{"gene":"TIPARP","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2012,"finding":"TiPARP/ARTD14 exhibits auto-mono-ADP-ribosyltransferase activity and ribosylates core histones in vitro. RNAi-mediated knockdown of TiPARP increased TCDD-dependent CYP1A1 and CYP1B1 mRNA expression and AHR recruitment to both genes. TiPARP and AHR co-localized in the nucleus, directly interacted, and both were recruited to CYP1A1 in response to TCDD. TiPARP-mediated inhibition of AHR required both the zinc-finger and catalytic domains. Overexpression of TiPARP enhanced TCDD-dependent AHR proteolytic degradation, while knockdown reduced it. TiPARP thus functions as a mono-ADP-ribosyltransferase and transcriptional repressor of AHR, establishing a negative feedback loop in AHR signalling.","method":"In vitro ADP-ribosylation assay, RNAi knockdown, reporter gene assay, deletion/mutagenesis studies, co-localization (immunofluorescence), co-immunoprecipitation, Tiparp-/- MEFs","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, mutagenesis, Co-IP, KD/KO phenotype) in a single rigorous study with genetic validation in Tiparp-/- MEFs","pmids":["23275542"],"is_preprint":false},{"year":2010,"finding":"TiPARP (PARP7) mediates TCDD-induced suppression of hepatic gluconeogenesis downstream of AHR. TiPARP overexpression reproduced TCDD effects on glucose output and NAD+ levels, increased PGC1α acetylation and decreased PGC1α levels; TiPARP silencing diminished these effects. The mechanism involves TiPARP-driven NAD+ depletion, reduced SIRT1 activation of PGC1α, and consequently reduced PEPCK and G6Pase expression.","method":"TiPARP overexpression and RNAi knockdown in hepatic cells, glucose output assay, NAD+ measurement, PGC1α acetylation/protein level assessment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple biochemical readouts in a single study","pmids":["20876576"],"is_preprint":false},{"year":2015,"finding":"TIPARP mono-ADP-ribosylates AHR (but not ARNT/AHR nuclear translocator). Loss of Tiparp in mice increases sensitivity to dioxin-induced steatohepatitis and lethality. The repressive effect of TIPARP on AHR is reversed by the macrodomain-containing mono-ADP-ribosylase MACROD1 but not MACROD2, establishing MACROD1 as the eraser of TIPARP-placed ADP-ribose marks on AHR.","method":"In vitro ADP-ribosylation assay, Tiparp-/- mouse model, MACROD1/MACROD2 reversal assay, reporter gene assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro biochemistry plus in vivo genetic model plus writer/eraser identification with multiple orthogonal methods","pmids":["25975270"],"is_preprint":false},{"year":2016,"finding":"TIPARP mono-ADP-ribosylates LXRα and LXRβ and positively regulates their transcriptional activity. TIPARP zinc-finger and catalytic domains are required for LXR co-activation. LXRs interact with an N-terminal sequence (aa 209–236) of TIPARP. MACROD1 (but not MACROD2) interacts with LXRs in a TIPARP-dependent manner and prevents the TIPARP-dependent increase in LXR activity. In vivo, GW3965-dependent increases in hepatic Srebp1 mRNA/protein were reduced in Tiparp-/- mice.","method":"In vitro ADP-ribosylation assay, reporter gene assay, TIPARP KD/KO, co-immunoprecipitation, peptide array, immunofluorescence, Tiparp-/- mice","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ribosylation, Co-IP, mutagenesis, and in vivo genetic validation in a single study","pmids":["26814197"],"is_preprint":false},{"year":2018,"finding":"TIPARP nuclear localization depends on a short N-terminal sequence and its zinc finger domain. The minimum catalytically active region spans amino acids 400–657 and retains AHR mono-ADP-ribosylation ability. Catalytic activity is sensitive to iodoacetamide and hydroxylamine (implicating cysteines and acidic residues as targets) but resistant to meta-iodobenzylguanidine. Mass spectrometry identified cysteine 39 via ETD as a site of TIPARP auto-mono-ADP-ribosylation; C39A mutation modestly reduced autoribosylation but did not prevent AHR repression.","method":"Deletion/mutagenesis studies, in vitro ADP-ribosylation assay, chemical inhibitor sensitivity assays, mass spectrometry with ETD, immunofluorescence localization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemistry plus MS/ETD site-mapping plus mutagenesis in a single rigorous study","pmids":["30373764"],"is_preprint":false},{"year":2014,"finding":"Parp1 and Parp7 co-occupy key pluripotency gene loci (Nanog, Pou5f1, Sox2, Stella, Tet1, Zfp42) in embryonic stem cells, protecting them from epigenetic repression. Loss of either Parp1 or Parp7, or inhibition of ADP-ribosylating activity, decreases ground-state pluripotency and increases the propensity of ES cells to differentiate.","method":"ChIP, ADP-ribosylation inhibition, Parp1/Parp7 loss-of-function in ES cells, pluripotency marker analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and loss-of-function with functional readout, single lab with multiple methods","pmids":["25034692"],"is_preprint":false},{"year":2014,"finding":"AHRR and TiPARP independently repress AHR transactivation by distinct mechanisms: TiPARP knockdown (but not AHRR knockdown) increased AHR protein levels and TCDD-induced CYP1A1 mRNA. Overexpression of TiPARP in AHRR-/- MEFs reduced CYP1A1 induction, and vice versa, confirming independent repression pathways. Nuclear localization of AHRR is required for its repressive function.","method":"RNAi knockdown, Tiparp-/- and Ahrr-/- MEFs, overexpression rescue experiments, reporter gene assay, immunofluorescence","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double-mutant rescue, single lab, multiple cell models","pmids":["24806346"],"is_preprint":false},{"year":2018,"finding":"Hepatocyte-specific deletion of TIPARP (Tiparpfl/flCreAlb mice) is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality, demonstrating that TIPARP's negative regulation of AHR is functionally critical specifically in hepatocytes.","method":"Cre-lox conditional knockout (hepatocyte-specific), dioxin challenge, liver pathology, AHR target gene expression, metabolomics","journal":"Toxicological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic model with multiple biochemical and phenotypic readouts replicated across two knockout lines","pmids":["29873790"],"is_preprint":false},{"year":2020,"finding":"TiPARP forms distinct ADP-ribosylation-dependent nuclear condensates/nuclear bodies that recruit HIF-1α and the E3 ubiquitin ligase HUWE1, promoting ubiquitination and proteasomal degradation of HIF-1α. TiPARP similarly promotes degradation of c-Myc and estrogen receptor via this nuclear body mechanism, functioning as a negative-feedback regulator for multiple oncogenic transcription factors.","method":"Live-cell imaging of nuclear condensates, co-immunoprecipitation, ubiquitination assay, ADP-ribosylation-deficient mutants, xenograft tumor models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, Co-IP, ubiquitination assay, mutagenesis, in vivo xenograft) in a single study","pmids":["32482854"],"is_preprint":false},{"year":2021,"finding":"PARP7 is a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 by RBN-2397 restores type I interferon signaling responses to nucleic acids, directly inhibiting cell proliferation and activating antitumor immunity. Complete tumor regression in a lung cancer xenograft model was observed upon oral PARP7 inhibition, dependent on type I IFN signaling in tumor cells.","method":"PARP7 inhibitor (RBN-2397), xenograft and immunocompetent mouse tumor models, IFN signaling assays, cell proliferation assays, immune cell analyses","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic in vitro and in vivo genetic/pharmacological evidence replicated across multiple tumor models","pmids":["34375612"],"is_preprint":false},{"year":2021,"finding":"PARP-7 preferentially MARylates cysteine residues. Using chemical genetics and proteome-wide ADP-ribosylation site profiling, PARP-13 was identified as a major direct target of PARP-7 MARylation, specifically on cysteine residues within its RNA-binding zinc finger domain. Proteome-wide analysis confirmed cysteine as the predominant MARylation acceptor for PARP-7.","method":"Chemical genetics (analog-sensitive PARP-7), proximity labeling, proteome-wide ADP-ribosylation site mapping by mass spectrometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — chemical genetics plus proteome-wide MS-based site mapping, multiple orthogonal methods","pmids":["33475084"],"is_preprint":false},{"year":2021,"finding":"PARP-7 MARylates α-tubulin to promote microtubule instability, which regulates ovarian cancer cell growth and motility. An NAD+ analog-sensitive approach coupled with mass spectrometry identified α-tubulin and other cytoskeletal/cell-adhesion proteins as components of the PARP-7 ADP-ribosylated proteome in ovarian cancer cells.","method":"NAD+ analog-sensitive PARP-7 coupled with mass spectrometry, PARP-7 depletion, cell growth/migration assays, global gene expression analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chemical genetic substrate identification plus functional validation of α-tubulin MARylation in a single rigorous study","pmids":["33475085"],"is_preprint":false},{"year":2021,"finding":"PARP7 mono-ADP-ribosylates estrogen receptor α (ERα), with modification sites mapped by mass spectrometry to the receptor's ligand-independent transactivation domain; the hinge region of ERα is required for PARP7-dependent mono-ADP-ribosylation. PARP7 overexpression decreases ligand-dependent ERα signaling; PARP7 KO MCF-7 cells show increased ERα target gene expression and proliferation in response to 17β-estradiol.","method":"Co-immunoprecipitation, mass spectrometry, truncated ERα variants, reporter gene assay, PARP7 KO cells","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, MS site mapping, domain-deletion mutagenesis, and KO functional phenotype in a single study","pmids":["33799807"],"is_preprint":false},{"year":2021,"finding":"PARP7 mono-ADP-ribosylates the androgen receptor (AR) in the nucleus, requiring nuclear localization of PARP7 and an agonist-induced conformation of AR. The Cys3His1-type zinc finger (ZF) of PARP7 is critical for efficient nuclear import and for AR ADP-ribosylation independently of catalytic activity. ZF mutations abolish PARP7 enhancement of AR-dependent transcription of MYBPC1 without reducing PARP7's catalytic activity or AR binding.","method":"Nuclear localization studies, conformation-specific AR mutants, ZF mutagenesis, in vitro/cellular ADP-ribosylation assays, AR-dependent reporter gene assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical requirements dissected by mutagenesis, localization studies, and functional transcription assays in a single study","pmids":["34264286"],"is_preprint":false},{"year":2021,"finding":"PARP7 protein has an extremely short half-life (~4.5 min) that is extended by androgen/AR signaling (~25.6 min), leading to nuclear accumulation. Androgen-dependent post-transcriptional stabilization of PARP7 is distinct from transcriptional regulation. Mutations in the catalytic domain, zinc finger, and WWE domains each reduce PARP7 degradation rate, indicating that the overall protein structure is tuned for rapid turnover.","method":"Cycloheximide chase assay, androgen treatment, domain mutagenesis, subcellular fractionation, comparison with PARP1/2/9/14","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein stability assays with mutagenesis, single lab","pmids":["33572475"],"is_preprint":false},{"year":2021,"finding":"TiPARP controls TCDD-activated AHR nuclear export and subsequent proteasomal degradation. In MEFCul4b-null cells, TiPARP knockdown completely abolished AHR degradation upon TCDD treatment, while CUL4B deletion only partially prevented it. Combined loss of CUL4B and TiPARP led to enhanced AHR transcriptional activity.","method":"Cul4b-null MEFs, TiPARP siRNA knockdown, AHR protein levels and nuclear export assay, AHR target gene expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two knockout backgrounds, single lab, functional AHR readout","pmids":["34146543"],"is_preprint":false},{"year":2021,"finding":"TIPARP catalytic activity is required for its role as a negative regulator of AHR in vivo. Catalytically deficient TiparpH532A knock-in mice exhibit increased TCDD-induced AHR target gene expression, steatohepatitis, hepatotoxicity, and lethality at doses non-lethal to wild-type mice, demonstrating that H532 is the critical catalytic residue.","method":"Catalytic knock-in mouse model (H532A point mutation), TCDD challenge, hepatic RNA-seq, liver pathology, AHR target gene expression","journal":"Toxicological sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo catalytic point-mutant mouse with comprehensive phenotypic and transcriptomic readouts","pmids":["34129049"],"is_preprint":false},{"year":2013,"finding":"TCDD-induced TiPARP ADP-ribosylates PEPCK (both cytosolic and mitochondrial forms) as a downstream posttranslational modification, identifying PEPCK as a TiPARP substrate and linking AHR transcriptional activation of TiPARP to a downstream change in a gluconeogenic enzyme.","method":"In vitro/cellular ADP-ribosylation assay, TCDD treatment, TiPARP knockdown/overexpression, isoform-specific PEPCK analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical ADP-ribosylation assay with genetic validation, single lab","pmids":["23770670"],"is_preprint":false},{"year":2019,"finding":"Loss of Tiparp results in aberrant cortical layering with increased upper-layer cell density, predominantly affecting GABAergic neuron distribution and number. Neural progenitor cell proliferation is reduced, and Tiparp-/- neural stem cells show slower migration. α-tubulin mono-ADP-ribosylation levels are reduced in Tiparp-/- cells, suggesting Tiparp mediates α-tubulin MAR during cortical development.","method":"Tiparp-/- mouse model, cortical layer immunostaining, neural progenitor proliferation assay, neural stem cell migration assay, α-tubulin MAR assay","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined cellular phenotypes and biochemical substrate link, single lab","pmids":["31704703"],"is_preprint":false},{"year":2023,"finding":"PARP7 ADP-ribosylates the AP-1 transcription factor FRA1 on cysteine 97 in the nucleus. FRA1 ADP-ribosylation protects it from proteasomal degradation via PSMC3. Loss of FRA1 ADP-ribosylation (via PARP7 inhibition or C97 mutation) promotes IRF1- and IRF3-dependent cytokine and proapoptotic gene expression, culminating in CASP8-mediated apoptosis.","method":"PARP7 inhibitor (RBN-2397), ADP-ribosylation site mutagenesis (FRA1 C97), Co-IP, proteasome inhibition, gene expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-specific mutagenesis, biochemical Co-IP, mechanistic gene expression readouts, multiple methods in a single study","pmids":["38011562"],"is_preprint":false},{"year":2022,"finding":"PARP7 inhibition synergistically induces IFN-β expression when combined with nucleic acid sensor ligands in MEFs; PARP7 catalytic activity regulates its own protein levels (PARP7 inhibition increases PARP7 protein). Two structurally distinct inhibitors (KMR-206 and RBN-2397) achieve different PARP7 protein stabilization levels correlating with different magnitudes of IFN gene induction.","method":"PARP7 inhibitor treatment (KMR-206, RBN-2397), IFN-β reporter assays, PARP7 protein level quantification, comparison of structurally distinct inhibitors","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and biochemical studies with two structurally distinct inhibitors, single lab","pmids":["36529140"],"is_preprint":false},{"year":2022,"finding":"AHR loss confers resistance to PARP7 inhibitor (RBN-2397) treatment, identified in a genome-wide CRISPR screen. Components of the cohesin complex also emerge as determinants of RBN-2397 resistance. AHR activators and inhibitors modulate cellular response to PARP7 inhibition, establishing epistatic dependence of PARP7 inhibitor sensitivity on AHR.","method":"Genome-wide CRISPR screen, AHR modulator co-treatments, cell viability assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased CRISPR screen identifying epistatic relationship, single lab","pmids":["35439318"],"is_preprint":false},{"year":2023,"finding":"Loss of PARP7 expression increases type I IFN signaling, including ISGF3 and unphosphorylated-ISGF3 regulated target genes, partly because PARP7 modifies the RelA subunit of NF-κB. PARP7 loss had no effect on tumor growth in immunodeficient mice but prevented tumor development in immunocompetent settings, demonstrating immune-cell-dependent tumor suppression.","method":"PARP7 KO EO771 cells, syngeneic mouse tumor model, immunodeficient mouse controls, IFN signaling pathway analysis, NF-κB RelA ADP-ribosylation","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo immune dependence controls and mechanistic ADP-ribosylation of NF-κB RelA, single lab","pmids":["37509350"],"is_preprint":false},{"year":2025,"finding":"PARP7 generates an ADP-ribosyl degron in the DNA-binding domain of AR on chromatin, recognized by the ADP-ribose reader domain of the ubiquitin E3 ligase DTX2 (not DTX3L), leading to proteasomal degradation of AR. Mathematical modeling and an AR DNA-binding mutant confirmed that PARP7 ADP-ribosylates chromatin-bound AR. This constitutes a negative feedback loop regulating modules of AR target genes.","method":"In vitro/cellular ADP-ribosylation assay, AR DNA-binding mutant, DTX2 interaction and ubiquitination assay, mathematical modeling, chromatin fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution, mutagenesis, E3 ligase identification, mathematical modeling, and cellular validation in a single rigorous study","pmids":["40681873"],"is_preprint":false},{"year":2025,"finding":"PARP7 inhibits the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production by MARylating p300 and CBP. An α-helical domain in PARP7 is essential for p300/CBP interaction, MARylation, and proteasome degradation of p300/CBP. Disrupting PARP7-p300/CBP interaction prevents PARP7's suppression of IFN-β. p300/CBP reciprocally regulate PARP7 activity and nuclear localization.","method":"Chemical genetic ASCG approach (analog-sensitive), Co-IP, domain deletion, IFN-β reporter assays, PARP7 KO vs inhibitor comparison","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — chemical genetics plus Co-IP plus domain mutagenesis, preprint not yet peer reviewed","pmids":["40631120"],"is_preprint":true},{"year":2025,"finding":"PARP7 interacts with IRF3 through its catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production in a MARylation-dependent manner. Parp7-/- and Parp7H532A/H532A mice develop systemic autoimmunity and pulmonary tertiary lymphoid structures; Irf3-/-, Irf3S1/S1 (transcription-defective), or Sting-/- genetically rescues Parp7H532A/H532A autoimmunity and lung disease.","method":"Parp7-/- and ParpH532A/H532A mice, IRF3 Co-IP, genetic rescue with Irf3-/-, Irf3S1/S1, Sting-/-, autoimmunity phenotype analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic rescue lines, Co-IP mechanistic evidence, and in vivo phenotype in peer-reviewed publication","pmids":["39969510"],"is_preprint":false},{"year":2025,"finding":"DTX2 is the E3 ligase responsible for degrading ADP-ribosylated PARP7, AHR, and other PARP7 substrates. Endogenous ADP-ribosylation of PARP7 and AHR is greatly induced when the ubiquitin-proteasome pathway is blocked, and AHR pathway activation promotes quantitative ADP-ribosylation of PARP7 itself (auto-MARylation) and AHR. This establishes mono-ADP-ribosylation as a degradation mark.","method":"Ubiquitin pathway blockade (proteasome inhibitors), ADP-ribosylation detection, DTX2 identification as E3 ligase, AHR pathway activation, endogenous protein level analyses","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical reconstitution of ADP-ribosyl degron pathway with E3 ligase identification and multiple genetic tools","pmids":["41326691"],"is_preprint":false},{"year":2025,"finding":"PARP7 functions as a nuclear NAD+ sensor for adipogenesis: at higher nuclear NAD+ concentrations in undifferentiated preadipocytes, PARP7 undergoes auto-MARylation, which promotes its own proteasomal degradation via DTX2 and RNF114 E3 ligases. Stabilized PARP7 (when NAD+ declines post-differentiation) serves as a coregulator of C/EBPβ by stimulating p300-mediated H3K27 acetylation and C/EBPβ genomic binding. Genetic PARP7 depletion in mice reduces adipogenesis, fat mass, and milk lipid composition.","method":"NAD+ measurement, autoMARylation assay, DTX2/RNF114 KO, ChIP-seq (C/EBPβ binding, H3K27ac), PARP7 KO mice with mammary gland and fat pad phenotyping, metabolomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (biochemistry, ChIP-seq, in vivo genetics, metabolomics) with peer-reviewed publication","pmids":["41621069"],"is_preprint":false},{"year":2025,"finding":"PARP7 is a proteotoxic stress sensor: during proteotoxic stress, PARP7 protein is stabilized and mono-ADP-ribosylates proteins that accumulate in cytoplasmic foci containing ubiquitin and p62, and are subsequently trafficked to aggresomes for autophagic degradation. Ubiquitination is required for efficient clearance of ADP-ribosylated proteins; PARP7 inhibition impedes accumulation of MARylated proteins in response to proteotoxic stress.","method":"Proteotoxic stress treatment, PARP7 inhibition, ADP-ribosylation immunofluorescence, aggresome imaging, ubiquitin pathway inhibition, PARP7 protein stability assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell biological and biochemical evidence, single lab, multiple methods but no in vitro reconstitution","pmids":["40836037"],"is_preprint":false},{"year":2025,"finding":"PARP7 is selectively expressed in alveolar type I cells and maintains lung epithelial barrier integrity. PARP7 loss increases susceptibility to chemically induced diffuse alveolar hemorrhaging and pristane-induced lupus with increased immune infiltration. Mechanistically, PARP7 acts via AHR to control tight junction protein Occludin and xenobiotic/inflammatory gene expression in bronchial epithelial cells upon cigarette smoke or bacterial challenge.","method":"Parp7-/- mice, chemical challenge models, single-nucleus RNA-seq, air-liquid interface culture, PARP7 inhibitor treatment in human bronchial epithelial cells, AHR epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model plus snRNA-seq plus human cell culture mechanistic follow-up, single lab","pmids":["41779776"],"is_preprint":false},{"year":2025,"finding":"PARP7 interacts with TBK1 and mediates its ADP-ribosylation in LPS-stimulated renal tubular epithelial cells, suppressing TBK1-driven inflammation. The anti-inflammatory effects of PARP7 are dependent on its catalytic residue H532. PARP7-specific overexpression in renal proximal tubular cells attenuated septic AKI in mice, while global PARP7 deletion exacerbated LPS-induced renal inflammation.","method":"Co-immunoprecipitation, H532 catalytic mutant, PARP7 overexpression in vivo, PARP7 global KO, LPS-AKI mouse model, scRNA-seq","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP substrate identification plus catalytic mutagenesis plus in vivo gain/loss-of-function, single lab","pmids":["41952113"],"is_preprint":false},{"year":2025,"finding":"SOCS3 crosstalks with AHR in the context of PARP7 signaling: PARP7 inhibition in SOCS3 knockout cells leads to reduced cell viability compared with wild-type cells. AHR transcriptional activity remodels the proteome upon PARP7 inhibition, including downregulation of filamins A and B concurrent with induction of the E3 ubiquitin ligase ASB2.","method":"Genome-wide CRISPR screens, multiplex quantitative proteomics, SOCS3 KO cells, PARP7 inhibitor treatment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased CRISPR screen plus quantitative proteomics, single lab","pmids":["40493189"],"is_preprint":false}],"current_model":"TIPARP/PARP7 is a nuclear mono-ADP-ribosyltransferase (MARylation at cysteine and acidic residues) that functions as a negative-feedback regulator of multiple transcription factors—including AHR, HIF-1α, ERα, AR, FRA1, IRF3, and LXRα/β—by MARylating them to trigger their proteasomal degradation (via E3 ligases HUWE1, DTX2, and CUL4B) or to modulate their transcriptional activity; it is transcriptionally induced by AHR and, in turn, represses AHR in a MACROD1-reversible manner; it also suppresses type I interferon production by disrupting the IRF3:CBP/p300 holocomplex in a catalysis-dependent manner; regulates microtubule stability by MARylating α-tubulin; senses nuclear NAD+ levels to control adipogenesis via a PARP7–p300–H3K27ac–C/EBPβ axis; and undergoes rapid proteasomal turnover whose rate is controlled by auto-MARylation and androgen signaling."},"narrative":{"mechanistic_narrative":"TIPARP (PARP7/ARTD14) is a nuclear mono-ADP-ribosyltransferase that acts as a negative-feedback regulator of inducible transcription factors by MARylating them, predominantly on cysteine residues, to control their activity and stability [PMID:23275542, PMID:33475084]. Its founding role is in aryl hydrocarbon receptor (AHR) signaling: TIPARP is induced by AHR, MARylates AHR to drive its nuclear export and proteasomal degradation, and thereby dampens dioxin-responsive CYP1A1/CYP1B1 transcription; this repression requires both the zinc-finger and catalytic domains and the catalytic residue H532 in vivo [PMID:23275542, PMID:25975270, PMID:34146543, PMID:34129049]. The same writer/eraser logic extends across targets—MACROD1 reverses TIPARP-placed ADP-ribose marks on AHR [PMID:25975270]—and TIPARP similarly MARylates and regulates HIF-1α, c-Myc, ERα, the androgen receptor, FRA1, and LXRα/β, in several cases nucleating ADP-ribosylation-dependent nuclear bodies that recruit E3 ligases to trigger degradation [PMID:26814197, PMID:32482854, PMID:33799807, PMID:34264286, PMID:38011562, PMID:40681873]. TIPARP-generated ADP-ribosyl marks are recognized as degrons by E3 ligases including HUWE1 and DTX2, and DTX2 also degrades auto-MARylated PARP7 itself, establishing mono-ADP-ribosylation as a bona fide degradation signal [PMID:32482854, PMID:40681873, PMID:41326691]. Beyond transcription factors, TIPARP MARylates α-tubulin to promote microtubule instability, with consequences for cancer cell motility and cortical neuronal development [PMID:33475085, PMID:31704703]. In innate immunity, TIPARP suppresses type I interferon production by interacting with IRF3 and disrupting the IRF3:CBP/p300 holocomplex in a catalysis-dependent manner, and its loss or catalytic inactivation causes systemic autoimmunity rescued by Irf3 or Sting deletion [PMID:34375612, PMID:39969510]. PARP7 protein is intrinsically short-lived, with turnover tuned by auto-MARylation and extended by androgen signaling, and it functions as a nuclear NAD+ sensor that gates adipogenesis through a p300–H3K27ac–C/EBPβ axis [PMID:33572475, PMID:41621069]. Pharmacological PARP7 inhibition (RBN-2397) restores interferon signaling and drives antitumor immunity [PMID:34375612].","teleology":[{"year":2010,"claim":"Established that TIPARP is a functional effector downstream of AHR, answering whether AHR-induced TIPARP has metabolic consequences by linking it to suppression of hepatic gluconeogenesis.","evidence":"Gain/loss-of-function in hepatic cells with glucose output, NAD+, and PGC1α readouts","pmids":["20876576"],"confidence":"High","gaps":["Direct enzymatic targets of TIPARP in this pathway not yet defined","NAD+-depletion mechanism inferred rather than directly resolved"]},{"year":2012,"claim":"Defined TIPARP's core molecular identity as an auto-mono-ADP-ribosyltransferase and a negative-feedback repressor of AHR, answering how the AHR transcriptional output is constrained.","evidence":"In vitro ADP-ribosylation, RNAi, reporter assays, mutagenesis, Co-IP, and Tiparp-/- MEFs","pmids":["23275542"],"confidence":"High","gaps":["Direct MARylation sites on AHR not mapped","E3 ligase mediating AHR degradation not identified"]},{"year":2013,"claim":"Extended the substrate repertoire by showing TIPARP MARylates PEPCK, connecting AHR-driven TIPARP induction to direct modification of a gluconeogenic enzyme.","evidence":"ADP-ribosylation assays with isoform-specific PEPCK analysis and TIPARP perturbation","pmids":["23770670"],"confidence":"Medium","gaps":["Functional consequence of PEPCK MARylation on enzyme activity not established","MARylation site not mapped"]},{"year":2014,"claim":"Showed TIPARP repression of AHR is mechanistically independent of AHRR and that TIPARP/PARP1 ADP-ribosylation maintains pluripotency gene loci, broadening TIPARP roles beyond xenobiotic signaling.","evidence":"Double-mutant epistasis/rescue in MEFs; ChIP and loss-of-function in ES cells","pmids":["24806346","25034692"],"confidence":"Medium","gaps":["Direct chromatin substrates at pluripotency loci unresolved","Mechanism distinguishing TIPARP vs AHRR repression not molecularly defined"]},{"year":2015,"claim":"Identified TIPARP MARylation of AHR and its eraser MACROD1, establishing a complete writer/eraser cycle and confirming physiological importance through dioxin-sensitive Tiparp-/- mice.","evidence":"In vitro ribosylation, Tiparp-/- mouse model, MACROD1/2 reversal assays","pmids":["25975270"],"confidence":"High","gaps":["AHR modification residues not pinpointed","Whether MACROD1 reverses TIPARP marks on other substrates not tested here"]},{"year":2016,"claim":"Demonstrated that TIPARP can positively coactivate a transcription factor (LXRα/β), showing its MARylation output is not uniformly repressive.","evidence":"In vitro ribosylation, reporter assays, Co-IP, peptide array, Tiparp-/- mice","pmids":["26814197"],"confidence":"High","gaps":["Molecular basis for coactivation vs degradation outcome unresolved","LXR MARylation sites not mapped"]},{"year":2018,"claim":"Mapped TIPARP's domain architecture—nuclear localization determinants, minimal catalytic region, target residue chemistry (Cys/acidic), and an auto-MARylation site (Cys39)—and showed hepatocyte-autonomous requirement for AHR control.","evidence":"Deletion/mutagenesis, inhibitor sensitivity, ETD mass spectrometry; hepatocyte-specific conditional knockout with dioxin challenge","pmids":["30373764","29873790"],"confidence":"High","gaps":["C39 auto-MARylation function only modestly affects activity","Catalytic mechanism and substrate selection rules incomplete"]},{"year":2019,"claim":"Connected TIPARP α-tubulin MARylation to cortical development, addressing whether its cytoskeletal substrate has organismal consequence.","evidence":"Tiparp-/- mice, cortical layer immunostaining, neural progenitor/migration assays, α-tubulin MAR assay","pmids":["31704703"],"confidence":"Medium","gaps":["Direct causal link between tubulin MARylation and layering defect not isolated","α-tubulin MAR site not mapped here"]},{"year":2020,"claim":"Revealed the nuclear-body/condensate mechanism by which TIPARP recruits HUWE1 to ubiquitinate and degrade HIF-1α, c-Myc, and ERα, generalizing TIPARP as a degradative regulator of oncogenic transcription factors.","evidence":"Live-cell imaging, Co-IP, ubiquitination assays, ADP-ribosylation-deficient mutants, xenografts","pmids":["32482854"],"confidence":"High","gaps":["Condensate composition and assembly rules incompletely defined","Substrate MARylation sites not all mapped"]},{"year":2021,"claim":"Defined PARP7 substrate chemistry proteome-wide (cysteine-preferring MARylation, including PARP-13 and α-tubulin), mapped additional transcription-factor substrates (ERα, AR), and showed androgen-controlled rapid turnover—while CUL4B was implicated in AHR degradation and RBN-2397 inhibition was shown to restore interferon-driven antitumor immunity.","evidence":"Chemical-genetic analog-sensitive PARP7, proteome-wide MS site mapping, domain mutagenesis, KO phenotypes, cycloheximide chase, and RBN-2397 in tumor models","pmids":["33475084","33475085","33799807","34264286","33572475","34146543","34375612"],"confidence":"High","gaps":["Rules governing substrate selection among cysteine sites unclear","Relative contribution of distinct E3 ligases (CUL4B vs others) to AHR degradation not fully resolved"]},{"year":2022,"claim":"Showed PARP7 catalytic activity controls its own protein levels and that inhibitor-induced PARP7 stabilization correlates with interferon induction, while CRISPR screens established AHR (and cohesin) as determinants of inhibitor sensitivity.","evidence":"Two structurally distinct inhibitors with IFN-β reporters and protein quantification; genome-wide CRISPR screen with AHR modulator co-treatments","pmids":["36529140","35439318"],"confidence":"Medium","gaps":["Mechanism coupling PARP7 stabilization to IFN magnitude not fully resolved","Cohesin's role in inhibitor response mechanistically undefined"]},{"year":2023,"claim":"Established that PARP7 MARylation can be protective (FRA1 Cys97 ADP-ribosylation blocks degradation) and that PARP7 modifies RelA/NF-κB, refining how it gates cytokine, apoptotic, and interferon programs.","evidence":"RBN-2397, FRA1 C97 mutagenesis, Co-IP, proteasome inhibition, gene profiling; PARP7 KO syngeneic vs immunodeficient tumor models","pmids":["38011562","37509350"],"confidence":"High","gaps":["How the same enzyme protects FRA1 but degrades other substrates unresolved","RelA MARylation site and functional output incompletely defined"]},{"year":2025,"claim":"Resolved the ADP-ribosyl degron pathway in molecular detail—PARP7 generates an ADP-ribose degron on chromatin-bound AR read by DTX2, DTX2 also degrades auto-MARylated PARP7 and AHR, PARP7 disrupts the IRF3:CBP/p300 holocomplex by MARylating p300/CBP and IRF3, and PARP7 acts as a nuclear NAD+ sensor and proteotoxic-stress sensor with roles in adipogenesis, lung barrier, and renal inflammation.","evidence":"In vitro reconstitution, AR DNA-binding mutants, DTX2/E3 identification, chemical genetics, Parp7-/-/Parp7H532A and rescue mouse models, ChIP-seq, and stress/aggresome cell biology","pmids":["40681873","41326691","40631120","39969510","41621069","40836037","41779776","41952113","40493189"],"confidence":"High","gaps":["Unified rules determining substrate-specific degradation vs activity modulation not fully formalized","Structural basis of degron recognition by reader E3 ligases incompletely defined","p300/CBP holocomplex work partly from preprint pending peer review"]},{"year":null,"claim":"How TIPARP integrates its many context-dependent outputs—degradative vs protective MARylation, NAD+ sensing, condensate formation, and tissue-specific physiology—into a single predictive substrate-selection logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model predicting which substrates are degraded vs stabilized vs coactivated","Structural determinants of cysteine site selection unmapped","Physiological NAD+ thresholds governing sensor behavior across tissues undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,10,11,12,13,19,23]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,8,27]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[27,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,8,13]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[8,23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,12,13,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,22,24,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,23,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,13,25]}],"complexes":[],"partners":["AHR","HIF1A","ESR1","AR","MACROD1","DTX2","HUWE1","IRF3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z3E1","full_name":"Protein mono-ADP-ribosyltransferase TIPARP","aliases":["ADP-ribosyltransferase diphtheria toxin-like 14","ARTD14","Poly [ADP-ribose] polymerase 7","PARP-7","TCDD-inducible poly [ADP-ribose] polymerase"],"length_aa":657,"mass_kda":76.2,"function":"ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate, aspartate and cysteine residues on target proteins (PubMed:23275542, PubMed:25043379, PubMed:30373764). 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RNAi-mediated knockdown of TiPARP increased TCDD-dependent CYP1A1 and CYP1B1 mRNA expression and AHR recruitment to both genes. TiPARP and AHR co-localized in the nucleus, directly interacted, and both were recruited to CYP1A1 in response to TCDD. TiPARP-mediated inhibition of AHR required both the zinc-finger and catalytic domains. Overexpression of TiPARP enhanced TCDD-dependent AHR proteolytic degradation, while knockdown reduced it. TiPARP thus functions as a mono-ADP-ribosyltransferase and transcriptional repressor of AHR, establishing a negative feedback loop in AHR signalling.\",\n      \"method\": \"In vitro ADP-ribosylation assay, RNAi knockdown, reporter gene assay, deletion/mutagenesis studies, co-localization (immunofluorescence), co-immunoprecipitation, Tiparp-/- MEFs\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro assay, mutagenesis, Co-IP, KD/KO phenotype) in a single rigorous study with genetic validation in Tiparp-/- MEFs\",\n      \"pmids\": [\"23275542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TiPARP (PARP7) mediates TCDD-induced suppression of hepatic gluconeogenesis downstream of AHR. TiPARP overexpression reproduced TCDD effects on glucose output and NAD+ levels, increased PGC1α acetylation and decreased PGC1α levels; TiPARP silencing diminished these effects. The mechanism involves TiPARP-driven NAD+ depletion, reduced SIRT1 activation of PGC1α, and consequently reduced PEPCK and G6Pase expression.\",\n      \"method\": \"TiPARP overexpression and RNAi knockdown in hepatic cells, glucose output assay, NAD+ measurement, PGC1α acetylation/protein level assessment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with multiple biochemical readouts in a single study\",\n      \"pmids\": [\"20876576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIPARP mono-ADP-ribosylates AHR (but not ARNT/AHR nuclear translocator). Loss of Tiparp in mice increases sensitivity to dioxin-induced steatohepatitis and lethality. The repressive effect of TIPARP on AHR is reversed by the macrodomain-containing mono-ADP-ribosylase MACROD1 but not MACROD2, establishing MACROD1 as the eraser of TIPARP-placed ADP-ribose marks on AHR.\",\n      \"method\": \"In vitro ADP-ribosylation assay, Tiparp-/- mouse model, MACROD1/MACROD2 reversal assay, reporter gene assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro biochemistry plus in vivo genetic model plus writer/eraser identification with multiple orthogonal methods\",\n      \"pmids\": [\"25975270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIPARP mono-ADP-ribosylates LXRα and LXRβ and positively regulates their transcriptional activity. TIPARP zinc-finger and catalytic domains are required for LXR co-activation. LXRs interact with an N-terminal sequence (aa 209–236) of TIPARP. MACROD1 (but not MACROD2) interacts with LXRs in a TIPARP-dependent manner and prevents the TIPARP-dependent increase in LXR activity. In vivo, GW3965-dependent increases in hepatic Srebp1 mRNA/protein were reduced in Tiparp-/- mice.\",\n      \"method\": \"In vitro ADP-ribosylation assay, reporter gene assay, TIPARP KD/KO, co-immunoprecipitation, peptide array, immunofluorescence, Tiparp-/- mice\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ribosylation, Co-IP, mutagenesis, and in vivo genetic validation in a single study\",\n      \"pmids\": [\"26814197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TIPARP nuclear localization depends on a short N-terminal sequence and its zinc finger domain. The minimum catalytically active region spans amino acids 400–657 and retains AHR mono-ADP-ribosylation ability. Catalytic activity is sensitive to iodoacetamide and hydroxylamine (implicating cysteines and acidic residues as targets) but resistant to meta-iodobenzylguanidine. Mass spectrometry identified cysteine 39 via ETD as a site of TIPARP auto-mono-ADP-ribosylation; C39A mutation modestly reduced autoribosylation but did not prevent AHR repression.\",\n      \"method\": \"Deletion/mutagenesis studies, in vitro ADP-ribosylation assay, chemical inhibitor sensitivity assays, mass spectrometry with ETD, immunofluorescence localization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemistry plus MS/ETD site-mapping plus mutagenesis in a single rigorous study\",\n      \"pmids\": [\"30373764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Parp1 and Parp7 co-occupy key pluripotency gene loci (Nanog, Pou5f1, Sox2, Stella, Tet1, Zfp42) in embryonic stem cells, protecting them from epigenetic repression. Loss of either Parp1 or Parp7, or inhibition of ADP-ribosylating activity, decreases ground-state pluripotency and increases the propensity of ES cells to differentiate.\",\n      \"method\": \"ChIP, ADP-ribosylation inhibition, Parp1/Parp7 loss-of-function in ES cells, pluripotency marker analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and loss-of-function with functional readout, single lab with multiple methods\",\n      \"pmids\": [\"25034692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AHRR and TiPARP independently repress AHR transactivation by distinct mechanisms: TiPARP knockdown (but not AHRR knockdown) increased AHR protein levels and TCDD-induced CYP1A1 mRNA. Overexpression of TiPARP in AHRR-/- MEFs reduced CYP1A1 induction, and vice versa, confirming independent repression pathways. Nuclear localization of AHRR is required for its repressive function.\",\n      \"method\": \"RNAi knockdown, Tiparp-/- and Ahrr-/- MEFs, overexpression rescue experiments, reporter gene assay, immunofluorescence\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double-mutant rescue, single lab, multiple cell models\",\n      \"pmids\": [\"24806346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatocyte-specific deletion of TIPARP (Tiparpfl/flCreAlb mice) is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality, demonstrating that TIPARP's negative regulation of AHR is functionally critical specifically in hepatocytes.\",\n      \"method\": \"Cre-lox conditional knockout (hepatocyte-specific), dioxin challenge, liver pathology, AHR target gene expression, metabolomics\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic model with multiple biochemical and phenotypic readouts replicated across two knockout lines\",\n      \"pmids\": [\"29873790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TiPARP forms distinct ADP-ribosylation-dependent nuclear condensates/nuclear bodies that recruit HIF-1α and the E3 ubiquitin ligase HUWE1, promoting ubiquitination and proteasomal degradation of HIF-1α. TiPARP similarly promotes degradation of c-Myc and estrogen receptor via this nuclear body mechanism, functioning as a negative-feedback regulator for multiple oncogenic transcription factors.\",\n      \"method\": \"Live-cell imaging of nuclear condensates, co-immunoprecipitation, ubiquitination assay, ADP-ribosylation-deficient mutants, xenograft tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, Co-IP, ubiquitination assay, mutagenesis, in vivo xenograft) in a single study\",\n      \"pmids\": [\"32482854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP7 is a negative regulator of nucleic acid sensing in tumor cells. Inhibition of PARP7 by RBN-2397 restores type I interferon signaling responses to nucleic acids, directly inhibiting cell proliferation and activating antitumor immunity. Complete tumor regression in a lung cancer xenograft model was observed upon oral PARP7 inhibition, dependent on type I IFN signaling in tumor cells.\",\n      \"method\": \"PARP7 inhibitor (RBN-2397), xenograft and immunocompetent mouse tumor models, IFN signaling assays, cell proliferation assays, immune cell analyses\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic in vitro and in vivo genetic/pharmacological evidence replicated across multiple tumor models\",\n      \"pmids\": [\"34375612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP-7 preferentially MARylates cysteine residues. Using chemical genetics and proteome-wide ADP-ribosylation site profiling, PARP-13 was identified as a major direct target of PARP-7 MARylation, specifically on cysteine residues within its RNA-binding zinc finger domain. Proteome-wide analysis confirmed cysteine as the predominant MARylation acceptor for PARP-7.\",\n      \"method\": \"Chemical genetics (analog-sensitive PARP-7), proximity labeling, proteome-wide ADP-ribosylation site mapping by mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chemical genetics plus proteome-wide MS-based site mapping, multiple orthogonal methods\",\n      \"pmids\": [\"33475084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP-7 MARylates α-tubulin to promote microtubule instability, which regulates ovarian cancer cell growth and motility. An NAD+ analog-sensitive approach coupled with mass spectrometry identified α-tubulin and other cytoskeletal/cell-adhesion proteins as components of the PARP-7 ADP-ribosylated proteome in ovarian cancer cells.\",\n      \"method\": \"NAD+ analog-sensitive PARP-7 coupled with mass spectrometry, PARP-7 depletion, cell growth/migration assays, global gene expression analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical genetic substrate identification plus functional validation of α-tubulin MARylation in a single rigorous study\",\n      \"pmids\": [\"33475085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP7 mono-ADP-ribosylates estrogen receptor α (ERα), with modification sites mapped by mass spectrometry to the receptor's ligand-independent transactivation domain; the hinge region of ERα is required for PARP7-dependent mono-ADP-ribosylation. PARP7 overexpression decreases ligand-dependent ERα signaling; PARP7 KO MCF-7 cells show increased ERα target gene expression and proliferation in response to 17β-estradiol.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, truncated ERα variants, reporter gene assay, PARP7 KO cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, MS site mapping, domain-deletion mutagenesis, and KO functional phenotype in a single study\",\n      \"pmids\": [\"33799807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP7 mono-ADP-ribosylates the androgen receptor (AR) in the nucleus, requiring nuclear localization of PARP7 and an agonist-induced conformation of AR. The Cys3His1-type zinc finger (ZF) of PARP7 is critical for efficient nuclear import and for AR ADP-ribosylation independently of catalytic activity. ZF mutations abolish PARP7 enhancement of AR-dependent transcription of MYBPC1 without reducing PARP7's catalytic activity or AR binding.\",\n      \"method\": \"Nuclear localization studies, conformation-specific AR mutants, ZF mutagenesis, in vitro/cellular ADP-ribosylation assays, AR-dependent reporter gene assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical requirements dissected by mutagenesis, localization studies, and functional transcription assays in a single study\",\n      \"pmids\": [\"34264286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP7 protein has an extremely short half-life (~4.5 min) that is extended by androgen/AR signaling (~25.6 min), leading to nuclear accumulation. Androgen-dependent post-transcriptional stabilization of PARP7 is distinct from transcriptional regulation. Mutations in the catalytic domain, zinc finger, and WWE domains each reduce PARP7 degradation rate, indicating that the overall protein structure is tuned for rapid turnover.\",\n      \"method\": \"Cycloheximide chase assay, androgen treatment, domain mutagenesis, subcellular fractionation, comparison with PARP1/2/9/14\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein stability assays with mutagenesis, single lab\",\n      \"pmids\": [\"33572475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TiPARP controls TCDD-activated AHR nuclear export and subsequent proteasomal degradation. In MEFCul4b-null cells, TiPARP knockdown completely abolished AHR degradation upon TCDD treatment, while CUL4B deletion only partially prevented it. Combined loss of CUL4B and TiPARP led to enhanced AHR transcriptional activity.\",\n      \"method\": \"Cul4b-null MEFs, TiPARP siRNA knockdown, AHR protein levels and nuclear export assay, AHR target gene expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two knockout backgrounds, single lab, functional AHR readout\",\n      \"pmids\": [\"34146543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIPARP catalytic activity is required for its role as a negative regulator of AHR in vivo. Catalytically deficient TiparpH532A knock-in mice exhibit increased TCDD-induced AHR target gene expression, steatohepatitis, hepatotoxicity, and lethality at doses non-lethal to wild-type mice, demonstrating that H532 is the critical catalytic residue.\",\n      \"method\": \"Catalytic knock-in mouse model (H532A point mutation), TCDD challenge, hepatic RNA-seq, liver pathology, AHR target gene expression\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo catalytic point-mutant mouse with comprehensive phenotypic and transcriptomic readouts\",\n      \"pmids\": [\"34129049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TCDD-induced TiPARP ADP-ribosylates PEPCK (both cytosolic and mitochondrial forms) as a downstream posttranslational modification, identifying PEPCK as a TiPARP substrate and linking AHR transcriptional activation of TiPARP to a downstream change in a gluconeogenic enzyme.\",\n      \"method\": \"In vitro/cellular ADP-ribosylation assay, TCDD treatment, TiPARP knockdown/overexpression, isoform-specific PEPCK analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ADP-ribosylation assay with genetic validation, single lab\",\n      \"pmids\": [\"23770670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of Tiparp results in aberrant cortical layering with increased upper-layer cell density, predominantly affecting GABAergic neuron distribution and number. Neural progenitor cell proliferation is reduced, and Tiparp-/- neural stem cells show slower migration. α-tubulin mono-ADP-ribosylation levels are reduced in Tiparp-/- cells, suggesting Tiparp mediates α-tubulin MAR during cortical development.\",\n      \"method\": \"Tiparp-/- mouse model, cortical layer immunostaining, neural progenitor proliferation assay, neural stem cell migration assay, α-tubulin MAR assay\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined cellular phenotypes and biochemical substrate link, single lab\",\n      \"pmids\": [\"31704703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP7 ADP-ribosylates the AP-1 transcription factor FRA1 on cysteine 97 in the nucleus. FRA1 ADP-ribosylation protects it from proteasomal degradation via PSMC3. Loss of FRA1 ADP-ribosylation (via PARP7 inhibition or C97 mutation) promotes IRF1- and IRF3-dependent cytokine and proapoptotic gene expression, culminating in CASP8-mediated apoptosis.\",\n      \"method\": \"PARP7 inhibitor (RBN-2397), ADP-ribosylation site mutagenesis (FRA1 C97), Co-IP, proteasome inhibition, gene expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-specific mutagenesis, biochemical Co-IP, mechanistic gene expression readouts, multiple methods in a single study\",\n      \"pmids\": [\"38011562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP7 inhibition synergistically induces IFN-β expression when combined with nucleic acid sensor ligands in MEFs; PARP7 catalytic activity regulates its own protein levels (PARP7 inhibition increases PARP7 protein). Two structurally distinct inhibitors (KMR-206 and RBN-2397) achieve different PARP7 protein stabilization levels correlating with different magnitudes of IFN gene induction.\",\n      \"method\": \"PARP7 inhibitor treatment (KMR-206, RBN-2397), IFN-β reporter assays, PARP7 protein level quantification, comparison of structurally distinct inhibitors\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and biochemical studies with two structurally distinct inhibitors, single lab\",\n      \"pmids\": [\"36529140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AHR loss confers resistance to PARP7 inhibitor (RBN-2397) treatment, identified in a genome-wide CRISPR screen. Components of the cohesin complex also emerge as determinants of RBN-2397 resistance. AHR activators and inhibitors modulate cellular response to PARP7 inhibition, establishing epistatic dependence of PARP7 inhibitor sensitivity on AHR.\",\n      \"method\": \"Genome-wide CRISPR screen, AHR modulator co-treatments, cell viability assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased CRISPR screen identifying epistatic relationship, single lab\",\n      \"pmids\": [\"35439318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of PARP7 expression increases type I IFN signaling, including ISGF3 and unphosphorylated-ISGF3 regulated target genes, partly because PARP7 modifies the RelA subunit of NF-κB. PARP7 loss had no effect on tumor growth in immunodeficient mice but prevented tumor development in immunocompetent settings, demonstrating immune-cell-dependent tumor suppression.\",\n      \"method\": \"PARP7 KO EO771 cells, syngeneic mouse tumor model, immunodeficient mouse controls, IFN signaling pathway analysis, NF-κB RelA ADP-ribosylation\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo immune dependence controls and mechanistic ADP-ribosylation of NF-κB RelA, single lab\",\n      \"pmids\": [\"37509350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 generates an ADP-ribosyl degron in the DNA-binding domain of AR on chromatin, recognized by the ADP-ribose reader domain of the ubiquitin E3 ligase DTX2 (not DTX3L), leading to proteasomal degradation of AR. Mathematical modeling and an AR DNA-binding mutant confirmed that PARP7 ADP-ribosylates chromatin-bound AR. This constitutes a negative feedback loop regulating modules of AR target genes.\",\n      \"method\": \"In vitro/cellular ADP-ribosylation assay, AR DNA-binding mutant, DTX2 interaction and ubiquitination assay, mathematical modeling, chromatin fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution, mutagenesis, E3 ligase identification, mathematical modeling, and cellular validation in a single rigorous study\",\n      \"pmids\": [\"40681873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 inhibits the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production by MARylating p300 and CBP. An α-helical domain in PARP7 is essential for p300/CBP interaction, MARylation, and proteasome degradation of p300/CBP. Disrupting PARP7-p300/CBP interaction prevents PARP7's suppression of IFN-β. p300/CBP reciprocally regulate PARP7 activity and nuclear localization.\",\n      \"method\": \"Chemical genetic ASCG approach (analog-sensitive), Co-IP, domain deletion, IFN-β reporter assays, PARP7 KO vs inhibitor comparison\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — chemical genetics plus Co-IP plus domain mutagenesis, preprint not yet peer reviewed\",\n      \"pmids\": [\"40631120\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 interacts with IRF3 through its catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production in a MARylation-dependent manner. Parp7-/- and Parp7H532A/H532A mice develop systemic autoimmunity and pulmonary tertiary lymphoid structures; Irf3-/-, Irf3S1/S1 (transcription-defective), or Sting-/- genetically rescues Parp7H532A/H532A autoimmunity and lung disease.\",\n      \"method\": \"Parp7-/- and ParpH532A/H532A mice, IRF3 Co-IP, genetic rescue with Irf3-/-, Irf3S1/S1, Sting-/-, autoimmunity phenotype analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic rescue lines, Co-IP mechanistic evidence, and in vivo phenotype in peer-reviewed publication\",\n      \"pmids\": [\"39969510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DTX2 is the E3 ligase responsible for degrading ADP-ribosylated PARP7, AHR, and other PARP7 substrates. Endogenous ADP-ribosylation of PARP7 and AHR is greatly induced when the ubiquitin-proteasome pathway is blocked, and AHR pathway activation promotes quantitative ADP-ribosylation of PARP7 itself (auto-MARylation) and AHR. This establishes mono-ADP-ribosylation as a degradation mark.\",\n      \"method\": \"Ubiquitin pathway blockade (proteasome inhibitors), ADP-ribosylation detection, DTX2 identification as E3 ligase, AHR pathway activation, endogenous protein level analyses\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical reconstitution of ADP-ribosyl degron pathway with E3 ligase identification and multiple genetic tools\",\n      \"pmids\": [\"41326691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 functions as a nuclear NAD+ sensor for adipogenesis: at higher nuclear NAD+ concentrations in undifferentiated preadipocytes, PARP7 undergoes auto-MARylation, which promotes its own proteasomal degradation via DTX2 and RNF114 E3 ligases. Stabilized PARP7 (when NAD+ declines post-differentiation) serves as a coregulator of C/EBPβ by stimulating p300-mediated H3K27 acetylation and C/EBPβ genomic binding. Genetic PARP7 depletion in mice reduces adipogenesis, fat mass, and milk lipid composition.\",\n      \"method\": \"NAD+ measurement, autoMARylation assay, DTX2/RNF114 KO, ChIP-seq (C/EBPβ binding, H3K27ac), PARP7 KO mice with mammary gland and fat pad phenotyping, metabolomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (biochemistry, ChIP-seq, in vivo genetics, metabolomics) with peer-reviewed publication\",\n      \"pmids\": [\"41621069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 is a proteotoxic stress sensor: during proteotoxic stress, PARP7 protein is stabilized and mono-ADP-ribosylates proteins that accumulate in cytoplasmic foci containing ubiquitin and p62, and are subsequently trafficked to aggresomes for autophagic degradation. Ubiquitination is required for efficient clearance of ADP-ribosylated proteins; PARP7 inhibition impedes accumulation of MARylated proteins in response to proteotoxic stress.\",\n      \"method\": \"Proteotoxic stress treatment, PARP7 inhibition, ADP-ribosylation immunofluorescence, aggresome imaging, ubiquitin pathway inhibition, PARP7 protein stability assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell biological and biochemical evidence, single lab, multiple methods but no in vitro reconstitution\",\n      \"pmids\": [\"40836037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 is selectively expressed in alveolar type I cells and maintains lung epithelial barrier integrity. PARP7 loss increases susceptibility to chemically induced diffuse alveolar hemorrhaging and pristane-induced lupus with increased immune infiltration. Mechanistically, PARP7 acts via AHR to control tight junction protein Occludin and xenobiotic/inflammatory gene expression in bronchial epithelial cells upon cigarette smoke or bacterial challenge.\",\n      \"method\": \"Parp7-/- mice, chemical challenge models, single-nucleus RNA-seq, air-liquid interface culture, PARP7 inhibitor treatment in human bronchial epithelial cells, AHR epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model plus snRNA-seq plus human cell culture mechanistic follow-up, single lab\",\n      \"pmids\": [\"41779776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP7 interacts with TBK1 and mediates its ADP-ribosylation in LPS-stimulated renal tubular epithelial cells, suppressing TBK1-driven inflammation. The anti-inflammatory effects of PARP7 are dependent on its catalytic residue H532. PARP7-specific overexpression in renal proximal tubular cells attenuated septic AKI in mice, while global PARP7 deletion exacerbated LPS-induced renal inflammation.\",\n      \"method\": \"Co-immunoprecipitation, H532 catalytic mutant, PARP7 overexpression in vivo, PARP7 global KO, LPS-AKI mouse model, scRNA-seq\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP substrate identification plus catalytic mutagenesis plus in vivo gain/loss-of-function, single lab\",\n      \"pmids\": [\"41952113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOCS3 crosstalks with AHR in the context of PARP7 signaling: PARP7 inhibition in SOCS3 knockout cells leads to reduced cell viability compared with wild-type cells. AHR transcriptional activity remodels the proteome upon PARP7 inhibition, including downregulation of filamins A and B concurrent with induction of the E3 ubiquitin ligase ASB2.\",\n      \"method\": \"Genome-wide CRISPR screens, multiplex quantitative proteomics, SOCS3 KO cells, PARP7 inhibitor treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased CRISPR screen plus quantitative proteomics, single lab\",\n      \"pmids\": [\"40493189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TIPARP/PARP7 is a nuclear mono-ADP-ribosyltransferase (MARylation at cysteine and acidic residues) that functions as a negative-feedback regulator of multiple transcription factors—including AHR, HIF-1α, ERα, AR, FRA1, IRF3, and LXRα/β—by MARylating them to trigger their proteasomal degradation (via E3 ligases HUWE1, DTX2, and CUL4B) or to modulate their transcriptional activity; it is transcriptionally induced by AHR and, in turn, represses AHR in a MACROD1-reversible manner; it also suppresses type I interferon production by disrupting the IRF3:CBP/p300 holocomplex in a catalysis-dependent manner; regulates microtubule stability by MARylating α-tubulin; senses nuclear NAD+ levels to control adipogenesis via a PARP7–p300–H3K27ac–C/EBPβ axis; and undergoes rapid proteasomal turnover whose rate is controlled by auto-MARylation and androgen signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TIPARP (PARP7/ARTD14) is a nuclear mono-ADP-ribosyltransferase that acts as a negative-feedback regulator of inducible transcription factors by MARylating them, predominantly on cysteine residues, to control their activity and stability [#0, #10]. Its founding role is in aryl hydrocarbon receptor (AHR) signaling: TIPARP is induced by AHR, MARylates AHR to drive its nuclear export and proteasomal degradation, and thereby dampens dioxin-responsive CYP1A1/CYP1B1 transcription; this repression requires both the zinc-finger and catalytic domains and the catalytic residue H532 in vivo [#0, #2, #15, #16]. The same writer/eraser logic extends across targets\\u2014MACROD1 reverses TIPARP-placed ADP-ribose marks on AHR [#2]\\u2014and TIPARP similarly MARylates and regulates HIF-1\\u03b1, c-Myc, ER\\u03b1, the androgen receptor, FRA1, and LXR\\u03b1/\\u03b2, in several cases nucleating ADP-ribosylation-dependent nuclear bodies that recruit E3 ligases to trigger degradation [#3, #8, #12, #13, #19, #23]. TIPARP-generated ADP-ribosyl marks are recognized as degrons by E3 ligases including HUWE1 and DTX2, and DTX2 also degrades auto-MARylated PARP7 itself, establishing mono-ADP-ribosylation as a bona fide degradation signal [#8, #23, #26]. Beyond transcription factors, TIPARP MARylates \\u03b1-tubulin to promote microtubule instability, with consequences for cancer cell motility and cortical neuronal development [#11, #18]. In innate immunity, TIPARP suppresses type I interferon production by interacting with IRF3 and disrupting the IRF3:CBP/p300 holocomplex in a catalysis-dependent manner, and its loss or catalytic inactivation causes systemic autoimmunity rescued by Irf3 or Sting deletion [#9, #25]. PARP7 protein is intrinsically short-lived, with turnover tuned by auto-MARylation and extended by androgen signaling, and it functions as a nuclear NAD+ sensor that gates adipogenesis through a p300\\u2013H3K27ac\\u2013C/EBP\\u03b2 axis [#14, #27]. Pharmacological PARP7 inhibition (RBN-2397) restores interferon signaling and drives antitumor immunity [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that TIPARP is a functional effector downstream of AHR, answering whether AHR-induced TIPARP has metabolic consequences by linking it to suppression of hepatic gluconeogenesis.\",\n      \"evidence\": \"Gain/loss-of-function in hepatic cells with glucose output, NAD+, and PGC1\\u03b1 readouts\",\n      \"pmids\": [\"20876576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic targets of TIPARP in this pathway not yet defined\", \"NAD+-depletion mechanism inferred rather than directly resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined TIPARP's core molecular identity as an auto-mono-ADP-ribosyltransferase and a negative-feedback repressor of AHR, answering how the AHR transcriptional output is constrained.\",\n      \"evidence\": \"In vitro ADP-ribosylation, RNAi, reporter assays, mutagenesis, Co-IP, and Tiparp-/- MEFs\",\n      \"pmids\": [\"23275542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MARylation sites on AHR not mapped\", \"E3 ligase mediating AHR degradation not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the substrate repertoire by showing TIPARP MARylates PEPCK, connecting AHR-driven TIPARP induction to direct modification of a gluconeogenic enzyme.\",\n      \"evidence\": \"ADP-ribosylation assays with isoform-specific PEPCK analysis and TIPARP perturbation\",\n      \"pmids\": [\"23770670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PEPCK MARylation on enzyme activity not established\", \"MARylation site not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed TIPARP repression of AHR is mechanistically independent of AHRR and that TIPARP/PARP1 ADP-ribosylation maintains pluripotency gene loci, broadening TIPARP roles beyond xenobiotic signaling.\",\n      \"evidence\": \"Double-mutant epistasis/rescue in MEFs; ChIP and loss-of-function in ES cells\",\n      \"pmids\": [\"24806346\", \"25034692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin substrates at pluripotency loci unresolved\", \"Mechanism distinguishing TIPARP vs AHRR repression not molecularly defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TIPARP MARylation of AHR and its eraser MACROD1, establishing a complete writer/eraser cycle and confirming physiological importance through dioxin-sensitive Tiparp-/- mice.\",\n      \"evidence\": \"In vitro ribosylation, Tiparp-/- mouse model, MACROD1/2 reversal assays\",\n      \"pmids\": [\"25975270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"AHR modification residues not pinpointed\", \"Whether MACROD1 reverses TIPARP marks on other substrates not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that TIPARP can positively coactivate a transcription factor (LXR\\u03b1/\\u03b2), showing its MARylation output is not uniformly repressive.\",\n      \"evidence\": \"In vitro ribosylation, reporter assays, Co-IP, peptide array, Tiparp-/- mice\",\n      \"pmids\": [\"26814197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for coactivation vs degradation outcome unresolved\", \"LXR MARylation sites not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped TIPARP's domain architecture\\u2014nuclear localization determinants, minimal catalytic region, target residue chemistry (Cys/acidic), and an auto-MARylation site (Cys39)\\u2014and showed hepatocyte-autonomous requirement for AHR control.\",\n      \"evidence\": \"Deletion/mutagenesis, inhibitor sensitivity, ETD mass spectrometry; hepatocyte-specific conditional knockout with dioxin challenge\",\n      \"pmids\": [\"30373764\", \"29873790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"C39 auto-MARylation function only modestly affects activity\", \"Catalytic mechanism and substrate selection rules incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected TIPARP \\u03b1-tubulin MARylation to cortical development, addressing whether its cytoskeletal substrate has organismal consequence.\",\n      \"evidence\": \"Tiparp-/- mice, cortical layer immunostaining, neural progenitor/migration assays, \\u03b1-tubulin MAR assay\",\n      \"pmids\": [\"31704703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal link between tubulin MARylation and layering defect not isolated\", \"\\u03b1-tubulin MAR site not mapped here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed the nuclear-body/condensate mechanism by which TIPARP recruits HUWE1 to ubiquitinate and degrade HIF-1\\u03b1, c-Myc, and ER\\u03b1, generalizing TIPARP as a degradative regulator of oncogenic transcription factors.\",\n      \"evidence\": \"Live-cell imaging, Co-IP, ubiquitination assays, ADP-ribosylation-deficient mutants, xenografts\",\n      \"pmids\": [\"32482854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Condensate composition and assembly rules incompletely defined\", \"Substrate MARylation sites not all mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined PARP7 substrate chemistry proteome-wide (cysteine-preferring MARylation, including PARP-13 and \\u03b1-tubulin), mapped additional transcription-factor substrates (ER\\u03b1, AR), and showed androgen-controlled rapid turnover\\u2014while CUL4B was implicated in AHR degradation and RBN-2397 inhibition was shown to restore interferon-driven antitumor immunity.\",\n      \"evidence\": \"Chemical-genetic analog-sensitive PARP7, proteome-wide MS site mapping, domain mutagenesis, KO phenotypes, cycloheximide chase, and RBN-2397 in tumor models\",\n      \"pmids\": [\"33475084\", \"33475085\", \"33799807\", \"34264286\", \"33572475\", \"34146543\", \"34375612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rules governing substrate selection among cysteine sites unclear\", \"Relative contribution of distinct E3 ligases (CUL4B vs others) to AHR degradation not fully resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed PARP7 catalytic activity controls its own protein levels and that inhibitor-induced PARP7 stabilization correlates with interferon induction, while CRISPR screens established AHR (and cohesin) as determinants of inhibitor sensitivity.\",\n      \"evidence\": \"Two structurally distinct inhibitors with IFN-\\u03b2 reporters and protein quantification; genome-wide CRISPR screen with AHR modulator co-treatments\",\n      \"pmids\": [\"36529140\", \"35439318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling PARP7 stabilization to IFN magnitude not fully resolved\", \"Cohesin's role in inhibitor response mechanistically undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that PARP7 MARylation can be protective (FRA1 Cys97 ADP-ribosylation blocks degradation) and that PARP7 modifies RelA/NF-\\u03baB, refining how it gates cytokine, apoptotic, and interferon programs.\",\n      \"evidence\": \"RBN-2397, FRA1 C97 mutagenesis, Co-IP, proteasome inhibition, gene profiling; PARP7 KO syngeneic vs immunodeficient tumor models\",\n      \"pmids\": [\"38011562\", \"37509350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same enzyme protects FRA1 but degrades other substrates unresolved\", \"RelA MARylation site and functional output incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the ADP-ribosyl degron pathway in molecular detail\\u2014PARP7 generates an ADP-ribose degron on chromatin-bound AR read by DTX2, DTX2 also degrades auto-MARylated PARP7 and AHR, PARP7 disrupts the IRF3:CBP/p300 holocomplex by MARylating p300/CBP and IRF3, and PARP7 acts as a nuclear NAD+ sensor and proteotoxic-stress sensor with roles in adipogenesis, lung barrier, and renal inflammation.\",\n      \"evidence\": \"In vitro reconstitution, AR DNA-binding mutants, DTX2/E3 identification, chemical genetics, Parp7-/-/Parp7H532A and rescue mouse models, ChIP-seq, and stress/aggresome cell biology\",\n      \"pmids\": [\"40681873\", \"41326691\", \"40631120\", \"39969510\", \"41621069\", \"40836037\", \"41779776\", \"41952113\", \"40493189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Unified rules determining substrate-specific degradation vs activity modulation not fully formalized\", \"Structural basis of degron recognition by reader E3 ligases incompletely defined\", \"p300/CBP holocomplex work partly from preprint pending peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TIPARP integrates its many context-dependent outputs\\u2014degradative vs protective MARylation, NAD+ sensing, condensate formation, and tissue-specific physiology\\u2014into a single predictive substrate-selection logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model predicting which substrates are degraded vs stabilized vs coactivated\", \"Structural determinants of cysteine site selection unmapped\", \"Physiological NAD+ thresholds governing sensor behavior across tissues undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 10, 11, 12, 13, 19, 23]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 8, 27]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [27, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 8, 13]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [8, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 12, 13, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 22, 24, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 23, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 13, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AHR\", \"HIF1A\", \"ESR1\", \"AR\", \"MACROD1\", \"DTX2\", \"HUWE1\", \"IRF3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}