Affinage

TIPARP

Protein mono-ADP-ribosyltransferase TIPARP · UniProt Q7Z3E1

Length
657 aa
Mass
76.2 kDa
Annotated
2026-04-28
71 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIPARP (PARP7) is a nuclear mono-ADP-ribosyltransferase that transfers single ADP-ribose units preferentially onto cysteine residues of diverse substrate proteins—including AHR, AR, ERα, LXRα/β, FRA1, PARP-13, α-tubulin, HIF-1α, p300/CBP, and PEPCK—thereby tagging them for recognition by ADP-ribose-reading E3 ubiquitin ligases (DTX2, RNF114, HUWE1) and subsequent proteasomal degradation (PMID:23275542, PMID:25975270, PMID:40681873, PMID:41326691, PMID:32482854). This ADP-ribosyl degron mechanism establishes TIPARP as a negative-feedback repressor of AHR, estrogen receptor, and type I interferon signaling; in the interferon pathway, TIPARP MARylates IRF3 and disrupts the IRF3–CBP/p300 transcriptional complex required for IFN-β production, and genetic loss of IRF3 or STING rescues the autoimmune phenotype of catalytic-dead Parp7 knock-in mice (PMID:39969510, PMID:34375612, PMID:38011562). TIPARP also functions as a nuclear NAD⁺ sensor: high NAD⁺ promotes autoMARylation that drives its own rapid proteasomal turnover (~4.5 min half-life), while declining NAD⁺ stabilizes the protein, enabling it to act as a transcriptional coregulator—for example, stimulating p300-mediated H3K27 acetylation and C/EBPβ chromatin binding during adipogenesis (PMID:41621069, PMID:33572475). In vivo, Tiparp knockout or catalytic-dead knock-in mice exhibit dramatically increased sensitivity to dioxin-induced steatohepatitis, aberrant cortical neuronal layering, and spontaneous type I interferon–driven autoimmunity, underscoring the enzyme's essential homeostatic roles (PMID:25975270, PMID:34129049, PMID:31704703, PMID:39969510).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2010 High

    Before TIPARP's enzymatic activity toward specific substrates was defined, this study revealed that TCDD-induced TIPARP consumes NAD⁺ to suppress hepatic gluconeogenesis by reducing SIRT1 activity and destabilizing PGC1α, establishing TIPARP as a metabolically active ADP-ribosyltransferase with physiological consequences.

    Evidence TIPARP overexpression and siRNA knockdown in hepatic cells with NAD⁺ measurement and glucose output assays

    PMID:20876576

    Open questions at the time
    • Direct ADP-ribosylation of PGC1α not shown
    • In vivo hepatic glucose phenotype not tested
  2. 2012 High

    The central question of what TIPARP does enzymatically was answered: TIPARP is a mono-ADP-ribosyltransferase that auto-ribosylates and ribosylates histones, interacts directly with AHR, and represses AHR transcriptional activity through a negative feedback loop requiring both the zinc-finger and catalytic domains.

    Evidence In vitro ADP-ribosylation assay, Co-IP, ChIP at CYP1A1, reporter assay with domain mutants, KO MEFs

    PMID:23275542

    Open questions at the time
    • AHR residues modified by TIPARP not mapped
    • Mechanism of AHR degradation (proteasomal vs other) not resolved
  3. 2013 Medium

    PEPCK was identified as a direct ADP-ribosylation substrate of TIPARP, extending the enzyme's substrate repertoire beyond AHR to metabolic enzymes.

    Evidence In vitro ADP-ribosylation assay and immunoprecipitation from TCDD-treated cells

    PMID:23770670

    Open questions at the time
    • Functional consequence of PEPCK MARylation on enzyme activity not determined
    • Single laboratory finding
  4. 2014 High

    TIPARP was placed at the genetic-epigenetic interface of pluripotency: Parp7 occupies key pluripotency loci and its loss decreases ground-state pluripotency, revealing a role beyond xenobiotic defense.

    Evidence ChIP-seq in embryonic stem cells, Parp7 KO ES cells, pluripotency marker analysis

    PMID:25034692

    Open questions at the time
    • Direct substrates at pluripotency loci not identified
    • Whether catalytic activity or scaffolding drives the pluripotency effect is unclear
  5. 2015 High

    The AHR feedback mechanism was sharpened: TIPARP directly MARylates AHR (not ARNT), this modification promotes AHR degradation, the de-MARylase MACROD1 reverses the modification, and Tiparp-null mice exhibit extreme dioxin sensitivity, validating the pathway in vivo.

    Evidence In vitro ADP-ribosylation with AHR/ARNT, MACROD1/2 rescue, Tiparp⁻/⁻ mouse TCDD challenge

    PMID:25975270

    Open questions at the time
    • AHR modification sites not mapped
    • Whether MACROD1 acts on AHR in vivo not tested
  6. 2016 High

    TIPARP's substrate repertoire was extended to nuclear receptors LXRα/β, where it acts as a co-activator rather than repressor, demonstrating context-dependent transcriptional outcomes of MARylation.

    Evidence In vitro ADP-ribosylation, reporter assay, Co-IP, Tiparp⁻/⁻ MEFs and mice

    PMID:26814197

    Open questions at the time
    • LXR MARylation sites not mapped
    • Whether LXR MARylation leads to degradation or activation in vivo unclear
  7. 2018 High

    The catalytic architecture and amino acid specificity were defined: cysteine 39 was identified as an auto-MARylation site by mass spectrometry, cysteine and acidic residues serve as acceptors, the minimal catalytic region spans aa 400–657, and nuclear localization requires the N-terminal sequence and zinc-finger domain.

    Evidence Deletion mutagenesis, chemical sensitivity assays, ETD mass spectrometry, subcellular fractionation

    PMID:30373764

    Open questions at the time
    • Full catalog of cysteine auto-modification sites incomplete
    • Structural basis for cysteine preference unknown
  8. 2018 High

    Hepatocyte-specific deletion confirmed the cell-autonomous role of TIPARP as an AHR repressor in liver, ruling out systemic or immune-mediated contributions to the dioxin-sensitivity phenotype.

    Evidence Conditional Tiparpᶠˡ/ᶠˡ CreAlb knockout mice, TCDD challenge, RNA-seq, metabolomics

    PMID:29873790

    Open questions at the time
    • Contribution of non-hepatocyte TIPARP to systemic dioxin effects not addressed
  9. 2019 Medium

    TIPARP was shown to MARylate α-tubulin in the developing brain; Tiparp-null mice display aberrant cortical layering and impaired neural progenitor migration, connecting TIPARP's cytoskeletal substrate to a neurodevelopmental phenotype.

    Evidence Tiparp⁻/⁻ mouse brain histology, neural stem cell migration assay, MAR-tubulin detection

    PMID:31704703

    Open questions at the time
    • Tubulin modification sites not mapped in vivo
    • Single study without independent replication
    • Causal link between tubulin MARylation and migration phenotype not formally tested
  10. 2020 High

    TIPARP was found to form ADP-ribosylation-dependent nuclear condensates that recruit HUWE1 E3 ligase and promote proteasomal degradation of HIF-1α, c-Myc, and estrogen receptor, establishing a general condensate-based degradation mechanism for oncogenic transcription factors.

    Evidence Live-cell imaging, Co-IP, ubiquitination assay, proteasome inhibitor, xenograft models

    PMID:32482854

    Open questions at the time
    • Liquid-liquid phase separation properties not biophysically characterized
    • Whether condensate formation is required for all substrates unclear
  11. 2021 High

    Multiple parallel discoveries in 2021 dramatically expanded the substrate landscape and functional contexts: PARP-13/ZAP and α-tubulin were identified as major substrates by proteome-wide chemical genetics, confirming cysteine as the predominant acceptor; ERα and AR were shown to be MARylated with functional consequences for hormone-dependent transcription; PARP7 protein half-life was measured at ~4.5 min and is extended by androgen signaling; CUL4B was shown to cooperate with TIPARP for AHR export/degradation; a catalytic-dead knock-in mouse phenocopied the full knockout; and pharmacological PARP7 inhibition restored type I IFN signaling via the STING/TBK1 pathway to suppress tumor growth.

    Evidence Chemical genetics with analog-sensitive PARP7, proteome-wide MS, CRISPR KO cells, cycloheximide chase, catalytic-mutant knock-in mice, PARP7 inhibitor in syngeneic tumor models with immune depletion

    PMID:33475084 PMID:33475085 PMID:33572475 PMID:33799807 PMID:34129049 PMID:34146543 PMID:34264286 PMID:34375612

    Open questions at the time
    • Complete cellular MARylome of PARP7 under physiological conditions not catalogued
    • Structural basis for substrate selectivity unresolved
    • Relative contributions of different E3 ligases to different substrates unclear
  12. 2022 Medium

    Auto-MARylation was established as a self-destabilizing mechanism: PARP7 inhibitors increase PARP7 protein levels, and this stabilization correlates with IFN induction. AHR loss was identified as a resistance mechanism to PARP7 inhibitors via genome-wide CRISPR screening.

    Evidence Two structurally distinct PARP7 inhibitors with western blot quantification; genome-wide CRISPR screen with AHR modulator validation

    PMID:35439318 PMID:36529140

    Open questions at the time
    • E3 ligase responsible for MARylation-dependent PARP7 turnover not identified in these studies
    • Whether AHR-independent mechanisms of inhibitor sensitivity exist
  13. 2023 High

    Site-specific MARylation of FRA1 at cysteine C97 was shown to protect FRA1 from PSMC3-mediated proteasomal degradation; loss of this modification upon PARP7 inhibition activates IRF1/IRF3-dependent apoptosis, providing a molecular mechanism for PARP7 inhibitor antitumor activity.

    Evidence PARP7 inhibitor, FRA1 C97 mutagenesis, Co-IP with PSMC3, gene expression and apoptosis assays

    PMID:38011562

    Open questions at the time
    • Whether FRA1 stabilization is the dominant antitumor mechanism or one of several parallel pathways
    • PSMC3 interaction mechanism not structurally resolved
  14. 2025 High

    The type I IFN suppression mechanism was resolved at the molecular level: PARP7 MARylates substrates in the IRF3–CBP/p300 axis to disrupt the transcriptional holocomplex required for IFN-β, and genetic epistasis with Irf3⁻/⁻, Irf3ˢ¹/ˢ¹, and Sting⁻/⁻ rescues autoimmunity in catalytic-dead mice, definitively placing PARP7 upstream of IRF3/STING.

    Evidence Parp7H532A/H532A mice crossed with Irf3⁻/⁻, Irf3ˢ¹/ˢ¹, Sting⁻/⁻; Co-IP of PARP7–IRF3 and IRF3–CBP/p300

    PMID:39969510

    Open questions at the time
    • Specific IRF3 cysteine residues MARylated not mapped
    • Whether PARP7 also acts on downstream effectors (e.g. ISG products) independently of IRF3
  15. 2025 High

    The ADP-ribosyl degron concept was biochemically reconstituted: PARP7 MARylates chromatin-bound AR on its DNA-binding domain, creating a degron recognized by DTX2's ADP-ribose reader domain, leading to non-canonical ubiquitin conjugation to ADP-ribosyl-cysteine and proteasomal degradation. DTX2 was also identified as the E3 ligase for PARP7 itself and AHR.

    Evidence Mathematical modeling, AR DNA-binding mutant rescue, DTX2 reader domain binding, in vitro ubiquitination, MS; DTX2 KO/KD with endogenous substrate validation

    PMID:40681873 PMID:41326691

    Open questions at the time
    • Whether DTX2 is the universal reader for all PARP7-generated degrons or specific to AR/AHR substrates
    • Structural details of DTX2 recognition of ADP-ribosyl-cysteine unknown
  16. 2025 High

    PARP7 was established as a nuclear NAD⁺ sensor: fluctuations in nuclear NAD⁺ tune auto-MARylation and thereby protein stability, which in turn regulates C/EBPβ-dependent adipogenesis by promoting p300-mediated H3K27 acetylation.

    Evidence NAD⁺ measurement in preadipocytes/adipocytes, in vitro autoMARylation, DTX2/RNF114 ubiquitination assay, ChIP-seq, PARP7 KO mouse fat analysis

    PMID:41621069

    Open questions at the time
    • Whether NAD⁺ sensing is specific to adipogenesis or generalizable
    • Quantitative relationship between NAD⁺ concentration and PARP7 activity not modeled
  17. 2025 Medium

    PARP7 was identified as a proteotoxic stress sensor that stabilizes under stress to MARylate substrates routed to aggresomes via ubiquitin and p62 for autophagic clearance, revealing a cytoplasmic quality-control function.

    Evidence PARP7 inhibitor during proteotoxic stress, aggresome marker immunofluorescence, ADP-ribosylation detection

    PMID:40836037

    Open questions at the time
    • Single study; identity of MARylated stress substrates not determined
    • Whether aggresome routing requires DTX2 or other specific E3 ligases unknown
    • Mechanism of PARP7 stabilization under proteotoxic stress not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of PARP7 explaining cysteine substrate selectivity, zinc-finger-mediated substrate recognition, and the interplay between nuclear condensate formation and degron-dependent degradation remains to be determined.
  • No crystal or cryo-EM structure of full-length PARP7 or PARP7–substrate complex
  • Complete in vivo cysteine MARylome not catalogued
  • Relative contributions of DTX2, RNF114, and HUWE1 to different substrates not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 12 GO:0140096 catalytic activity, acting on a protein 7 GO:0140110 transcription regulator activity 6 GO:0140299 molecular sensor activity 1
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-392499 Metabolism of proteins 6 GO:0098772 molecular function regulator activity 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AHRCUL4BDTX2EP300HUWE1IRF3MACROD1RNF114

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 TIPARP (TiPARP/ARTD14/PARP7) is a mono-ADP-ribosyltransferase that auto-ribosylates and ribosylates core histones; it directly interacts with AHR in the nucleus, co-localizes at CYP1A1, and functions as a transcriptional repressor of AHR by promoting AHR proteolytic degradation, establishing a negative feedback loop in AHR signaling. Inhibition required both the zinc-finger and catalytic domains. In vitro ADP-ribosylation assay, RNAi knockdown, overexpression reporter assay, deletion/mutagenesis studies, co-immunoprecipitation, co-localization by immunofluorescence, ChIP Nucleic Acids Research High 23275542
2010 TIPARP mediates TCDD-induced suppression of hepatic gluconeogenesis by consuming NAD+, reducing SIRT1 activation of PGC1α, and increasing PGC1α acetylation and proteasomal degradation, thereby suppressing PEPCK and G6Pase transcription. TIPARP overexpression reproduced TCDD effects while TIPARP silencing diminished them. TIPARP overexpression and siRNA knockdown in hepatic cells, glucose output assay, NAD+ measurement, qPCR, western blot Journal of Biological Chemistry High 20876576
2013 TCDD-induced TIPARP directly ADP-ribosylates PEPCK (both cytosolic and mitochondrial forms), identifying ADP-ribosylation as a novel post-translational modification of PEPCK downstream of AHR activation. In vitro ADP-ribosylation assay, immunoprecipitation of ADP-ribosylated proteins from TCDD-treated cells Journal of Biological Chemistry Medium 23770670
2015 TIPARP mono-ADP-ribosylates AHR (but not ARNT/AHR nuclear translocator); this ADP-ribosylation promotes AHR degradation. The de-ADP-ribosylase MACROD1 (but not MACROD2) reverses TIPARP's repressive effect on AHR. Loss of Tiparp in mice dramatically increases sensitivity to dioxin-induced steatohepatitis and lethality. In vitro ADP-ribosylation assay with AHR and ARNT substrates, MACROD1/2 rescue experiments, Tiparp−/− mouse model with TCDD challenge Journal of Biological Chemistry High 25975270
2016 TIPARP mono-ADP-ribosylates LXRα and LXRβ and acts as a co-activator of LXR transcriptional activity; the zinc-finger and catalytic domains are required. TIPARP interacts with LXRs via an N-terminal sequence (aa 209–236). MACROD1 (not MACROD2) interacts with LXRs in a TIPARP-dependent manner and prevents the TIPARP-dependent increase in LXR activity. In vitro ADP-ribosylation assay, reporter gene assay, co-immunoprecipitation, peptide array, immunofluorescence co-localization, Tiparp−/− MEFs and mice Biochemical Journal High 26814197
2014 Parp7 occupies key pluripotency gene loci (Nanog, Pou5f1, Sox2, Stella, Tet1, Zfp42) in embryonic stem cells; loss of Parp7 (or inhibition of ADP-ribosylating activity) decreases ground-state pluripotency and increases propensity to differentiate, placing Parp7 at the genetic-epigenetic interface of pluripotency networks. ChIP-seq, Parp1/Parp7 KO ES cells, inhibitor treatment, pluripotency marker analysis Nucleic Acids Research High 25034692
2018 Nuclear localization of TIPARP depends on a short N-terminal sequence and its zinc-finger domain. The minimum catalytically active region spans aa 400–657. TIPARP activity is sensitive to iodoacetamide and hydroxylamine (implicating cysteines and acidic residues as acceptors). Mass spectrometry and ETD identified cysteine 39 as an auto-ADP-ribosylation site. TIPARP mono-ADP-ribosylates AHR at multiple peptides. Both catalytic activity and zinc-finger domain are required for AHR repression in cells. Deletion mutagenesis, in vitro ADP-ribosylation assay, chemical sensitivity assays (MIBG, iodoacetamide, hydroxylamine), mass spectrometry with ETD fragmentation, subcellular fractionation/immunofluorescence Biochemical Journal High 30373764
2018 Hepatocyte-specific deletion of TIPARP (Tiparpfl/fl CreAlb mice) is sufficient to increase sensitivity to dioxin-induced steatohepatitis and lethality, demonstrating that TIPARP acts as a negative regulator of AHR in hepatocytes. Tiparp-null mice show augmented AHR target gene expression and altered lipid/amino acid metabolism. Conditional Cre-lox knockout mouse model, TCDD challenge, histology, serum ALT, RNA-seq, metabolomics Toxicological Sciences High 29873790
2020 TiPARP forms 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. Similarly, TiPARP promotes degradation of c-Myc and estrogen receptor, establishing TiPARP as a negative-feedback regulator of multiple oncogenic transcription factors. Live-cell imaging of nuclear condensates, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, xenograft mouse models PNAS High 32482854
2021 PARP7 is a negative regulator of nucleic acid sensing in tumor cells; its inhibition restores type I interferon (IFN) signaling responses to nucleic acids, directly inhibits cancer cell proliferation, and activates antitumor immunity. The mechanism is dependent on inducing type I IFN signaling in tumor cells, and antitumor effects require STING pathway and TBK1 activity. PARP7 inhibitor (RBN-2397) in cancer cell lines and mouse models (xenograft and syngeneic), IFN pathway reporter assays, immune cell depletion experiments Cancer Cell High 34375612
2021 PARP-13 (ZAP), a critical antiviral innate immune regulator, is a major substrate of PARP-7-mediated MARylation; PARP-7 preferentially MARylates PARP-13 on cysteine residues within its RNA-binding zinc-finger domain. Proteome-wide analysis reveals cysteine as the predominant MARylation acceptor for PARP-7. Chemical genetics (analog-sensitive PARP-7), proximity labeling, proteome-wide ADP-ribosylation site profiling by mass spectrometry eLife High 33475084
2021 PARP-7 MARylates α-tubulin to promote microtubule instability in ovarian cancer cells, regulating cancer cell growth and motility. PARP-7 substrates were identified using an NAD+ analog-sensitive approach coupled with mass spectrometry. NAD+ analog-sensitive PARP-7 coupled with mass spectrometry, cell growth/migration assays with PARP-7 depletion, gene expression analysis eLife High 33475085
2021 PARP7 mono-ADP-ribosylates estrogen receptor α (ERα); the modification is mapped by mass spectrometry to peptides in the ligand-independent transactivation domain, and the ERα hinge region is required for PARP7-dependent MARylation. PARP7 overexpression reduces ligand-dependent ERα signaling; PARP7 KO MCF-7 cells show increased ERα target gene expression and proliferation. Co-immunoprecipitation, mass spectrometry, truncated ERα variant experiments, PARP7 KO cells (CRISPR), reporter assays Cells High 33799807
2021 PARP7 protein stability is regulated post-transcriptionally by androgen signaling: PARP7 has an extremely short half-life (~4.5 min) that is extended to ~25.6 min by androgen/AR signaling in prostate cancer cells. Androgen-dependent stabilization leads to nuclear accumulation of PARP7. Mutations in the catalytic domain, zinc-finger, or WWE domains each reduce the degradation rate of PARP7. Cycloheximide chase assay, androgen treatment, domain-mutation analysis, subcellular fractionation Cells High 33572475
2021 PARP7 mono-ADP-ribosylates the androgen receptor (AR) in an agonist-conformation- and nuclear-localization-dependent manner. The PARP7 Cys3His1 zinc finger (ZF) is critical for AR ADP-ribosylation and for PARP7 nuclear import; ZF mutations abrogate PARP7 enhancement of AR-dependent transcription of MYBPC1 without reducing catalytic activity or AR binding. In vitro ADP-ribosylation assay, ZF mutagenesis, nuclear import assays, reporter gene assay, AR conformation mutants Biochemical Journal High 34264286
2021 CUL4B (E3 ubiquitin ligase) and TiPARP cooperate to promote TCDD-activated AHR nuclear export and proteasomal degradation; knockdown of TiPARP in CUL4B-null MEFs completely abolished AHR degradation after TCDD, demonstrating that TiPARP is required for AHR nuclear export downstream of CUL4B. MEF cell lines with CUL4B deletion and TiPARP siRNA knockdown, AHR protein level/localization assay, AHR transcriptional activity measurement Journal of Biological Chemistry High 34146543
2021 Loss of TIPARP catalytic activity (H532A knock-in mouse) increases sensitivity to TCDD-induced hepatotoxicity and lethality to the same degree as full TIPARP loss, confirming that the ADP-ribosyltransferase activity of TIPARP is the mechanistic basis for its AHR repressor function in vivo. Catalytic mutant knock-in mouse (TiparpH532A), TCDD challenge, RNA-seq, histology, ALT measurements Toxicological Sciences High 34129049
2023 PARP7 MARylates the AP-1 transcription factor FRA1 on cysteine C97; this modification protects FRA1 from proteasomal degradation via PSMC3. Loss of FRA1 ADP-ribosylation (by PARP7 inhibition or C97 mutation) promotes IRF1- and IRF3-dependent cytokine and proapoptotic gene expression, culminating in CASP8-mediated apoptosis. PARP7 inhibitor (RBN-2397), site-directed mutagenesis of FRA1 C97, co-immunoprecipitation, proteasome inhibition, gene expression analysis PNAS High 38011562
2019 Loss of Tiparp in mice causes aberrant cortical layering, particularly increased cell density in upper cortical layers with predominant effects on GABAergic neuron distribution, reduced neural progenitor cell proliferation, and slower neural stem cell migration. α-tubulin mono-ADP-ribosylation levels are reduced in Tiparp−/− cells, suggesting TIPARP MARylates α-tubulin during cortical development. Tiparp−/− mouse histological analysis, cell counting, neural stem cell migration assay, MAR-tubulin detection eNeuro Medium 31704703
2022 AHR loss was identified as a mechanism of resistance to PARP7 inhibitor RBN-2397 via a genome-wide CRISPR screen; multiple cohesin complex components also modulate RBN-2397 response. AHR activators and inhibitors modulate cellular response to PARP7 inhibition, establishing AHR as a key determinant of PARP7 inhibitor sensitivity. Genome-wide CRISPR screen, AHR modulator experiments Molecular Cancer Therapeutics Medium 35439318
2022 PARP7 catalytic activity regulates its own protein levels (autoMARylation promotes instability); treatment with PARP7 inhibitors increases PARP7 protein levels in cells, and this increase correlates with the magnitude of type I interferon gene expression. PARP7 inhibitor treatment (KMR-206 and RBN-2397), western blot for PARP7 protein levels, IFN-β reporter assays Cell Chemical Biology Medium 36529140
2025 PARP7 inhibits type I IFN production by directly interacting with IRF3 through its catalytic domain and disrupting the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production. This is MARylation-dependent. Irf3−/− or transcription-defective Irf3S1/S1 or Sting−/− rescues Parp7H532A/H532A autoimmunity and lung disease, placing PARP7 upstream of IRF3 and STING. Parp7−/− and Parp7H532A/H532A mice, genetic epistasis with Irf3−/−/Irf3S1/S1/Sting−/− rescue, Co-IP of PARP7-IRF3 and IRF3-CBP/p300, MARylation assays Journal of Experimental Medicine High 39969510
2025 PARP7 generates an ADP-ribosyl degron on the DNA-binding domain of AR (chromatin-bound AR), which is recognized by the ADP-ribose reader domain of the E3 ubiquitin ligase DTX2, leading to non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and proteasomal degradation of AR. Mathematical modeling and an AR DNA-binding mutant confirmed that PARP7 preferentially ADP-ribosylates chromatin-bound AR. Mathematical modeling, AR DNA-binding mutant rescue, DTX2 reader domain binding assay, in vitro ubiquitination assay, mass spectrometry EMBO Journal High 40681873
2025 PARP7 functions as a nuclear NAD+ sensor: at higher nuclear NAD+ concentrations (in undifferentiated preadipocytes), PARP7 is catalytically active for autoMARylation; as NAD+ declines upon differentiation, autoMARylation decreases. AutoMARylation promotes PARP7 instability via the E3 ligases DTX2 and RNF114 through the ubiquitin-proteasome pathway. Stabilized PARP7 serves as a coregulator of C/EBPβ by stimulating p300-mediated H3K27ac and C/EBPβ genome-wide binding. NAD+ measurement in preadipocytes vs adipocytes, in vitro autoMARylation assay, DTX2/RNF114 Co-IP/ubiquitination assay, ChIP-seq for C/EBPβ and H3K27ac, PARP7 KO mouse model with fat-pad analysis Cell Reports High 41621069
2025 PARP7 is a proteotoxic stress sensor: during proteotoxic stress PARP7 is stabilized and MARylates substrates that accumulate in cytoplasmic foci containing ubiquitin and p62, subsequently trafficked to aggresomes and degraded by autophagy. Ubiquitination is required for this process. PARP7 inhibition impedes accumulation of MARylated proteins during stress. PARP7 inhibitor treatment during proteotoxic stress, immunofluorescence for aggresome markers, ADP-ribosylation detection, ubiquitination pathway blockade EMBO Journal Medium 40836037
2025 p300 and CBP are direct nuclear PARP7 substrates; PARP7 contains an α-helical domain essential for p300/CBP interaction, MARylation, and their proteasomal degradation. Disrupting PARP7–p300/CBP interaction prevents PARP7's suppression of IFNβ. PARP7 inhibitors induce IFNβ via two mechanisms: inhibiting MARylation of p300/CBP (loss-of-function) and stabilizing the PARP7–p300/CBP complex (gain-of-function). Analog-sensitive chemical genetic approach, Co-IP, domain deletion mutagenesis, proteasome inhibition, IFNβ reporter assay bioRxiv (preprint)preprint Medium 40631120
2025 DTX2 is the E3 ligase responsible for degrading ADP-ribosylated PARP7, AHR, and other PARP7 substrates; mono-ADP-ribosylation by PARP7 acts as a degradation mark. Blocking the ubiquitin/proteasome pathway reveals high levels of endogenous ADP-ribosylation by PARP7 on PARP7 itself and AHR. Ubiquitin pathway blockade, mass spectrometry identification of ADP-ribosylated substrates, DTX2 KO/knockdown, Co-IP EMBO Journal High 41326691
2024 TIPARP interacts with EIF3B (eukaryotic translation initiation factor 3 subunit B) through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp or inhibition with a TIPARP inhibitor (XG-04-B1) restores mitochondrial homeostasis in ischemic stroke mice. EIF3B is identified as a direct target of TIPARP. Co-immunoprecipitation/interaction assay, Tiparp knockdown and inhibitor treatment in ischemic stroke mouse model, mitochondrial function assays Pharmacological Research Medium 39547463
2024 METTL16 directly binds TIPARP mRNA and enhances its m6A modification, thereby stabilizing TIPARP transcripts and upregulating TIPARP protein expression. This METTL16-m6A-TIPARP axis promotes cerebral ischemia-reperfusion injury; TIPARP overexpression abolishes protective effects of METTL16 knockdown. RIP assay, m6A-RIP-qPCR, cycloheximide chase for protein stability, MCAO mouse model, rescue experiments with TIPARP overexpression International Journal of General Medicine Medium 42004240
2017 AHR directly regulates TIPARP expression by binding to two genomic regions containing multiple AHR response elements (AHREs) at the TIPARP promoter; AHR also co-regulates TIPARP-AS1, a cis long non-coding RNA upstream of TIPARP exon 1, via a proximal AHRE cluster. Reporter gene and deletion assays, ChIP for AHR at TIPARP promoter, qPCR for TIPARP and TIPARP-AS1 Biochemical and Biophysical Research Communications Medium 29274782

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Novel insight into circular RNA HECTD1 in astrocyte activation via autophagy by targeting MIR142-TIPARP: implications for cerebral ischemic stroke. Autophagy 315 29938598
2008 The DDF1 transcriptional activator upregulates expression of a gibberellin-deactivating gene, GA2ox7, under high-salinity stress in Arabidopsis. The Plant journal : for cell and molecular biology 240 18643985
2019 Circular RNA TLK1 Aggravates Neuronal Injury and Neurological Deficits after Ischemic Stroke via miR-335-3p/TIPARP. The Journal of neuroscience : the official journal of the Society for Neuroscience 177 31311824
2012 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic acids research 140 23275542
2021 PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer cell 138 34375612
2010 Identification of the aryl hydrocarbon receptor target gene TiPARP as a mediator of suppression of hepatic gluconeogenesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin and of nicotinamide as a corrective agent for this effect. The Journal of biological chemistry 96 20876576
2020 TiPARP forms nuclear condensates to degrade HIF-1α and suppress tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 81 32482854
2003 Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31. International journal of oncology 74 12851707
2021 Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets. eLife 71 33475084
2014 ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells. Nucleic acids research 66 25034692
2021 Identification of PARP-7 substrates reveals a role for MARylation in microtubule control in ovarian cancer cells. eLife 64 33475085
2015 Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality. The Journal of biological chemistry 62 25975270
2011 Overexpression of FTL1/DDF1, an AP2 transcription factor, enhances tolerance to cold, drought, and heat stresses in Arabidopsis thaliana. Plant science : an international journal of experimental plant biology 61 21421412
2018 Characterization of TCDD-inducible poly-ADP-ribose polymerase (TIPARP/ARTD14) catalytic activity. The Biochemical journal 56 30373764
2016 TCDD-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) mono-ADP-ribosylates and co-activates liver X receptors. The Biochemical journal 52 26814197
2021 PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells. Cells 50 33799807
2024 Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition. Journal of medicinal chemistry 49 38456618
2014 Aryl hydrocarbon receptor repressor and TiPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. International journal of molecular sciences 49 24806346
2023 PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America 36 38011562
2022 Structurally distinct PARP7 inhibitors provide new insights into the function of PARP7 in regulating nucleic acid-sensing and IFN-β signaling. Cell chemical biology 36 36529140
2021 Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling. Cells 30 33572475
2021 Roles of the ubiquitin ligase CUL4B and ADP-ribosyltransferase TiPARP in TCDD-induced nuclear export and proteasomal degradation of the transcription factor AHR. The Journal of biological chemistry 30 34146543
2021 PARP7 mono-ADP-ribosylates the agonist conformation of the androgen receptor in the nucleus. The Biochemical journal 26 34264286
2023 Loss of PARP7 Increases Type I Interferon Signaling in EO771 Breast Cancer Cells and Prevents Mammary Tumor Growth by Increasing Antitumor Immunity. Cancers 24 37509350
2022 A Whole-Genome CRISPR Screen Identifies AHR Loss as a Mechanism of Resistance to a PARP7 Inhibitor. Molecular cancer therapeutics 24 35439318
2018 Hepatocyte-Specific Deletion of TIPARP, a Negative Regulator of the Aryl Hydrocarbon Receptor, Is Sufficient to Increase Sensitivity to Dioxin-Induced Wasting Syndrome. Toxicological sciences : an official journal of the Society of Toxicology 24 29873790
2017 The aryl hydrocarbon receptor regulates the expression of TIPARP and its cis long non-coding RNA, TIPARP-AS1. Biochemical and biophysical research communications 24 29274782
2013 Aryl hydrocarbon receptor activation by dioxin targets phosphoenolpyruvate carboxykinase (PEPCK) for ADP-ribosylation via 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiPARP). The Journal of biological chemistry 24 23770670
2019 TCDD-Inducible Poly-ADP-Ribose Polymerase (TIPARP), A Novel Therapeutic Target Of Breast Cancer. Cancer management and research 21 31695491
2023 Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells. Cancer research communications 17 37077937
2025 PARP7 as a new target for activating anti-tumor immunity in cancer. EMBO molecular medicine 16 40128585
2024 Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment. Journal of medicinal chemistry 16 38912753
2023 Chorioallantoic membrane assay revealed the role of TIPARP (2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase) in lung adenocarcinoma-induced angiogenesis. Cancer cell international 14 36841751
2022 Reduced Colonic Mucosal Injury in 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Poly ADP-Ribose Polymerase (TIPARP/PARP7)-Deficient Mice. International journal of molecular sciences 14 35055106
2021 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)-Inducible Poly-ADP-Ribose Polymerase (TIPARP/PARP7) Catalytic Mutant Mice (TiparpH532A) Exhibit Increased Sensitivity to TCDD-Induced Hepatotoxicity and Lethality. Toxicological sciences : an official journal of the Society of Toxicology 14 34129049
2025 PARP7 Inhibitors and AHR Agonists Act Synergistically across a Wide Range of Cancer Models. Molecular cancer therapeutics 12 39313957
2021 LncRNA XIST Promoted OGD-Induced Neuronal Injury Through Modulating/miR-455-3p/TIPARP Axis. Neurochemical research 12 33738662
2019 Loss of Tiparp Results in Aberrant Layering of the Cerebral Cortex. eNeuro 12 31704703
2023 Discovery of Highly Selective PARP7 Inhibitors with a Novel Scaffold for Cancer Immunotherapy. Journal of medicinal chemistry 11 38059836
2019 3-Methylcholanthrene Induces Chylous Ascites in TCDD-Inducible Poly-ADP-Ribose Polymerase (Tiparp) Knockout Mice. International journal of molecular sciences 11 31083300
2025 PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease. The Journal of experimental medicine 9 39969510
2024 New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke. Pharmacological research 9 39547463
2025 CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor-driven proteome through PARP7 activity. Proceedings of the National Academy of Sciences of the United States of America 8 40493189
2025 Parp7 generates an ADP-ribosyl degron that controls negative feedback of androgen signaling. The EMBO journal 8 40681873
2023 PARP7 Inhibition: A Promising Pathway to Advancements in Cancer Therapy. ACS medicinal chemistry letters 8 37736186
2021 Knockdown of lncRNA SNHG15 Ameliorates Oxygen and Glucose Deprivation (OGD)-Induced Neuronal Injury via Regulating the miR-9-5p/TIPARP Axis. Biochemical genetics 8 34453220
2022 TIPARP is involved in the regulation of intraocular pressure. Communications biology 7 36536086
2018 Methods to Study TCDD-Inducible Poly-ADP-Ribose Polymerase (TIPARP) Mono-ADP-Ribosyltransferase Activity. Methods in molecular biology (Clifton, N.J.) 7 30097864
2024 Discovery of highly potent PARP7 inhibitors for cancer immunotherapy. Bioorganic chemistry 5 38781669
2025 Loss of Parp7 increases type I interferon signalling and reduces pancreatic tumour growth by enhancing immune cell infiltration. Frontiers in immunology 4 39867896
2024 Unleashing viral mimicry: A combinatorial strategy to enhance the efficacy of PARP7 inhibitors. BioEssays : news and reviews in molecular, cellular and developmental biology 4 39502005
2025 NAD + Sensing by PARP7 Regulates the C/EBPβ-Dependent Transcription Program in Adipose Tissue In Vivo. bioRxiv : the preprint server for biology 3 40291749
2025 The IFN I response in tumor cells is shaped by PARP7-p300/CBP interactions through distinct loss- and gain-of-function mechanisms. bioRxiv : the preprint server for biology 3 40631120
2023 Quantification of PARP7 Protein Levels and PARP7 Inhibitor Target Engagement in Cells Using a Split Nanoluciferase System. Methods in molecular biology (Clifton, N.J.) 3 36515849
2025 PARP7: an Emerging Therapeutic Target-Insights into Biological Functions and Advances in Small-Molecule Inhibitor Development. Journal of medicinal chemistry 2 40994152
2025 Advances in TCDD-inducible poly(ADP-ribose) polymerase (TiPARP/PARP7) research: From molecular mechanisms to therapeutic applications. Biochemical pharmacology 2 41365471
2011 [Genetic analysis and gene mapping of DDF1, a pleiotropic gene involving in both vegetable and reproductive growth in rice]. Yi chuan = Hereditas 2 22207384
2026 High PARP7 Expression is Associated with Higher Estrogen Response and Immune Suppression but Less Cell Proliferation and Better Survival in Breast Cancer. Annals of surgical oncology 1 41712159
2025 PARP7 is a proteotoxic stress sensor that labels proteins for degradation. The EMBO journal 1 40836037
2024 RBN-2397, a PARP7 Inhibitor, Synergizes with Paclitaxel to Inhibit Proliferation and Migration of Ovarian Cancer Cells. bioRxiv : the preprint server for biology 1 39229139
2023 The association between TIPARP gene polymorphisms rs2665390 and ovarian cancer susceptibility. Gynecologic oncology reports 1 37091214
2026 Identification of a Two-Gene Biomarker Correlated with Sensitivity to Combined PARP7 Inhibition and AHR Activation in Cancer Cells. Cancer research communications 0 41295982
2026 NAD+ sensing by PARP7 regulates the C/EBPβ-dependent transcription program during adipogenesis. Cell reports 0 41621069
2026 Design and Synthesis of KRASG12C Inhibitors for Antitumor Evaluation Harboring Combination Therapy with Nrf2, PARP-7, and Pan-USP Inhibitors to Alleviate Drug Resistance Synergistically. Journal of medicinal chemistry 0 41633936
2026 Novel Compounds as TIPARP Inhibitors for Treating Head and Neck Squamous Cell Carcinoma (HNSCC). ACS medicinal chemistry letters 0 41704360
2026 PARP7 protects the lung epithelial barrier from diverse environmental threats. Proceedings of the National Academy of Sciences of the United States of America 0 41779776
2026 PARP7 inhibition and a STING agonist potentiate radiation-induced immunogenicity in glioblastoma. Oncoimmunology 0 41979168
2026 METTL16 Promotes Cerebral Ischemia-Reperfusion Injury via m6A-Dependent Upregulation of TIPARP. International journal of general medicine 0 42004240
2025 PARP7 Suppresses Radiation-induced Necroptosis and Abscopal Immunity. Research square 0 41282221
2025 Ubiquitin pathway blockade reveals endogenous ADP-ribosylation marking PARP7 and AHR for degradation. The EMBO journal 0 41326691
2025 PARP7 and aryl hydrocarbon receptor differentially regulate mammary cancer cell proliferation and STING-induced type I interferon signalling. Cellular oncology (Dordrecht, Netherlands) 0 41432900