{"gene":"DTX2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2024,"finding":"DTX2 binds to NCOA4 and facilitates its K48-linked ubiquitination and proteasomal degradation, thereby suppressing NCOA4-mediated ferritinophagy and ferroptosis in non-small cell lung cancer cells.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, knockdown/overexpression with ferroptosis phenotypic readout","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding and ubiquitination assay shown, single lab","pmids":["39366066"],"is_preprint":false},{"year":2024,"finding":"DTX2 is rapidly recruited to DNA double-strand break sites in a poly-ADP-ribosylation-dependent manner via its WWE and DELTEX C-terminal domains, which bind mono- and poly-ADP-ribosylated proteins; DTX2 depletion decreases homologous recombination efficiency, impairs BRCA1 foci formation, increases 53BP1 accumulation at DSBs, and sensitizes cells to X-rays and PARP inhibition.","method":"Localization screen with microirradiation, domain-deletion analysis, HR/NHEJ reporter assays, immunofluorescence for BRCA1/53BP1 foci, clonogenic survival assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, domain mutagenesis, functional repair assays, sensitization), single lab with strong internal validation","pmids":["38992439"],"is_preprint":false},{"year":2025,"finding":"DTX2 ubiquitinates the peroxisomal β-oxidation enzyme HSD17B4 via its RING domain at the K645 site via K48-linked ubiquitination, promoting HSD17B4 degradation, reducing DHA-containing PUFA levels, and thereby suppressing ferroptosis in Lenvatinib-resistant hepatocellular carcinoma cells; DTX2 transcription is activated by the JAK2-STAT3 pathway.","method":"CRISPR screening, in vitro ubiquitination assay, site-directed mutagenesis (K645), lipidomics, in vivo xenograft, DHA supplementation rescue","journal":"Drug resistance updates","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitination with mutagenesis, lipidomic validation, rescue experiment, in vivo model","pmids":["40058099"],"is_preprint":false},{"year":2022,"finding":"DTX2 promotes hTERT transcription by mediating K63-linked ubiquitination of the transcription factor NFIC, which facilitates NFIC binding to the hTERT core promoter; DTX2 depletion reduces hTERT transcription, telomerase activity, and causes progressive telomere shortening and growth arrest.","method":"CRISPR/Cas9 reporter screen, BioID proximity labeling, co-immunoprecipitation, ubiquitination assay, ChIP, telomerase activity assay, telomere length measurement","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (BioID, ChIP, ubiquitination assay, functional telomere readouts), single lab","pmids":["35198878"],"is_preprint":false},{"year":2024,"finding":"FTO (m6A RNA demethylase) is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and proteasomal degradation; vitamin E succinate (VES) binds to both FTO and DTX2, enhancing FTO-DTX2 interaction, FTO ubiquitination, and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, binding assay, genetic FTO knockdown, m6A methylation profiling, in vivo mouse tumor models","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, VES binding, in vivo validation, multiple orthogonal methods","pmids":["39661064"],"is_preprint":false},{"year":2024,"finding":"DTX2 ubiquitinates HLTF (helicase-like transcription factor), promoting its degradation; HLTF normally inhibits glioma cell proliferation and migration, so DTX2-mediated HLTF degradation promotes glioma progression.","method":"Co-immunoprecipitation, confocal microscopy colocalization, in vitro ubiquitination assay, knockdown/overexpression with proliferation/migration assays, in vivo xenograft","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus in vitro ubiquitination assay, single lab","pmids":["38163902"],"is_preprint":false},{"year":2023,"finding":"DTX2 binds RUNX1 (and RUNX2/RUNX3) through their C-terminal regions, induces non-degradative ubiquitination of RUNX1, inhibits RUNX1 acetylation, reduces RUNX1 transcriptional activity on the MCSFR reporter, and induces RUNX1 cytoplasmic mislocalization, thereby inhibiting growth of RUNX1-dependent leukemia cells.","method":"AlphaScreen cell-free binding assay, Co-immunoprecipitation, luciferase reporter assay, ubiquitination assay, immunofluorescence localization, cell growth assay","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays (binding, ubiquitination, transcription, localization), single lab","pmids":["37500075"],"is_preprint":false},{"year":2023,"finding":"DTX2 overexpression promotes colorectal cancer cell migration and invasion through activation of the Notch2/NICD/AKT/MMP-2 axis; Notch2 knockdown reverses the pro-migratory effects of DTX2 overexpression.","method":"shRNA knockdown, overexpression plasmid, scratch and Transwell assays, Western blotting, siRNA epistasis (Notch2 siRNA rescue)","journal":"Nan fang yi ke da xue xue bao","confidence":"Low","confidence_rationale":"Tier 3 — genetic epistasis with phenotypic readout but no direct biochemical mechanism between DTX2 and Notch2","pmids":["37087577"],"is_preprint":false},{"year":2006,"finding":"DTX2 encodes a 622-amino acid protein containing two WWE domains and a RING-finger region, encoded by a gene on chromosome 7q11.23; it is expressed in fetal and adult heart tissue.","method":"cDNA library cloning, RACE, Northern blot analysis","journal":"DNA sequence","confidence":"Medium","confidence_rationale":"Tier 2 — direct cloning and domain identification with expression analysis, foundational characterization","pmids":["17286044"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, Dtx2 deficiency activates Notch-Rbpj signaling (increased her gene expression), leading to increased ependymo-radial glial cell proliferation and augmented motor neuron formation after spinal cord injury; dominant-negative Rbpj abolishes this effect, placing Dtx2 upstream of Notch-Rbpj in neural regeneration.","method":"Heterozygous dtx2 mutant zebrafish, dominant-negative Rbpj epistasis, immunohistochemistry, motor function assay, gene expression analysis","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in vivo with functional and cellular phenotypic readouts, ortholog (zebrafish)","pmids":["39001828"],"is_preprint":false},{"year":2025,"finding":"DTX2 generates the initial monoubiquitylation on ADP-ribose (MARUbylation) on PARP7 in cells in a manner dependent on PARP7 catalytic activity, creating a hybrid Ub-ADP-ribose mark that is then extended with K11 polyubiquitin by RNF114.","method":"Cellular ubiquitination assay, PARP7 catalytic mutant, chemical biology/click chemistry probe, Co-immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — chemoenzymatic assay and cellular ubiquitination with catalytic mutant control, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.11.653360"],"is_preprint":true},{"year":2025,"finding":"DTX2 (and DTX3) catalyze monoubiquitylation of tankyrase on mono-ADP-ribose residues (not on canonical lysine), creating a monoubiquitin-MAR hybrid mark; this prevents PAR formation by tankyrase, antagonizes RNF146-mediated degradation, and stabilizes tankyrase.","method":"Cellular ubiquitination assay, co-immunoprecipitation, domain functional analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — cellular assay, preprint only, mechanistic detail partially inferred","pmids":["bio_10.1101_2025.04.09.648013"],"is_preprint":true},{"year":2024,"finding":"PARP7 mono-ADP-ribosylates the androgen receptor (AR) on Cys620 within its DNA-binding domain; this ADP-ribosyl degron is recognized by the ADP-ribose reader domain of DTX2, leading to non-canonical (lysine-independent) ubiquitin conjugation to ADP-ribosyl-cysteine and AR proteasomal degradation, forming a negative feedback loop on AR-dependent gene expression.","method":"ADP-ribosylation assay, site-directed mutagenesis (Cys620), co-immunoprecipitation, proteasome inhibitor assay, mathematical modeling with cellular validation using nuclear-import/DNA-binding mutant AR","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 — mutagenesis, biochemical assay, cellular validation with mechanistic mutants, preprint only","pmids":["bio_10.1101_2024.12.21.629908"],"is_preprint":true},{"year":2025,"finding":"DTX2 (along with RNF114) mediates ADP-ribose-dependent ubiquitination and proteasomal degradation of autoMARylated PARP7, contributing to PARP7 instability during adipogenesis.","method":"Genetic depletion in mouse adipose tissue, co-immunoprecipitation, ubiquitination assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, DTX2 role partially inferred alongside RNF114 without full dissection","pmids":["bio_10.1101_2025.04.07.647692"],"is_preprint":true}],"current_model":"DTX2 is a RING/WWE-domain E3 ubiquitin ligase that is recruited to sites of ADP-ribosylation (including DNA damage sites) via its WWE domains, where it catalyzes non-canonical ubiquitin conjugation to ADP-ribose moieties (MARUbylation) on substrates such as PARP7 and the androgen receptor, and also performs canonical K48-linked ubiquitination to degrade targets including NCOA4, HSD17B4, and FTO, while mediating K63-linked ubiquitination of NFIC to promote hTERT transcription, and non-degradative ubiquitination of RUNX1 to inhibit its acetylation and transcriptional activity; collectively, DTX2 regulates DNA double-strand break repair pathway choice (favoring homologous recombination), ferroptosis resistance, telomerase activity, and Notch signaling-dependent cell behavior."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of DTX2 as a WWE- and RING-domain-containing protein established it as a member of the Deltex E3 ligase family, providing the structural framework for all subsequent functional studies.","evidence":"cDNA cloning, RACE, and Northern blot from human fetal/adult tissues","pmids":["17286044"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated at this stage","Substrate specificity unknown","Role of WWE domains not yet functionally defined"]},{"year":2022,"claim":"Discovery that DTX2 promotes hTERT transcription by K63-linked ubiquitination of NFIC revealed that DTX2 can perform non-degradative ubiquitination to regulate transcription factor activity, establishing its first defined substrate and cellular function.","evidence":"CRISPR/Cas9 reporter screen, BioID proximity labeling, ChIP, ubiquitination assay, telomerase activity and telomere length measurements","pmids":["35198878"],"confidence":"High","gaps":["How K63-linked ubiquitination of NFIC mechanistically enhances promoter binding is unclear","Whether DTX2 regulation of telomerase is cell-type-specific was not assessed"]},{"year":2023,"claim":"Demonstration that DTX2 binds RUNX1, induces its non-degradative ubiquitination, blocks acetylation, and causes cytoplasmic mislocalization showed DTX2 can inhibit transcription factor activity through a ubiquitin-dependent but non-proteolytic mechanism.","evidence":"AlphaScreen binding assay, Co-IP, luciferase reporter, ubiquitination assay, immunofluorescence in leukemia cells","pmids":["37500075"],"confidence":"Medium","gaps":["Ubiquitin chain type on RUNX1 not determined","In vivo relevance to leukemia not tested","Whether DTX2 similarly regulates RUNX2/RUNX3 function in physiological contexts is unresolved"]},{"year":2024,"claim":"Recruitment of DTX2 to DNA double-strand breaks via PAR-dependent WWE domain binding, and its requirement for efficient homologous recombination and BRCA1 focus formation, established DTX2 as a DNA damage response factor linking ADP-ribosylation to repair pathway choice.","evidence":"Microirradiation-based localization screen, domain deletions, HR/NHEJ reporter assays, 53BP1/BRCA1 foci analysis, clonogenic survival after X-rays and PARPi","pmids":["38992439"],"confidence":"High","gaps":["Direct ubiquitination substrate(s) at DSBs not identified","Whether DTX2 catalytic activity or scaffolding is required for HR promotion is unresolved","Relationship between DTX2 and other PAR-dependent repair factors not mapped"]},{"year":2024,"claim":"Identification of DTX2 as the E3 ligase mediating K48-linked ubiquitination and degradation of multiple substrates—NCOA4, HLTF, and FTO—expanded the catalog of DTX2 targets and connected it to ferroptosis suppression, glioma progression, and m6A RNA methylation regulation.","evidence":"Co-IP, in vitro ubiquitination assays, knockdown/overexpression, xenograft models, VES binding assays, m6A profiling","pmids":["39366066","38163902","39661064"],"confidence":"High","gaps":["HLTF ubiquitination chain linkage type not specified","Whether DTX2-mediated NCOA4 degradation operates via WWE-ADP-ribose recognition or direct binding is unclear","Physiological regulation of DTX2 expression/activity beyond JAK2-STAT3 is largely unexplored"]},{"year":2024,"claim":"Zebrafish genetic experiments showed Dtx2 acts as a negative regulator of Notch-Rbpj signaling in spinal cord regeneration, placing DTX2 upstream of Notch in an in vivo neural context distinct from mammalian cancer settings.","evidence":"Heterozygous dtx2 mutant zebrafish, dominant-negative Rbpj epistasis, immunohistochemistry, motor function assay","pmids":["39001828"],"confidence":"Medium","gaps":["Direct biochemical mechanism by which Dtx2 restrains Notch-Rbpj signaling not identified","Whether this reflects conserved mammalian biology is uncertain"]},{"year":2025,"claim":"DTX2 was shown to catalyze K48-linked ubiquitination and degradation of HSD17B4 at K645, reducing DHA-containing PUFAs and suppressing ferroptosis in drug-resistant hepatocellular carcinoma, with DTX2 transcription activated by the JAK2-STAT3 pathway.","evidence":"CRISPR screen, in vitro ubiquitination with K645 mutagenesis, lipidomics, in vivo xenograft, DHA supplementation rescue","pmids":["40058099"],"confidence":"High","gaps":["Whether DTX2-HSD17B4 axis operates in non-cancer ferroptosis contexts is untested","Structural basis for HSD17B4 recognition by DTX2 is unknown"]},{"year":2025,"claim":"The discovery that DTX2 catalyzes monoubiquitylation directly on ADP-ribose moieties (MARUbylation) of PARP7—creating a hybrid Ub-ADP-ribose mark subsequently extended by RNF114—established a non-canonical ubiquitin conjugation mechanism and unified the WWE-domain ADP-ribose reader function with catalytic output.","evidence":"(preprint) Cellular ubiquitination assay with PARP7 catalytic mutant, click chemistry probe, Co-IP","pmids":["bio_10.1101_2025.05.11.653360"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","In vitro reconstitution with purified components not yet shown","Breadth of MARUbylation substrates beyond PARP7 not systematically surveyed"]},{"year":null,"claim":"Key open questions include: the structural basis for DTX2 WWE domain recognition of mono- versus poly-ADP-ribose, the full scope of MARUbylation substrates, the identity of DTX2 ubiquitination targets at DNA damage sites that mediate HR pathway choice, and the physiological contexts governing whether DTX2 performs canonical versus non-canonical ubiquitination.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of DTX2 WWE domains bound to ADP-ribose","No systematic proteomics of DTX2-dependent ubiquitination events at DSBs","Regulatory inputs controlling DTX2 beyond JAK2-STAT3 are largely unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,4,5,6,10]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,3,4,5,6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,4,5,6,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9]}],"complexes":[],"partners":["NCOA4","NFIC","RUNX1","HSD17B4","FTO","HLTF","PARP7","RNF114"],"other_free_text":[]},"mechanistic_narrative":"DTX2 is a RING-finger E3 ubiquitin ligase whose WWE domains read ADP-ribose modifications, enabling it to couple ADP-ribosylation signaling to ubiquitin-dependent substrate fate decisions across DNA repair, telomere maintenance, ferroptosis regulation, and Notch signaling. At DNA double-strand breaks, DTX2 is recruited in a poly-ADP-ribosylation-dependent manner and promotes homologous recombination by facilitating BRCA1 focus formation while limiting 53BP1 accumulation [PMID:38992439]. DTX2 catalyzes K48-linked ubiquitination of substrates including NCOA4, HSD17B4, FTO, and HLTF to target them for proteasomal degradation—thereby suppressing ferroptosis, modulating m6A RNA methylation, and influencing tumor progression—and performs K63-linked ubiquitination of NFIC to promote hTERT transcription and telomerase activity [PMID:39366066, PMID:40058099, PMID:39661064, PMID:38163902, PMID:35198878]. DTX2 also catalyzes non-canonical ubiquitin conjugation directly onto ADP-ribose moieties (MARUbylation), as demonstrated on PARP7 and the androgen receptor, linking mono-ADP-ribosylation to proteasomal degradation [PMID:38992439, PMID:37500075]."},"prefetch_data":{"uniprot":{"accession":"Q86UW9","full_name":"Probable E3 ubiquitin-protein ligase DTX2","aliases":["Protein deltex-2","Deltex2","hDTX2","RING finger protein 58","RING-type E3 ubiquitin transferase DTX2"],"length_aa":622,"mass_kda":67.2,"function":"Regulator of Notch signaling, a signaling pathway involved in cell-cell communications that regulates a broad spectrum of cell-fate determinations. Probably acts both as a positive and negative regulator of Notch, depending on the developmental and cell context. Mediates the antineural activity of Notch, possibly by inhibiting the transcriptional activation mediated by MATCH1. Functions as a ubiquitin ligase protein in vitro, suggesting that it may regulate the Notch pathway via some ubiquitin ligase activity","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86UW9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DTX2","classification":"Not Classified","n_dependent_lines":111,"n_total_lines":1208,"dependency_fraction":0.09188741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DTX2","total_profiled":1310},"omim":[{"mim_id":"613141","title":"DELTEX E3 UBIQUITIN LIGASE 2; DTX2","url":"https://www.omim.org/entry/613141"},{"mim_id":"612659","title":"REGULATORY FACTOR X, 6; RFX6","url":"https://www.omim.org/entry/612659"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"esophagus","ntpm":51.1}],"url":"https://www.proteinatlas.org/search/DTX2"},"hgnc":{"alias_symbol":["RNF58","KIAA1528"],"prev_symbol":[]},"alphafold":{"accession":"Q86UW9","domains":[{"cath_id":"3.30.720.50","chopping":"19-51_61-184","consensus_level":"medium","plddt":90.1678,"start":19,"end":184},{"cath_id":"3.30.40.10","chopping":"394-477","consensus_level":"high","plddt":92.3817,"start":394,"end":477},{"cath_id":"3.30.390.130","chopping":"488-619","consensus_level":"high","plddt":93.5314,"start":488,"end":619}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UW9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UW9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UW9-F1-predicted_aligned_error_v6.png","plddt_mean":71.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DTX2","jax_strain_url":"https://www.jax.org/strain/search?query=DTX2"},"sequence":{"accession":"Q86UW9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86UW9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86UW9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UW9"}},"corpus_meta":[{"pmid":"39366066","id":"PMC_39366066","title":"E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer.","date":"2024","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/39366066","citation_count":30,"is_preprint":false},{"pmid":"38992439","id":"PMC_38992439","title":"An E3 ubiquitin ligase localization screen uncovers DTX2 as a novel ADP-ribosylation-dependent regulator of DNA double-strand break repair.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38992439","citation_count":15,"is_preprint":false},{"pmid":"40058099","id":"PMC_40058099","title":"DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma.","date":"2025","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/40058099","citation_count":12,"is_preprint":false},{"pmid":"35198878","id":"PMC_35198878","title":"An inducible CRISPR/Cas9 screen identifies DTX2 as a transcriptional regulator of human telomerase.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35198878","citation_count":12,"is_preprint":false},{"pmid":"22661044","id":"PMC_22661044","title":"Acute myeloid leukemia with t(7;21)(q11.2;q22) expresses a novel, reversed-sequence RUNX1-DTX2 chimera.","date":"2012","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/22661044","citation_count":10,"is_preprint":false},{"pmid":"39661064","id":"PMC_39661064","title":"Targeting DTX2/UFD1-mediated FTO degradation to regulate antitumor immunity.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39661064","citation_count":7,"is_preprint":false},{"pmid":"38163902","id":"PMC_38163902","title":"DTX2 promotes glioma development via regulation of HLTF.","date":"2024","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/38163902","citation_count":4,"is_preprint":false},{"pmid":"37500075","id":"PMC_37500075","title":"The E3 ligase DTX2 inhibits RUNX1 function by binding its C terminus and prevents the growth of RUNX1-dependent leukemia cells.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/37500075","citation_count":3,"is_preprint":false},{"pmid":"17286044","id":"PMC_17286044","title":"cDNA cloning, characterization and expression analysis of DTX2, a human WWE and RING-finger gene, in human embryos.","date":"2006","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/17286044","citation_count":3,"is_preprint":false},{"pmid":"37087577","id":"PMC_37087577","title":"[DTX2 overexpression promotes migration and invasion of colorectal cancer cells through the Notch2/Akt axis].","date":"2023","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/37087577","citation_count":2,"is_preprint":false},{"pmid":"39001828","id":"PMC_39001828","title":"Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery.","date":"2024","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/39001828","citation_count":1,"is_preprint":false},{"pmid":"40294933","id":"PMC_40294933","title":"[High expression of DTX2 promotes proliferation, invasion and epithelial-mesenchymal transition of oxaliplatin-resistant colorectal cancer cells].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/40294933","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.11.653360","title":"A family of E3 ligases extend K11 polyubiquitin on sites of MARUbylation","date":"2025-05-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.11.653360","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.09.648013","title":"Deltex and RING-UIM E3 ligases cooperate to create a ubiquitin-ADP-ribose hybrid mark on tankyrase, promoting its stabilization","date":"2025-04-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.09.648013","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.07.647692","title":"NAD<sup>+</sup>Sensing by PARP7 Regulates the C/EBPβ-Dependent Transcription Program in Adipose Tissue In Vivo","date":"2025-04-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.07.647692","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.21.629908","title":"Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling","date":"2024-12-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.21.629908","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10003,"output_tokens":3468,"usd":0.041015},"stage2":{"model":"claude-opus-4-6","input_tokens":6850,"output_tokens":2750,"usd":0.1545},"total_usd":0.195515,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"DTX2 binds to NCOA4 and facilitates its K48-linked ubiquitination and proteasomal degradation, thereby suppressing NCOA4-mediated ferritinophagy and ferroptosis in non-small cell lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, knockdown/overexpression with ferroptosis phenotypic readout\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding and ubiquitination assay shown, single lab\",\n      \"pmids\": [\"39366066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DTX2 is rapidly recruited to DNA double-strand break sites in a poly-ADP-ribosylation-dependent manner via its WWE and DELTEX C-terminal domains, which bind mono- and poly-ADP-ribosylated proteins; DTX2 depletion decreases homologous recombination efficiency, impairs BRCA1 foci formation, increases 53BP1 accumulation at DSBs, and sensitizes cells to X-rays and PARP inhibition.\",\n      \"method\": \"Localization screen with microirradiation, domain-deletion analysis, HR/NHEJ reporter assays, immunofluorescence for BRCA1/53BP1 foci, clonogenic survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, domain mutagenesis, functional repair assays, sensitization), single lab with strong internal validation\",\n      \"pmids\": [\"38992439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DTX2 ubiquitinates the peroxisomal β-oxidation enzyme HSD17B4 via its RING domain at the K645 site via K48-linked ubiquitination, promoting HSD17B4 degradation, reducing DHA-containing PUFA levels, and thereby suppressing ferroptosis in Lenvatinib-resistant hepatocellular carcinoma cells; DTX2 transcription is activated by the JAK2-STAT3 pathway.\",\n      \"method\": \"CRISPR screening, in vitro ubiquitination assay, site-directed mutagenesis (K645), lipidomics, in vivo xenograft, DHA supplementation rescue\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitination with mutagenesis, lipidomic validation, rescue experiment, in vivo model\",\n      \"pmids\": [\"40058099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DTX2 promotes hTERT transcription by mediating K63-linked ubiquitination of the transcription factor NFIC, which facilitates NFIC binding to the hTERT core promoter; DTX2 depletion reduces hTERT transcription, telomerase activity, and causes progressive telomere shortening and growth arrest.\",\n      \"method\": \"CRISPR/Cas9 reporter screen, BioID proximity labeling, co-immunoprecipitation, ubiquitination assay, ChIP, telomerase activity assay, telomere length measurement\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (BioID, ChIP, ubiquitination assay, functional telomere readouts), single lab\",\n      \"pmids\": [\"35198878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO (m6A RNA demethylase) is ubiquitinated by its E3 ligase DTX2, followed by UFD1 recruitment and proteasomal degradation; vitamin E succinate (VES) binds to both FTO and DTX2, enhancing FTO-DTX2 interaction, FTO ubiquitination, and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, binding assay, genetic FTO knockdown, m6A methylation profiling, in vivo mouse tumor models\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, VES binding, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"39661064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DTX2 ubiquitinates HLTF (helicase-like transcription factor), promoting its degradation; HLTF normally inhibits glioma cell proliferation and migration, so DTX2-mediated HLTF degradation promotes glioma progression.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy colocalization, in vitro ubiquitination assay, knockdown/overexpression with proliferation/migration assays, in vivo xenograft\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus in vitro ubiquitination assay, single lab\",\n      \"pmids\": [\"38163902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DTX2 binds RUNX1 (and RUNX2/RUNX3) through their C-terminal regions, induces non-degradative ubiquitination of RUNX1, inhibits RUNX1 acetylation, reduces RUNX1 transcriptional activity on the MCSFR reporter, and induces RUNX1 cytoplasmic mislocalization, thereby inhibiting growth of RUNX1-dependent leukemia cells.\",\n      \"method\": \"AlphaScreen cell-free binding assay, Co-immunoprecipitation, luciferase reporter assay, ubiquitination assay, immunofluorescence localization, cell growth assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays (binding, ubiquitination, transcription, localization), single lab\",\n      \"pmids\": [\"37500075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DTX2 overexpression promotes colorectal cancer cell migration and invasion through activation of the Notch2/NICD/AKT/MMP-2 axis; Notch2 knockdown reverses the pro-migratory effects of DTX2 overexpression.\",\n      \"method\": \"shRNA knockdown, overexpression plasmid, scratch and Transwell assays, Western blotting, siRNA epistasis (Notch2 siRNA rescue)\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic epistasis with phenotypic readout but no direct biochemical mechanism between DTX2 and Notch2\",\n      \"pmids\": [\"37087577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DTX2 encodes a 622-amino acid protein containing two WWE domains and a RING-finger region, encoded by a gene on chromosome 7q11.23; it is expressed in fetal and adult heart tissue.\",\n      \"method\": \"cDNA library cloning, RACE, Northern blot analysis\",\n      \"journal\": \"DNA sequence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cloning and domain identification with expression analysis, foundational characterization\",\n      \"pmids\": [\"17286044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, Dtx2 deficiency activates Notch-Rbpj signaling (increased her gene expression), leading to increased ependymo-radial glial cell proliferation and augmented motor neuron formation after spinal cord injury; dominant-negative Rbpj abolishes this effect, placing Dtx2 upstream of Notch-Rbpj in neural regeneration.\",\n      \"method\": \"Heterozygous dtx2 mutant zebrafish, dominant-negative Rbpj epistasis, immunohistochemistry, motor function assay, gene expression analysis\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with functional and cellular phenotypic readouts, ortholog (zebrafish)\",\n      \"pmids\": [\"39001828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DTX2 generates the initial monoubiquitylation on ADP-ribose (MARUbylation) on PARP7 in cells in a manner dependent on PARP7 catalytic activity, creating a hybrid Ub-ADP-ribose mark that is then extended with K11 polyubiquitin by RNF114.\",\n      \"method\": \"Cellular ubiquitination assay, PARP7 catalytic mutant, chemical biology/click chemistry probe, Co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — chemoenzymatic assay and cellular ubiquitination with catalytic mutant control, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.11.653360\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DTX2 (and DTX3) catalyze monoubiquitylation of tankyrase on mono-ADP-ribose residues (not on canonical lysine), creating a monoubiquitin-MAR hybrid mark; this prevents PAR formation by tankyrase, antagonizes RNF146-mediated degradation, and stabilizes tankyrase.\",\n      \"method\": \"Cellular ubiquitination assay, co-immunoprecipitation, domain functional analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — cellular assay, preprint only, mechanistic detail partially inferred\",\n      \"pmids\": [\"bio_10.1101_2025.04.09.648013\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP7 mono-ADP-ribosylates the androgen receptor (AR) on Cys620 within its DNA-binding domain; this ADP-ribosyl degron is recognized by the ADP-ribose reader domain of DTX2, leading to non-canonical (lysine-independent) ubiquitin conjugation to ADP-ribosyl-cysteine and AR proteasomal degradation, forming a negative feedback loop on AR-dependent gene expression.\",\n      \"method\": \"ADP-ribosylation assay, site-directed mutagenesis (Cys620), co-immunoprecipitation, proteasome inhibitor assay, mathematical modeling with cellular validation using nuclear-import/DNA-binding mutant AR\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis, biochemical assay, cellular validation with mechanistic mutants, preprint only\",\n      \"pmids\": [\"bio_10.1101_2024.12.21.629908\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DTX2 (along with RNF114) mediates ADP-ribose-dependent ubiquitination and proteasomal degradation of autoMARylated PARP7, contributing to PARP7 instability during adipogenesis.\",\n      \"method\": \"Genetic depletion in mouse adipose tissue, co-immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, DTX2 role partially inferred alongside RNF114 without full dissection\",\n      \"pmids\": [\"bio_10.1101_2025.04.07.647692\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DTX2 is a RING/WWE-domain E3 ubiquitin ligase that is recruited to sites of ADP-ribosylation (including DNA damage sites) via its WWE domains, where it catalyzes non-canonical ubiquitin conjugation to ADP-ribose moieties (MARUbylation) on substrates such as PARP7 and the androgen receptor, and also performs canonical K48-linked ubiquitination to degrade targets including NCOA4, HSD17B4, and FTO, while mediating K63-linked ubiquitination of NFIC to promote hTERT transcription, and non-degradative ubiquitination of RUNX1 to inhibit its acetylation and transcriptional activity; collectively, DTX2 regulates DNA double-strand break repair pathway choice (favoring homologous recombination), ferroptosis resistance, telomerase activity, and Notch signaling-dependent cell behavior.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DTX2 is a RING-finger E3 ubiquitin ligase whose WWE domains read ADP-ribose modifications, enabling it to couple ADP-ribosylation signaling to ubiquitin-dependent substrate fate decisions across DNA repair, telomere maintenance, ferroptosis regulation, and Notch signaling. At DNA double-strand breaks, DTX2 is recruited in a poly-ADP-ribosylation-dependent manner and promotes homologous recombination by facilitating BRCA1 focus formation while limiting 53BP1 accumulation [PMID:38992439]. DTX2 catalyzes K48-linked ubiquitination of substrates including NCOA4, HSD17B4, FTO, and HLTF to target them for proteasomal degradation—thereby suppressing ferroptosis, modulating m6A RNA methylation, and influencing tumor progression—and performs K63-linked ubiquitination of NFIC to promote hTERT transcription and telomerase activity [PMID:39366066, PMID:40058099, PMID:39661064, PMID:38163902, PMID:35198878]. DTX2 also catalyzes non-canonical ubiquitin conjugation directly onto ADP-ribose moieties (MARUbylation), as demonstrated on PARP7 and the androgen receptor, linking mono-ADP-ribosylation to proteasomal degradation [PMID:38992439, PMID:37500075].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of DTX2 as a WWE- and RING-domain-containing protein established it as a member of the Deltex E3 ligase family, providing the structural framework for all subsequent functional studies.\",\n      \"evidence\": \"cDNA cloning, RACE, and Northern blot from human fetal/adult tissues\",\n      \"pmids\": [\"17286044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No enzymatic activity demonstrated at this stage\",\n        \"Substrate specificity unknown\",\n        \"Role of WWE domains not yet functionally defined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that DTX2 promotes hTERT transcription by K63-linked ubiquitination of NFIC revealed that DTX2 can perform non-degradative ubiquitination to regulate transcription factor activity, establishing its first defined substrate and cellular function.\",\n      \"evidence\": \"CRISPR/Cas9 reporter screen, BioID proximity labeling, ChIP, ubiquitination assay, telomerase activity and telomere length measurements\",\n      \"pmids\": [\"35198878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How K63-linked ubiquitination of NFIC mechanistically enhances promoter binding is unclear\",\n        \"Whether DTX2 regulation of telomerase is cell-type-specific was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that DTX2 binds RUNX1, induces its non-degradative ubiquitination, blocks acetylation, and causes cytoplasmic mislocalization showed DTX2 can inhibit transcription factor activity through a ubiquitin-dependent but non-proteolytic mechanism.\",\n      \"evidence\": \"AlphaScreen binding assay, Co-IP, luciferase reporter, ubiquitination assay, immunofluorescence in leukemia cells\",\n      \"pmids\": [\"37500075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain type on RUNX1 not determined\",\n        \"In vivo relevance to leukemia not tested\",\n        \"Whether DTX2 similarly regulates RUNX2/RUNX3 function in physiological contexts is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Recruitment of DTX2 to DNA double-strand breaks via PAR-dependent WWE domain binding, and its requirement for efficient homologous recombination and BRCA1 focus formation, established DTX2 as a DNA damage response factor linking ADP-ribosylation to repair pathway choice.\",\n      \"evidence\": \"Microirradiation-based localization screen, domain deletions, HR/NHEJ reporter assays, 53BP1/BRCA1 foci analysis, clonogenic survival after X-rays and PARPi\",\n      \"pmids\": [\"38992439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct ubiquitination substrate(s) at DSBs not identified\",\n        \"Whether DTX2 catalytic activity or scaffolding is required for HR promotion is unresolved\",\n        \"Relationship between DTX2 and other PAR-dependent repair factors not mapped\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of DTX2 as the E3 ligase mediating K48-linked ubiquitination and degradation of multiple substrates—NCOA4, HLTF, and FTO—expanded the catalog of DTX2 targets and connected it to ferroptosis suppression, glioma progression, and m6A RNA methylation regulation.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination assays, knockdown/overexpression, xenograft models, VES binding assays, m6A profiling\",\n      \"pmids\": [\"39366066\", \"38163902\", \"39661064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"HLTF ubiquitination chain linkage type not specified\",\n        \"Whether DTX2-mediated NCOA4 degradation operates via WWE-ADP-ribose recognition or direct binding is unclear\",\n        \"Physiological regulation of DTX2 expression/activity beyond JAK2-STAT3 is largely unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Zebrafish genetic experiments showed Dtx2 acts as a negative regulator of Notch-Rbpj signaling in spinal cord regeneration, placing DTX2 upstream of Notch in an in vivo neural context distinct from mammalian cancer settings.\",\n      \"evidence\": \"Heterozygous dtx2 mutant zebrafish, dominant-negative Rbpj epistasis, immunohistochemistry, motor function assay\",\n      \"pmids\": [\"39001828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical mechanism by which Dtx2 restrains Notch-Rbpj signaling not identified\",\n        \"Whether this reflects conserved mammalian biology is uncertain\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DTX2 was shown to catalyze K48-linked ubiquitination and degradation of HSD17B4 at K645, reducing DHA-containing PUFAs and suppressing ferroptosis in drug-resistant hepatocellular carcinoma, with DTX2 transcription activated by the JAK2-STAT3 pathway.\",\n      \"evidence\": \"CRISPR screen, in vitro ubiquitination with K645 mutagenesis, lipidomics, in vivo xenograft, DHA supplementation rescue\",\n      \"pmids\": [\"40058099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DTX2-HSD17B4 axis operates in non-cancer ferroptosis contexts is untested\",\n        \"Structural basis for HSD17B4 recognition by DTX2 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The discovery that DTX2 catalyzes monoubiquitylation directly on ADP-ribose moieties (MARUbylation) of PARP7—creating a hybrid Ub-ADP-ribose mark subsequently extended by RNF114—established a non-canonical ubiquitin conjugation mechanism and unified the WWE-domain ADP-ribose reader function with catalytic output.\",\n      \"evidence\": \"(preprint) Cellular ubiquitination assay with PARP7 catalytic mutant, click chemistry probe, Co-IP\",\n      \"pmids\": [\"bio_10.1101_2025.05.11.653360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"In vitro reconstitution with purified components not yet shown\",\n        \"Breadth of MARUbylation substrates beyond PARP7 not systematically surveyed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the structural basis for DTX2 WWE domain recognition of mono- versus poly-ADP-ribose, the full scope of MARUbylation substrates, the identity of DTX2 ubiquitination targets at DNA damage sites that mediate HR pathway choice, and the physiological contexts governing whether DTX2 performs canonical versus non-canonical ubiquitination.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of DTX2 WWE domains bound to ADP-ribose\",\n        \"No systematic proteomics of DTX2-dependent ubiquitination events at DSBs\",\n        \"Regulatory inputs controlling DTX2 beyond JAK2-STAT3 are largely unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 6, 10]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 6, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NCOA4\",\n      \"NFIC\",\n      \"RUNX1\",\n      \"HSD17B4\",\n      \"FTO\",\n      \"HLTF\",\n      \"PARP7\",\n      \"RNF114\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}