"],"is_preprint":false},{"year":2017,"finding":"Noxin/DDIAS promotes breast cancer cell proliferation via the P38-ATF2 signaling pathway; Noxin overexpression increases phospho-P38 and phospho-ATF2 levels and upregulates Cyclin D1 and Cyclin E1, and these effects are reversed by a P38 inhibitor.","method":"Overexpression/siRNA knockdown, western blot (p-P38, p-ATF2, Cyclin D1, Cyclin E1), P38 inhibitor pharmacological rescue","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — defined pathway (P38-ATF2) with pharmacological rescue, single lab, no in vitro reconstitution","pmids":["28618963"],"is_preprint":false},{"year":2020,"finding":"DDIAS promotes STAT3 Y705 phosphorylation by binding to the STAT3 transactivation domain (TAD) and thereby competing with the phosphatase PTPRM to prevent PTPRM-mediated dephosphorylation of STAT3; PTPRM was identified as a novel STAT3 phosphatase via siRNA PTP library screening.","method":"siRNA PTP library screen (PTPRM identification), Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F STAT3 mutant, PTPRM overexpression/knockdown, IL-6 stimulation, western blot (pY705-STAT3)","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased siRNA library screen followed by domain-level Co-IP, mutant validation (Y705F), and competitive binding model established with multiple orthogonal methods","pmids":["31900385"],"is_preprint":false},{"year":2021,"finding":"The small molecule DGG-100629 inhibits DDIAS transcription by activating JNK and blocking NFATc1 nuclear translocation; JNK1 knockdown or JNK inhibitor SP600125 restores DDIAS expression and reverses DGG-100629-induced cell death, placing JNK upstream of NFATc1/DDIAS.","method":"Chemical library screen, JNK1 siRNA/pharmacological inhibitor (SP600125), NFATc1 nuclear translocation assay, DDIAS/STAT3 overexpression rescue, xenograft","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis defining JNK→NFATc1→DDIAS axis, single lab","pmids":["33859351"],"is_preprint":false},{"year":2025,"finding":"NAT10-mediated ac4C modification stabilizes DDIAS mRNA; decreased NAT10 levels reduce DDIAS mRNA stability, and ectopic DDIAS expression rescues the anti-proliferative/anti-invasive effects of NAT10 knockdown by modulating the PI3K/AKT pathway.","method":"AcRIP-seq (ac4C site identification on DDIAS mRNA), NAT10 knockdown, DDIAS overexpression rescue, western blot (PI3K/AKT)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acRIP-seq establishes direct ac4C modification of DDIAS mRNA, rescue experiment confirms pathway, single lab","pmids":["40389420"],"is_preprint":false},{"year":2025,"finding":"DDIAS is a phosphorylation-dependent component of the TOPBP1-CIP2A complex during mitosis; DDIAS directly binds TOPBP1 and possesses single-stranded DNA (ssDNA)-binding activity. Disruption of the DDIAS–TOPBP1 interaction or inactivation of DDIAS ssDNA-binding ability impairs genome integrity and causes synthetic lethality with BRCA1/BRCA2 deficiency. DDIAS suppresses ssDNA during mitosis rather than promoting end-tethering.","method":"Proximity ligation/interactome (DDIAS–TOPBP1 direct interaction), ssDNA-binding assay, domain mutant disruption, synthetic lethality screen (BRCA1/BRCA2 double mutant), genetic interaction with DNA polymerase delta","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two independent preprint studies converging on same mechanism; direct biochemical ssDNA-binding assay, mutational validation, synthetic lethality genetics, and patient biallelic mutations","pmids":[],"is_preprint":true},{"year":2025,"finding":"DDIAS knockdown in endometrial cancer cells suppresses β-catenin and its downstream targets (c-Myc, Cyclin D1, survivin) and inhibits EMT; these effects are rescued by β-catenin overexpression, establishing DDIAS as an upstream regulator of β-catenin in this context.","method":"siRNA knockdown, western blot (β-catenin pathway), β-catenin rescue overexpression, proliferation/migration/invasion assays","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA experiment with rescue, no direct biochemical interaction shown, single lab","pmids":["41052043"],"is_preprint":false},{"year":2024,"finding":"In a Kawasaki disease endothelial cell model, DDIAS knockdown reduces p-STAT3 and CCL2 expression, and decreases M1 macrophage polarization; STAT3 agonist reverses the DDIAS knockdown effects, placing DDIAS upstream of STAT3/CCL2 in this inflammatory context.","method":"siRNA knockdown (si-DDIAS), western blot (p-STAT3, CCL2), ELISA (cytokines), flow cytometry (CD86 M1 marker), STAT3 agonist rescue","journal":"Annals of clinical and laboratory science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA approach with pharmacological rescue, no direct biochemical interaction established, single lab","pmids":["39293834"],"is_preprint":false}],"current_model":"DDIAS (also known as hNoxin/C11orf82) is a stress- and oncogene-induced nuclear protein with ssDNA-binding activity that acts as a multifunctional anti-apoptotic and pro-survival factor: it is transcriptionally driven by NFATc1 and ERK5/MEF2B, post-translationally stabilized by HSP70 and destabilized by CHIP-mediated ubiquitination/proteasomal degradation, and ac4C-modified to stabilize its mRNA by NAT10; mechanistically it suppresses TRAIL-apoptosis by blocking FADD-DISC assembly and promoting RSK2-mediated caspase-8 degradation, sustains STAT3 activation by competing with the phosphatase PTPRM for STAT3 TAD binding, promotes invasion through post-translational stabilization of β-catenin, cofunctions with the DNA polymerase-primase complex for DNA synthesis, and—most recently established—acts as a phosphorylation-dependent ssDNA-binding effector of the mitotic TOPBP1-CIP2A complex to suppress ssDNA accumulation and maintain genome integrity during mitosis, with synthetic lethality in BRCA1/BRCA2-deficient cells."},"narrative":{"mechanistic_narrative":"DDIAS (hNoxin/C11orf82) is a stress- and oncogene-induced nuclear protein that functions as a multifunctional anti-apoptotic and pro-survival factor in cancer cells [PMID:17515607, PMID:24214091]. It is transcriptionally driven by stress and growth-factor signaling: NFATc1 binds the DDIAS promoter to confer cisplatin resistance [PMID:26493727], and EGF-activated ERK5/MEF2B induces DDIAS to promote invasion via post-translational β-catenin stabilization [PMID:27412911]; upstream, JNK activation blocks NFATc1 nuclear translocation to repress DDIAS [PMID:33859351]. Its protein level is controlled by an HSP70/CHIP axis, in which HSP70-bound DDIAS is recruited to the E3 ligase CHIP through its TPR domain and ubiquitinated by the CHIP U-box domain for proteasomal degradation [PMID:28079882], while its mRNA is stabilized by NAT10-mediated ac4C modification feeding into PI3K/AKT signaling [PMID:40389420]. Mechanistically, DDIAS suppresses TRAIL-induced apoptosis by binding the death effector domain of FADD to block DISC assembly and by promoting RSK2-mediated caspase-8 degradation [PMID:29242605], and it sustains oncogenic STAT3 signaling by binding the STAT3 transactivation domain to competitively exclude the phosphatase PTPRM and preserve Y705 phosphorylation [PMID:31900385]. DDIAS also operates in DNA metabolism, acting as a cofactor of the DNA polymerase α–primase complex to accelerate G1-S transition [PMID:25612832] and, as a single-stranded-DNA-binding effector of the mitotic TOPBP1–CIP2A complex, suppressing ssDNA accumulation to maintain genome integrity, with synthetic lethality in BRCA1/BRCA2-deficient cells.","teleology":[{"year":2007,"claim":"Established that the DDIAS ortholog Noxin is a stress-inducible nuclear protein that opposes apoptosis and arrests the cell cycle independently of p53, defining its baseline role as a pro-survival stress effector.","evidence":"Knockout mouse model, ectopic overexpression, and cell cycle analysis under genotoxic/oxidative stress","pmids":["17515607"],"confidence":"Medium","gaps":["No molecular partners identified","Mechanism of G1 arrest undefined","Human ortholog function not yet tested"]},{"year":2013,"claim":"Showed that human DDIAS is anti-apoptotic in NSCLC, with knockdown triggering p38 MAPK/p53-mediated apoptosis, transferring the mouse phenotype to a human cancer context.","evidence":"siRNA knockdown, comet assay, western blot, and shRNA xenograft in A549 cells","pmids":["24214091"],"confidence":"Medium","gaps":["DNA-binding C-domain function not biochemically dissected","Direct apoptotic targets not identified"]},{"year":2015,"claim":"Identified the transcriptional input NFATc1 and a DNA-replication function, linking DDIAS expression to chemoresistance and proliferation.","evidence":"NFATc1 promoter ChIP/binding plus caspase rescue (cisplatin); Co-IP with DNA polymerase α and cell cycle assays in HCC","pmids":["26493727","25612832"],"confidence":"Medium","gaps":["DDIAS–polymerase α interaction rests on single Co-IP","Direct role in DNA synthesis vs. indirect effect unresolved"]},{"year":2016,"claim":"Defined a second transcriptional axis (EGF→ERK5/MEF2B) and a pro-invasive output through post-translational β-catenin stabilization.","evidence":"MEF2B ChIP at DDIAS promoter, CA-MEK5/ERK5 inhibition, MEF2B siRNA, invasion assays","pmids":["27412911"],"confidence":"Medium","gaps":["Mechanism of β-catenin stabilization not biochemically defined","No direct DDIAS–β-catenin interaction shown"]},{"year":2017,"claim":"Resolved how DDIAS protein levels are controlled and how it directly blocks death-receptor apoptosis, providing concrete biochemical mechanisms.","evidence":"Y2H/Co-IP/ubiquitination with HSP70-CHIP; reciprocal Co-IP mapping DDIAS N-terminus to FADD DED, DISC assays, RSK2/caspase-8 degradation; p38-ATF2 proliferation pathway","pmids":["28079882","29242605","28618963"],"confidence":"High","gaps":["Stoichiometry of DDIAS within the DISC unclear","Whether FADD-blocking and RSK2 arms are coupled is unknown"]},{"year":2020,"claim":"Established a direct mechanism by which DDIAS sustains STAT3 signaling, identifying it as a competitor of the STAT3 phosphatase PTPRM.","evidence":"siRNA PTP library screen, domain Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F mutant, IL-6 stimulation","pmids":["31900385"],"confidence":"High","gaps":["Structural basis of TAD competition not determined","Whether competition occurs in nucleus or cytoplasm unclear"]},{"year":2021,"claim":"Placed JNK upstream of the NFATc1→DDIAS axis and demonstrated DDIAS transcription as a druggable node via DGG-100629.","evidence":"Chemical screen, JNK1 siRNA/SP600125 epistasis, NFATc1 translocation assay, DDIAS/STAT3 rescue, xenograft","pmids":["33859351"],"confidence":"Medium","gaps":["Direct molecular target of DGG-100629 not identified","JNK–NFATc1 connection not biochemically mapped"]},{"year":2025,"claim":"Added mRNA-level regulation by NAT10-mediated ac4C and reinforced β-catenin/STAT3 outputs in additional disease contexts.","evidence":"AcRIP-seq, NAT10 knockdown/DDIAS rescue (PI3K/AKT); β-catenin rescue in endometrial cancer; STAT3 agonist rescue in Kawasaki endothelial model","pmids":["40389420","41052043","39293834"],"confidence":"Medium","gaps":["β-catenin and STAT3 disease-context studies are single-siRNA with no direct interaction","Functional consequence of specific ac4C sites untested"]},{"year":2025,"claim":"Recast DDIAS as a phosphorylation-dependent ssDNA-binding effector of the mitotic TOPBP1-CIP2A complex that protects genome integrity and is synthetic lethal with BRCA1/BRCA2 loss.","evidence":"Interactome/PLA (DDIAS–TOPBP1), ssDNA-binding assay, domain mutants, BRCA1/BRCA2 synthetic lethality and DNA polymerase delta genetics (preprint)","pmids":[],"confidence":"High","gaps":["Preprint, not yet peer-reviewed","Phosphosites controlling complex assembly not fully mapped","Reconciliation of mitotic genome-integrity role with cytoplasmic apoptosis roles unresolved"]},{"year":null,"claim":"How DDIAS coordinates its distinct nuclear genome-protection role with its cytoplasmic anti-apoptotic and STAT3/β-catenin signaling functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of DDIAS domains","Spatiotemporal partitioning of functions unknown","Whether ssDNA-binding underlies all roles untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3]}],"complexes":["TOPBP1-CIP2A complex","DNA polymerase alpha-primase complex"],"partners":["TOPBP1","FADD","STAT3","STUB1","HSPA1A","POLA1","PTPRM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IXT1","full_name":"DNA damage-induced apoptosis suppressor protein","aliases":["Nitric oxide-inducible gene protein"],"length_aa":998,"mass_kda":111.6,"function":"May be an anti-apoptotic protein involved in DNA repair or cell survival","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IXT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDIAS","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DDIAS","total_profiled":1310},"omim":[{"mim_id":"618045","title":"DNA DAMAGE-INDUCED APOPTOSIS SUPPRESSOR; DDIAS","url":"https://www.omim.org/entry/618045"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":7.4},{"tissue":"testis","ntpm":10.2}],"url":"https://www.proteinatlas.org/search/DDIAS"},"hgnc":{"alias_symbol":["FLJ38838","FLJ25416","noxin"],"prev_symbol":["C11orf82"]},"alphafold":{"accession":"Q8IXT1","domains":[{"cath_id":"2.40.50.140","chopping":"11-135_157-193","consensus_level":"medium","plddt":84.5351,"start":11,"end":193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXT1-F1-predicted_aligned_error_v6.png","plddt_mean":43.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDIAS","jax_strain_url":"https://www.jax.org/strain/search?query=DDIAS"},"sequence":{"accession":"Q8IXT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXT1"}},"corpus_meta":[{"pmid":"26493727","id":"PMC_26493727","title":"DNA damage-induced apoptosis suppressor (DDIAS), a novel target of NFATc1, is associated with cisplatin resistance in lung cancer.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26493727","citation_count":36,"is_preprint":false},{"pmid":"31900385","id":"PMC_31900385","title":"DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31900385","citation_count":36,"is_preprint":false},{"pmid":"24214091","id":"PMC_24214091","title":"Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24214091","citation_count":32,"is_preprint":false},{"pmid":"27412911","id":"PMC_27412911","title":"DNA damage induced apoptosis suppressor (DDIAS) is upregulated via ERK5/MEF2B signaling and promotes β-catenin-mediated invasion.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27412911","citation_count":29,"is_preprint":false},{"pmid":"29242605","id":"PMC_29242605","title":"DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29242605","citation_count":25,"is_preprint":false},{"pmid":"28079882","id":"PMC_28079882","title":"Stability of the cancer target DDIAS is regulated by the CHIP/HSP70 pathway in lung cancer cells.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28079882","citation_count":24,"is_preprint":false},{"pmid":"25612832","id":"PMC_25612832","title":"NOXIN as a cofactor of DNA polymerase-primase complex could promote hepatocellular carcinoma.","date":"2015","source":"International journal of 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mitosis","date":"2025-09-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675193","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11091,"output_tokens":3723,"usd":0.044559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11544,"output_tokens":3467,"usd":0.072197,"stage2_stop_reason":"end_turn"},"total_usd":0.116756,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Noxin (mouse ortholog of DDIAS) accumulates in the nucleus in response to stress signals (gamma/UV irradiation, hydrogen peroxide, adriamycin, cytokines), and ectopic expression arrests the cell cycle at G1 independently of p53 activity. Loss of Noxin leads to increased cell death, suggesting it opposes apoptosis downstream of stress-induced p53.\",\n      \"method\": \"Knockout mouse model, ectopic overexpression, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype and nuclear localization by direct experiment, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17515607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human Noxin (hNoxin/DDIAS) contains a DNA-binding C-domain in RPA1 and functions as an anti-apoptotic protein in response to DNA damage; knockdown activates p38 MAPK/p53-mediated apoptosis in A549 NSCLC cells, while overexpression rescues cells from DNA damage-induced apoptosis.\",\n      \"method\": \"siRNA knockdown, comet assay, western blot (p38/p53 activation), adenoviral shRNA xenograft\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (p38 MAPK/p53), in vivo xenograft validation, single lab\",\n      \"pmids\": [\"24214091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NFATc1 transcriptionally activates DDIAS by binding to NFAT consensus sequences in the DDIAS promoter, and DDIAS expression contributes to cisplatin resistance in lung cancer cells; DDIAS overexpression rescues cells from cisplatin-mediated death and caspase-3/7 activation.\",\n      \"method\": \"DDIAS promoter analysis, NFATc1 ChIP/binding assay, siRNA knockdown, overexpression rescue, caspase-3/7 assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding established, functional rescue experiment, single lab\",\n      \"pmids\": [\"26493727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NOXIN/DDIAS interacts with DNA polymerase α, functioning as a cofactor of the DNA polymerase-primase complex to promote DNA synthesis and accelerate G1-S phase transition in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (NOXIN–DNA polymerase α interaction), cell cycle analysis, overexpression/knockdown proliferation assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP identifying binding partner with supporting functional data (G1-S acceleration), single lab\",\n      \"pmids\": [\"25612832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EGF activates the ERK5/MEF2B pathway to induce DDIAS transcription; MEF2B binds a MEF2 site in the DDIAS promoter (by ChIP), and DDIAS in turn promotes invasion by increasing β-catenin expression at the post-translational level.\",\n      \"method\": \"Chromatin immunoprecipitation (MEF2B at DDIAS promoter), CA-MEK5 overexpression, pharmacological ERK5 inhibition, MEF2B siRNA, invasion assay, western blot (β-catenin)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes promoter binding, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"27412911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDIAS stability is regulated by the E3 U-box ubiquitin ligase CHIP (carboxyl terminus of HSP70-interacting protein) via proteasomal degradation; CHIP physically associates with both the N- and C-terminal regions of DDIAS, and HSP70-bound DDIAS is recruited to CHIP via its TPR domain. The CHIP U-box domain is required for DDIAS ubiquitination.\",\n      \"method\": \"Yeast two-hybrid screening (CHIP isolation), Co-IP (CHIP–DDIAS), ubiquitination assay, domain mutant analysis (TPR, U-box), half-life measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — yeast two-hybrid identification confirmed by Co-IP, domain mutagenesis, and ubiquitination assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28079882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDIAS suppresses TRAIL-induced apoptosis by two mechanisms: (1) the N-terminus of DDIAS binds the death effector domain of FADD and prevents FADD recruitment to the DISC, blocking caspase-8 activation; (2) DDIAS promotes EGF-induced RSK2 phosphorylation, which leads to caspase-8 ubiquitination and proteasomal degradation.\",\n      \"method\": \"Co-IP (DDIAS N-terminus–FADD DED), DISC assembly assay, caspase-8 ubiquitination/proteasome assay, RSK2 overexpression rescue, siRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining binding domain, two orthogonal mechanistic pathways established with genetic rescue experiments, single lab\",\n      \"pmids\": [\"29242605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Noxin/DDIAS promotes breast cancer cell proliferation via the P38-ATF2 signaling pathway; Noxin overexpression increases phospho-P38 and phospho-ATF2 levels and upregulates Cyclin D1 and Cyclin E1, and these effects are reversed by a P38 inhibitor.\",\n      \"method\": \"Overexpression/siRNA knockdown, western blot (p-P38, p-ATF2, Cyclin D1, Cyclin E1), P38 inhibitor pharmacological rescue\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — defined pathway (P38-ATF2) with pharmacological rescue, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"28618963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDIAS promotes STAT3 Y705 phosphorylation by binding to the STAT3 transactivation domain (TAD) and thereby competing with the phosphatase PTPRM to prevent PTPRM-mediated dephosphorylation of STAT3; PTPRM was identified as a novel STAT3 phosphatase via siRNA PTP library screening.\",\n      \"method\": \"siRNA PTP library screen (PTPRM identification), Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F STAT3 mutant, PTPRM overexpression/knockdown, IL-6 stimulation, western blot (pY705-STAT3)\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased siRNA library screen followed by domain-level Co-IP, mutant validation (Y705F), and competitive binding model established with multiple orthogonal methods\",\n      \"pmids\": [\"31900385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The small molecule DGG-100629 inhibits DDIAS transcription by activating JNK and blocking NFATc1 nuclear translocation; JNK1 knockdown or JNK inhibitor SP600125 restores DDIAS expression and reverses DGG-100629-induced cell death, placing JNK upstream of NFATc1/DDIAS.\",\n      \"method\": \"Chemical library screen, JNK1 siRNA/pharmacological inhibitor (SP600125), NFATc1 nuclear translocation assay, DDIAS/STAT3 overexpression rescue, xenograft\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis defining JNK→NFATc1→DDIAS axis, single lab\",\n      \"pmids\": [\"33859351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NAT10-mediated ac4C modification stabilizes DDIAS mRNA; decreased NAT10 levels reduce DDIAS mRNA stability, and ectopic DDIAS expression rescues the anti-proliferative/anti-invasive effects of NAT10 knockdown by modulating the PI3K/AKT pathway.\",\n      \"method\": \"AcRIP-seq (ac4C site identification on DDIAS mRNA), NAT10 knockdown, DDIAS overexpression rescue, western blot (PI3K/AKT)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acRIP-seq establishes direct ac4C modification of DDIAS mRNA, rescue experiment confirms pathway, single lab\",\n      \"pmids\": [\"40389420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDIAS is a phosphorylation-dependent component of the TOPBP1-CIP2A complex during mitosis; DDIAS directly binds TOPBP1 and possesses single-stranded DNA (ssDNA)-binding activity. Disruption of the DDIAS–TOPBP1 interaction or inactivation of DDIAS ssDNA-binding ability impairs genome integrity and causes synthetic lethality with BRCA1/BRCA2 deficiency. DDIAS suppresses ssDNA during mitosis rather than promoting end-tethering.\",\n      \"method\": \"Proximity ligation/interactome (DDIAS–TOPBP1 direct interaction), ssDNA-binding assay, domain mutant disruption, synthetic lethality screen (BRCA1/BRCA2 double mutant), genetic interaction with DNA polymerase delta\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two independent preprint studies converging on same mechanism; direct biochemical ssDNA-binding assay, mutational validation, synthetic lethality genetics, and patient biallelic mutations\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDIAS knockdown in endometrial cancer cells suppresses β-catenin and its downstream targets (c-Myc, Cyclin D1, survivin) and inhibits EMT; these effects are rescued by β-catenin overexpression, establishing DDIAS as an upstream regulator of β-catenin in this context.\",\n      \"method\": \"siRNA knockdown, western blot (β-catenin pathway), β-catenin rescue overexpression, proliferation/migration/invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA experiment with rescue, no direct biochemical interaction shown, single lab\",\n      \"pmids\": [\"41052043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a Kawasaki disease endothelial cell model, DDIAS knockdown reduces p-STAT3 and CCL2 expression, and decreases M1 macrophage polarization; STAT3 agonist reverses the DDIAS knockdown effects, placing DDIAS upstream of STAT3/CCL2 in this inflammatory context.\",\n      \"method\": \"siRNA knockdown (si-DDIAS), western blot (p-STAT3, CCL2), ELISA (cytokines), flow cytometry (CD86 M1 marker), STAT3 agonist rescue\",\n      \"journal\": \"Annals of clinical and laboratory science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA approach with pharmacological rescue, no direct biochemical interaction established, single lab\",\n      \"pmids\": [\"39293834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDIAS (also known as hNoxin/C11orf82) is a stress- and oncogene-induced nuclear protein with ssDNA-binding activity that acts as a multifunctional anti-apoptotic and pro-survival factor: it is transcriptionally driven by NFATc1 and ERK5/MEF2B, post-translationally stabilized by HSP70 and destabilized by CHIP-mediated ubiquitination/proteasomal degradation, and ac4C-modified to stabilize its mRNA by NAT10; mechanistically it suppresses TRAIL-apoptosis by blocking FADD-DISC assembly and promoting RSK2-mediated caspase-8 degradation, sustains STAT3 activation by competing with the phosphatase PTPRM for STAT3 TAD binding, promotes invasion through post-translational stabilization of β-catenin, cofunctions with the DNA polymerase-primase complex for DNA synthesis, and—most recently established—acts as a phosphorylation-dependent ssDNA-binding effector of the mitotic TOPBP1-CIP2A complex to suppress ssDNA accumulation and maintain genome integrity during mitosis, with synthetic lethality in BRCA1/BRCA2-deficient cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDIAS (hNoxin/C11orf82) is a stress- and oncogene-induced nuclear protein that functions as a multifunctional anti-apoptotic and pro-survival factor in cancer cells [#0, #1]. It is transcriptionally driven by stress and growth-factor signaling: NFATc1 binds the DDIAS promoter to confer cisplatin resistance [#2], and EGF-activated ERK5/MEF2B induces DDIAS to promote invasion via post-translational β-catenin stabilization [#4]; upstream, JNK activation blocks NFATc1 nuclear translocation to repress DDIAS [#9]. Its protein level is controlled by an HSP70/CHIP axis, in which HSP70-bound DDIAS is recruited to the E3 ligase CHIP through its TPR domain and ubiquitinated by the CHIP U-box domain for proteasomal degradation [#5], while its mRNA is stabilized by NAT10-mediated ac4C modification feeding into PI3K/AKT signaling [#10]. Mechanistically, DDIAS suppresses TRAIL-induced apoptosis by binding the death effector domain of FADD to block DISC assembly and by promoting RSK2-mediated caspase-8 degradation [#6], and it sustains oncogenic STAT3 signaling by binding the STAT3 transactivation domain to competitively exclude the phosphatase PTPRM and preserve Y705 phosphorylation [#8]. DDIAS also operates in DNA metabolism, acting as a cofactor of the DNA polymerase α–primase complex to accelerate G1-S transition [#3] and, as a single-stranded-DNA-binding effector of the mitotic TOPBP1–CIP2A complex, suppressing ssDNA accumulation to maintain genome integrity, with synthetic lethality in BRCA1/BRCA2-deficient cells [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that the DDIAS ortholog Noxin is a stress-inducible nuclear protein that opposes apoptosis and arrests the cell cycle independently of p53, defining its baseline role as a pro-survival stress effector.\",\n      \"evidence\": \"Knockout mouse model, ectopic overexpression, and cell cycle analysis under genotoxic/oxidative stress\",\n      \"pmids\": [\"17515607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partners identified\", \"Mechanism of G1 arrest undefined\", \"Human ortholog function not yet tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that human DDIAS is anti-apoptotic in NSCLC, with knockdown triggering p38 MAPK/p53-mediated apoptosis, transferring the mouse phenotype to a human cancer context.\",\n      \"evidence\": \"siRNA knockdown, comet assay, western blot, and shRNA xenograft in A549 cells\",\n      \"pmids\": [\"24214091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DNA-binding C-domain function not biochemically dissected\", \"Direct apoptotic targets not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the transcriptional input NFATc1 and a DNA-replication function, linking DDIAS expression to chemoresistance and proliferation.\",\n      \"evidence\": \"NFATc1 promoter ChIP/binding plus caspase rescue (cisplatin); Co-IP with DNA polymerase α and cell cycle assays in HCC\",\n      \"pmids\": [\"26493727\", \"25612832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DDIAS–polymerase α interaction rests on single Co-IP\", \"Direct role in DNA synthesis vs. indirect effect unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a second transcriptional axis (EGF→ERK5/MEF2B) and a pro-invasive output through post-translational β-catenin stabilization.\",\n      \"evidence\": \"MEF2B ChIP at DDIAS promoter, CA-MEK5/ERK5 inhibition, MEF2B siRNA, invasion assays\",\n      \"pmids\": [\"27412911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of β-catenin stabilization not biochemically defined\", \"No direct DDIAS–β-catenin interaction shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how DDIAS protein levels are controlled and how it directly blocks death-receptor apoptosis, providing concrete biochemical mechanisms.\",\n      \"evidence\": \"Y2H/Co-IP/ubiquitination with HSP70-CHIP; reciprocal Co-IP mapping DDIAS N-terminus to FADD DED, DISC assays, RSK2/caspase-8 degradation; p38-ATF2 proliferation pathway\",\n      \"pmids\": [\"28079882\", \"29242605\", \"28618963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of DDIAS within the DISC unclear\", \"Whether FADD-blocking and RSK2 arms are coupled is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a direct mechanism by which DDIAS sustains STAT3 signaling, identifying it as a competitor of the STAT3 phosphatase PTPRM.\",\n      \"evidence\": \"siRNA PTP library screen, domain Co-IP (DDIAS–STAT3 TAD; PTPRM–STAT3), Y705F mutant, IL-6 stimulation\",\n      \"pmids\": [\"31900385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TAD competition not determined\", \"Whether competition occurs in nucleus or cytoplasm unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed JNK upstream of the NFATc1→DDIAS axis and demonstrated DDIAS transcription as a druggable node via DGG-100629.\",\n      \"evidence\": \"Chemical screen, JNK1 siRNA/SP600125 epistasis, NFATc1 translocation assay, DDIAS/STAT3 rescue, xenograft\",\n      \"pmids\": [\"33859351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of DGG-100629 not identified\", \"JNK–NFATc1 connection not biochemically mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added mRNA-level regulation by NAT10-mediated ac4C and reinforced β-catenin/STAT3 outputs in additional disease contexts.\",\n      \"evidence\": \"AcRIP-seq, NAT10 knockdown/DDIAS rescue (PI3K/AKT); β-catenin rescue in endometrial cancer; STAT3 agonist rescue in Kawasaki endothelial model\",\n      \"pmids\": [\"40389420\", \"41052043\", \"39293834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-catenin and STAT3 disease-context studies are single-siRNA with no direct interaction\", \"Functional consequence of specific ac4C sites untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recast DDIAS as a phosphorylation-dependent ssDNA-binding effector of the mitotic TOPBP1-CIP2A complex that protects genome integrity and is synthetic lethal with BRCA1/BRCA2 loss.\",\n      \"evidence\": \"Interactome/PLA (DDIAS–TOPBP1), ssDNA-binding assay, domain mutants, BRCA1/BRCA2 synthetic lethality and DNA polymerase delta genetics (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Phosphosites controlling complex assembly not fully mapped\", \"Reconciliation of mitotic genome-integrity role with cytoplasmic apoptosis roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DDIAS coordinates its distinct nuclear genome-protection role with its cytoplasmic anti-apoptotic and STAT3/β-catenin signaling functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of DDIAS domains\", \"Spatiotemporal partitioning of functions unknown\", \"Whether ssDNA-binding underlies all roles untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\n      \"TOPBP1-CIP2A complex\",\n      \"DNA polymerase alpha-primase complex\"\n    ],\n    \"partners\": [\n      \"TOPBP1\",\n      \"FADD\",\n      \"STAT3\",\n      \"STUB1\",\n      \"HSPA1A\",\n      \"POLA1\",\n      \"PTPRM\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}