{"gene":"PARP14","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2010,"finding":"PARP-14 functions as a transcriptional switch for STAT6-dependent gene activation: under non-stimulating conditions, PARP-14 recruits HDAC2 and HDAC3 to IL-4-responsive promoters to repress transcription; upon IL-4 stimulation, PARP-14 ADP-ribosylates the HDACs, causing their release, promoting STAT6 binding to target promoters, and enabling coactivator with HAT activity to replace the repressor complex.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, promoter reporter assays, ADP-ribosylation assays in T cells/B cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional reporter assays in a single focused study with multiple orthogonal methods","pmids":["21081493"],"is_preprint":false},{"year":2013,"finding":"PARP14 (ARTD8) macrodomains 2 and 3 act as readers of mono-ADP-ribosylation: crystal structures and isothermal titration calorimetry confirmed their interaction with ADP-ribose, and they specifically recognized mono-ADP-ribosylated ARTD10 and its substrate Ran, but not poly-ADP-ribosylated ARTD1, distinguishing them from the macroH2A1.1 macrodomain.","method":"Crystal structure determination, isothermal titration calorimetry, co-localization and binding assays in vitro and in cells","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with ITC and cellular validation, multiple orthogonal methods in one study","pmids":["23473667"],"is_preprint":false},{"year":2009,"finding":"PARP-14 mediates IL-4-dependent survival signaling in primary B cells: PARP-14-deficient mice show increased apoptosis in IL-4-treated B cells including after DNA damage, and PARP-14 regulates IL-4-induced expression of gene products controlling survival, proliferation, and lymphomagenesis. PARP-14 physically interacts with the IL-4-induced transcription factor STAT6.","method":"Knockout mouse studies, apoptosis assays, gene expression analysis, binding assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with defined cellular phenotype, replicated across multiple assays","pmids":["19147789"],"is_preprint":false},{"year":2011,"finding":"PARP14 is required for IL-4-induced enhancement of glycolysis in B cells, and this glycolytic activity mediates IL-4-dependent pro-survival signaling. PARP14 deficiency delayed B lymphomagenesis and reversed the block to B-cell maturation driven by the Myc oncogene; restoration of AMP-activated protein kinase activity rescued glycolytic activity and prosurvival signaling in Parp14-deficient B cells.","method":"Parp14 knockout mice, glycolysis assays, AMPK activity assays, lymphoma mouse models, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple in vivo and in vitro functional readouts, epistasis via AMPK rescue","pmids":["21911376"],"is_preprint":false},{"year":2012,"finding":"PARP14 is a downstream effector of JNK2-dependent pro-survival signaling in multiple myeloma: JNK2 constitutive activation maintains PARP14 expression; PARP14 promotes myeloma cell survival by physically binding and inhibiting the pro-apoptotic kinase JNK1; overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown.","method":"Loss-of-function (siRNA/shRNA) studies, overexpression rescue experiments, co-immunoprecipitation (PARP14-JNK1 interaction), apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating PARP14-JNK1 interaction, genetic epistasis via rescue experiments, multiple cell lines","pmids":["23045269"],"is_preprint":false},{"year":2015,"finding":"PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1: PARP14 suppresses JNK1 kinase activity, which prevents JNK1-mediated phosphorylation of PKM2 at Thr365 that would otherwise activate PKM2 and reduce aerobic glycolysis. This PARP14-JNK1-PKM2 axis links anti-apoptotic signaling to metabolic reprogramming.","method":"Loss-of-function studies (siRNA/shRNA) in vitro and in vivo (xenograft), PKM2 phosphorylation assays, glycolysis measurements, apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro loss-of-function, specific phosphorylation site identified, multiple orthogonal methods","pmids":["26258887"],"is_preprint":false},{"year":2015,"finding":"PARP14 promotes homologous recombination DNA repair and protects against replication stress: PARP14 interacts with PCNA and promotes replication of DNA lesions and common fragile sites; PARP14 depletion results in reduced homologous recombination, persistent RAD51 foci, hypersensitivity to DNA damaging agents, and accumulation of DNA strand breaks.","method":"Co-immunoprecipitation (PARP14-PCNA), siRNA knockdown, RAD51 foci assays, HR reporter assays, comet assays, sensitivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional HR assays, and multiple phenotypic readouts in a single focused study","pmids":["25753673"],"is_preprint":false},{"year":2016,"finding":"PARP14 induces ADP-ribosylation of STAT1, which suppresses STAT1 phosphorylation; PARP9 antagonizes this by suppressing PARP14-mediated ADP-ribosylation of STAT1. Mutations at the PARP14-dependent ADP-ribosylation sites on STAT1 lead to increased STAT1 phosphorylation. PARP14 and PARP9 thus cross-regulate macrophage activation via opposing effects on STAT1 activity.","method":"Global proteomic analysis, ADP-ribosylation assays, site-directed mutagenesis of STAT1, PARP14/PARP9 silencing in primary macrophages, phosphorylation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ADP-ribosylation site mapping with mutagenesis validation, multiple macrophage models, orthogonal proteomic and biochemical methods","pmids":["27796300"],"is_preprint":false},{"year":2014,"finding":"PARP-14 selectively regulates macrophage tissue factor (TF) mRNA stability by forming a ribonucleoprotein complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved AU-rich element in the TF mRNA 3' UTR; PARP-14 deficiency leads to increased TF mRNA stability, TF expression, and TF activity in macrophages, while TNFα mRNA (also regulated by TTP) is unaffected.","method":"Ribonucleoprotein immunoprecipitation, biotinylated RNA pulldown, PARP14-knockout macrophages (in vitro and in vivo), mRNA stability assays, TF functional coagulation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNP-IP and RNA pulldown demonstrate direct complex, validated in vivo in knockout mice with functional readout","pmids":["25293769"],"is_preprint":false},{"year":2018,"finding":"PARP14 translocates into the nucleus of macrophages upon inflammatory stimulation, binds a group of IFN-stimulated gene (ISG)-encoded proteins by quantitative mass spectrometry, and is required for their nuclear accumulation. PARP14 depletion attenuates IFN regulatory factor 3-dependent antiviral gene transcription including Ifnb1, reducing IFN-β production.","method":"Nuclear/cytoplasmic fractionation, quantitative mass spectrometry for interactors, siRNA knockdown, RT-qPCR, Salmonella infection assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct fractionation/localization with functional consequence, quantitative MS interactome, multiple orthogonal methods","pmids":["29500242"],"is_preprint":false},{"year":2018,"finding":"Using a chemical genetics approach (orthogonal NAD+ analog with engineered PARP14 variant) combined with BioID proximity-dependent labeling, 114 PARP14-specific MARylation substrates were identified, enriched for RNA regulatory proteins. PARP13 was identified as a direct PARP14 MARylation substrate, modified on several acidic amino acids.","method":"Chemical genetics (orthogonal NAD+ analog), BioID proximity labeling, mass spectrometry substrate identification, in vitro ADP-ribosylation assays","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — two orthogonal unbiased methods for substrate identification, in vitro validation of PARP13 as substrate","pmids":["30247868"],"is_preprint":false},{"year":2013,"finding":"PARP14 catalytic activity promotes Th17 cell differentiation and is required for IL-4-dependent IgE antibody responses (B cell-intrinsic) and IgA antibody responses (predominantly B cell-extrinsic involving Th17 cells and CD103+ dendritic cells). PARP14 enhances expression of RORα, Runx1, and Smad3 after T cell activation.","method":"PARP14-deficient mice, antibody isotype measurements, flow cytometric analysis of Th17 cells and DC populations, gene expression analysis, catalytic mutant studies","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mice with multiple functional immune readouts, direct evidence for catalytic activity requirement","pmids":["23956424"],"is_preprint":false},{"year":2017,"finding":"PARP14 catalyzes auto-ADP-ribosylation (auto-ribosylation), and co-crystal structures of PARP14 with inhibitor compounds showed that small-molecule inhibitors bind to the NAD+-binding site of the catalytic domain, acting as NAD+-competitive inhibitors.","method":"Purified PARP14 protein, RapidFire high-throughput mass spectrometry auto-ribosylation assay, [3H]NAD+ immunoradiometric assay, co-crystal structure determination, cell-based protein stabilization assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of PARP14 catalytic domain with inhibitors, in vitro enzymatic assays, single laboratory","pmids":["28315326"],"is_preprint":false},{"year":2023,"finding":"PARP14 is a dual-function enzyme with both mono-ADP-ribosyl transferase and ADP-ribosyl hydrolase activities: the macrodomain 1 of PARP14 acts as an active ADP-ribosyl hydrolase (de-MARylase). Inactivation of macrodomain 1 (hydrolase-dead mutant) results in marked increase of protein mono-ADP-ribosylation in human cells, including auto-MARylation of PARP14 and MARylation of antiviral PARP13. The SARS-CoV-2 Nsp3 Mac1 macrodomain efficiently reverses PARP14 ADP-ribosylation in vitro and in cells.","method":"In vitro ADP-ribosylation and hydrolysis assays, macrodomain 1 mutagenesis, cellular MARylation detection with improved antibodies, SARS-CoV-2 Mac1 reversal assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with mutagenesis validation, cellular phenotype confirmation, multiple orthogonal methods across substrates","pmids":["37703374"],"is_preprint":false},{"year":2023,"finding":"PARP14 macrodomain 1 and PARP9 macrodomain 1 both display ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains; this activity does not degrade poly(ADP-ribose). The F926A mutation of PARP14 and F244A of PARP9 strongly reduced glycohydrolase activity, revealing mechanistic homology to the SARS-CoV-2 Nsp3 Mac1 domain.","method":"Biochemical ADP-ribosylation hydrolysis assays, site-directed mutagenesis (F926A PARP14, F244A PARP9), comparison with PARP1 poly-ADP-ribose substrate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis, mechanistically informative negative result (no poly-ADP-ribose degradation), single lab","pmids":["37507011"],"is_preprint":false},{"year":2020,"finding":"PARP14 is a critical co-factor of MRE11 at reversed replication forks in BRCA-deficient cells: PARP14 is recruited to nascent DNA upon replication stress, and through its catalytic (mono-ADP-ribosyltransferase) activity mediates MRE11 engagement. The KU complex binds reversed forks and recruits the PARP14-MRE11 complex, which initiates partial resection to release KU and allow long-range resection by EXO1. Loss or inhibition of PARP14 suppresses MRE11-mediated fork degradation and ssDNA gap accumulation.","method":"iPOND (isolation of proteins on nascent DNA), proximity ligation assays, PARP14 inhibition/knockout, DNA fiber assays, S1 nuclease gap assays, MRE11 co-immunoprecipitation, KU interaction assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — iPOND for direct nascent DNA recruitment, Co-IP for complex formation, catalytic inhibitor validation, multiple epistatic relationships established","pmids":["36030235"],"is_preprint":false},{"year":2024,"finding":"IFNγ-induced ADP-ribosylation in cells depends on PARP14 catalytic activity; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms (not transcriptional) and both localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins. PARP14 itself and DTX3L are ADP-ribosylation targets; the SARS-CoV-2 Nsp3 macrodomain reverses these modifications.","method":"IFNγ treatment with mono-ADPr antibody detection, PARP14 catalytic mutant, siRNA knockdown of PARP9/DTX3L, immunofluorescence, western blot for protein levels, Nsp3 Mac1 reversal","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, two independent simultaneous publications (PMID 38834853 and 38834852) with convergent findings","pmids":["38834853","38834852"],"is_preprint":false},{"year":2021,"finding":"PARP14 regulates cyclin D1 expression at the mRNA level via cyclin D1 3'UTR stability: depletion of PARP14 decreases cyclin D1 protein levels, leading to G1 cell-cycle arrest in cells with functional RB pathway, dependent on an intact p53-p21 pathway.","method":"PARP14 siRNA depletion, luciferase 3'UTR reporter assays, cell cycle analysis (flow cytometry), western blot for cyclin D1/RB/p53 pathway components","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase 3'UTR assay and cell cycle analysis provide mechanistic evidence, single lab study","pmids":["34158578"],"is_preprint":false},{"year":2020,"finding":"Genome-wide CRISPR knockout screen in PARP14-deficient cells identified the ATR-CHK1 pathway as synthetically lethal with PARP14 loss, and mechanistically linked this to regulation of DNA replication dynamics; inhibition of the ATR-CHK1 pathway in PARP14-deficient cells leads to cell death through replication stress.","method":"Genome-wide CRISPR knockout genetic screen, ATR/CHK1 inhibitor treatment of PARP14-deficient cells, DNA fiber assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased genome-wide screen with mechanistic follow-up, single lab","pmids":["32542389"],"is_preprint":false},{"year":2014,"finding":"DTX3L (BBAP) forms a protein complex with PARP14 (ARTD8) and PARP9 (ARTD9) in metastatic prostate cancer cells; the enzymatic activity of PARP14 is required for survival of these cells, and the complex mediates proliferation, chemo-resistance, and survival.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, cell proliferation/survival assays, catalytic mutant analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP for complex formation, catalytic activity requirement established, single lab","pmids":["24886089"],"is_preprint":false},{"year":2022,"finding":"PARP14 regulates EP4 receptor expression in colon cancer cells through mono-ADP-ribosylation of HDAC1 and HDAC2; suppression of PARP14 activity by siRNA or inhibitors reduced EP4 receptor mRNA and protein expression.","method":"siRNA knockdown, PARP14 inhibitor treatment, RT-qPCR, western blot, HDAC ADP-ribosylation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mono-ADP-ribosylation of HDAC1/2 proposed mechanistically with siRNA and inhibitor data, single lab without direct biochemical reconstitution","pmids":["35914351"],"is_preprint":false},{"year":2024,"finding":"KH-like domains in PARP14 and PARP9/DTX3L coordinate protein-protein interactions important to pro-survival signaling: KH-like domains mediate PARP9-DTX3L and PARP14-DTX3L interactions; homodimerization of DTX3L is also coordinated by a KH-like domain. In vitro, DTX3L interaction with PARP14 suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.","method":"Co-immunoprecipitation, site-directed mutagenesis of KH domain, PARP14 truncation rescue experiments, in vitro ADP-ribosylation assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mutagenesis, in vitro enzymatic assays for regulation of activity, single lab","pmids":["38182103"],"is_preprint":false},{"year":2024,"finding":"PARP14 mono-ADP-ribosylates RACK1 (an integral ribosome component) on three acidic residues in ovarian cancer cells; MARylation of RACK1 is required for stress granule formation and promotes colocalization of RACK1 with G3BP1, eIF3η, and 40S ribosomal subunits in stress granules, while reducing translation of a subset of mRNAs including AKT. The ADP-ribosyl hydrolase TARG1 reverses this modification, allowing stress granule dissociation and translation restoration.","method":"Mass spectrometry identification of MARylation sites, PARP14 inhibitor, site-directed mutagenesis of RACK1 MARylation sites, stress granule imaging, polysome profiling, in vivo tumor xenograft","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified sites with mutagenesis validation and in vivo confirmation, preprint not yet peer-reviewed","pmids":["37873085"],"is_preprint":true},{"year":2025,"finding":"PARP14 catalytic activity enhances IFN-β and IFN-γ responses and restricts replication of ARH-deficient coronaviruses (MHV, SARS-CoV-2) and HSV-1. PARP14 has pro-viral function for VSV, as its knockout decreased VSV replication. The effects on HSV-1 and VSV were independent of PARP14 catalytic activity as demonstrated by an active site inhibitor having no effect.","method":"PARP14 knockout (CRISPR) A549 cells, viral replication assays for MHV, SARS-CoV-2, HSV-1, VSV, LCMV; PARP14 active site inhibitor treatment; IFN-β/IFN-γ ELISA","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple viral challenges and orthogonal catalytic inhibitor, single lab, peer-reviewed","pmids":["40937852"],"is_preprint":false},{"year":2025,"finding":"Interferon induces PARP14-mediated mono-ADP-ribosylation of SQSTM1/p62 at cysteine residues 113, 289/290, and 331; this creates cytoplasmic p62 foci colocalizing with ubiquitin and PARP14 but lacking LC3, distinguishing them from autophagosomes. TRIM21 prevents autophagic degradation of ADP-ribosylated p62. The SARS-CoV-2 macrodomain reverses this p62 modification.","method":"Mass spectrometry for site identification, site-directed mutagenesis of p62 cysteines, immunofluorescence, PARP14 catalytic inhibition, SARS-CoV-2 macrodomain reversal assays, TRIM21 knockdown","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified cysteine sites with mutagenesis, viral macrodomain reversal, preprint stage","pmids":["bio_10.1101_2024.06.29.601315"],"is_preprint":true},{"year":2025,"finding":"Interferon-induced PARP14-mediated ADP-ribosylation occurs within p62 body condensates: PARP14 physical presence and catalytic activity are both required for condensate formation. These PARP14/ADPr condensates contain p62, NBR1, TAX1BP1, and K48/K63-linked polyubiquitin but lack LC3B; p62 knockdown disrupts condensate formation. Condensate integrity is independent of autophagy but requires ubiquitination and proteasome activity.","method":"siRNA knockdown of PARP14 and p62, PARP14 catalytic mutant expression, immunofluorescence, autophagy inhibitors (bafilomycin), proteasome inhibitors, ubiquitination inhibitors","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — catalytic mutant distinguishes physical vs enzymatic role, multiple genetic knockdowns with convergent results, peer-reviewed","pmids":["40195501"],"is_preprint":false},{"year":2026,"finding":"PARP14 is recruited to nascent DNA at reversed replication forks in BRCA2-deficient cells via its RRM (RNA Recognition Motif) domains; these domains are necessary for MRE11 recruitment to reversed forks, for promotion of nascent strand degradation, and for replication stress-induced double-strand break formation in BRCA2-deficient cells.","method":"iPOND, PARP14 domain truncation/deletion constructs, DNA fiber assays, DSB (γH2AX) analysis, MRE11 foci assays in BRCA2-deficient cells","journal":"NAR cancer","confidence":"High","confidence_rationale":"Tier 2 / Moderate — iPOND for direct nascent DNA recruitment, domain-specific rescue experiments, functional epistasis, single lab with multiple orthogonal assays","pmids":["41684642"],"is_preprint":false},{"year":2026,"finding":"PARP14 mediates MARylation of GLUD1 (glutamate dehydrogenase 1), inhibiting GLUD1 enzyme activity via mono-ADP-ribosylation, which reduces alpha-ketoglutarate production and suppresses mitochondrial energy metabolism in granulosa cells.","method":"Co-immunoprecipitation, in vitro ADP-ribosylation assay, GLUD1 enzyme activity measurement, metabolite (α-KG) quantification, PARP14 overexpression/knockdown","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — Co-IP and enzymatic activity assay support substrate relationship, single lab, single paper","pmids":["41895093"],"is_preprint":false},{"year":2020,"finding":"PARP14 promotes post-stroke functional recovery by inhibiting microglial activation through suppression of LPAR5 (lysophosphatidic acid receptor 5) gene transcription; PARP14 overexpression in microglia attenuates post-stroke microglial activation possibly through modulation of macroautophagy.","method":"PARP14 genetic knockdown/overexpression in photothrombotic stroke mouse model, pharmacological PARP14 inhibition, microglial activation assays, LPAR5 promoter analysis, autophagy modulation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo loss/gain-of-function with defined molecular target (LPAR5 transcription), single lab","pmids":["33317392"],"is_preprint":false},{"year":2019,"finding":"PARP14 ADP-ribosylates itself (auto-ribosylation); mass spectrometry detected IFNγ-induced ADP-ribosylation of PARP14 (ARTD8) along with PARP9 (ARTD9) in macrophages, providing first characterization of ADP-ribosylation on these PARP family members.","method":"Af1521 enrichment of ADP-ribosylated peptides, anti-poly-ADPr antibody enrichment, EThcD and HCD MS/MS, IFNγ treatment of THP-1 macrophages","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mass spectrometry identification of modification sites, single lab, no mutagenesis validation of specific sites","pmids":["30848916"],"is_preprint":false},{"year":2022,"finding":"PARP14 promotes AML cell glycolysis by activating NF-κB signaling, which in turn promotes HIF-1α expression; HIF-1α silencing reverses the cancer-promoting effects of PARP14 overexpression.","method":"siRNA/overexpression of PARP14, NF-κB inhibitor (BAY11-7082), HIF-1α siRNA rescue, glycolysis assays (ECAR, glucose consumption, lactate production), xenograft tumor model","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway epistasis via rescue experiments and pharmacological inhibition, in vivo validation, single lab","pmids":["35944879"],"is_preprint":false},{"year":2025,"finding":"PARP14 inhibits microglial activation and depressive-like behavior by positively regulating nicotinamide nucleotide transhydrogenase (NNT) expression in microglia; NNT deficiency leads to ROS accumulation and microglial inflammation, which PARP14 suppresses via NNT-mediated ROS clearance.","method":"CUS mouse model, hippocampal PARP14 knockdown/overexpression, microglial-targeted AAV overexpression, NNT overexpression rescue, ROS inhibitor (NAC) treatment, microglial activation assays","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis via NNT rescue, in vivo targeted overexpression, single lab","pmids":["39978699"],"is_preprint":false},{"year":2025,"finding":"YTHDF2 (m6A reader) interacts with PARP14 mRNA under oxygen-glucose deprivation (OGD) conditions, promoting m6A-dependent degradation of PARP14 mRNA and reducing PARP14 protein levels; this mechanism enables YTHDF2-dependent suppression of PARP14-driven M2 microglial polarization.","method":"RIP (RNA immunoprecipitation) for YTHDF2-PARP14 mRNA interaction, siRNA knockdown of YTHDF2, mRNA stability assays, microglial phenotype assays","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP confirms mRNA-protein interaction, functional epistasis demonstrated, single lab","pmids":["40383033"],"is_preprint":false},{"year":2025,"finding":"PARP14 enhances SOCS2 mRNA stability, promoting M2 macrophage polarization relevant to hypertrophic scarring; overexpression of PARP14 restored M2 polarization in macrophages treated with botulinum toxin A, which was counteracted by additional SOCS2 silencing.","method":"RNA sequencing, PARP14 overexpression, SOCS2 silencing rescue experiments, mRNA stability assays, in vivo mouse HS model, THP-1 M2 polarization model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA stability assay and epistasis rescue, single lab, limited mechanistic detail on how ADP-ribosylation mediates mRNA stabilization","pmids":["40505894"],"is_preprint":false}],"current_model":"PARP14 is a large multidomain mono-ADP-ribosyltransferase (and its macrodomain 1 a de-MARylase) that acts as a bimodal transcriptional switch—recruiting HDACs to repress IL-4/STAT6 target genes at baseline and ADP-ribosylating them upon IL-4 stimulation to enable STAT6-driven transcription—while also directly ADP-ribosylating STAT1 to suppress pro-inflammatory signaling, interacting with and inhibiting the pro-apoptotic kinase JNK1 to promote cell survival and the Warburg effect, acting as a critical co-factor for MRE11-dependent replication fork processing via its RRM domains, functioning as a major IFN-induced ADP-ribosyltransferase whose activity is targeted by viral macrodomains (e.g., SARS-CoV-2 Nsp3 Mac1), and regulating mRNA stability of select transcripts through ribonucleoprotein complexes with tristetraprolin."},"narrative":{"mechanistic_narrative":"PARP14 is a large multidomain mono-ADP-ribosyltransferase that operates as a bimodal regulator of cytokine-driven transcription, innate immune signaling, and replication-stress responses [PMID:21081493, PMID:27796300, PMID:36030235]. In IL-4 signaling it acts as a transcriptional switch: at baseline it recruits HDAC2/HDAC3 to IL-4-responsive promoters to repress transcription, and upon IL-4 stimulation it ADP-ribosylates these HDACs to release them and permit STAT6-driven gene activation, supporting B-cell survival, glycolysis, and lymphomagenesis [PMID:21081493, PMID:19147789, PMID:21911376]. PARP14 catalytic activity also directly ADP-ribosylates STAT1 to suppress STAT1 phosphorylation and pro-inflammatory macrophage activation, an effect antagonized by PARP9 [PMID:27796300]. Beyond transcription, PARP14 binds and inhibits the pro-apoptotic kinase JNK1, blocking JNK1-mediated phosphorylation of PKM2 to enforce the Warburg effect and promote tumor-cell survival [PMID:23045269, PMID:26258887]. In genome maintenance, PARP14 is recruited to nascent DNA at reversed replication forks via its RRM domains and, through its catalytic activity, drives MRE11 engagement and fork resection, promoting homologous recombination and rendering its loss synthetically lethal with ATR-CHK1 inhibition [PMID:25753673, PMID:36030235, PMID:41684642, PMID:32542389]. PARP14 is a major interferon-induced ADP-ribosyltransferase: it auto-MARylates and modifies substrates including PARP13, RACK1, and SQSTM1/p62, and its activity is reversed by its own macrodomain 1—an active de-MARylase (glycohydrolase)—and by the SARS-CoV-2 Nsp3 Mac1 macrodomain [PMID:37703374, PMID:37507011, PMID:30247868, PMID:30848916, PMID:38834853, PMID:38834852]. PARP14 nucleates interferon-induced p62-body condensates and restricts replication of several viruses [PMID:40195501, PMID:40937852]. PARP14 additionally regulates the stability of select mRNAs, forming a ribonucleoprotein complex with tristetraprolin on tissue factor mRNA [PMID:25293769].","teleology":[{"year":2009,"claim":"Established that PARP14 is a functional partner of STAT6 controlling cytokine-driven cell fate, linking the protein to IL-4-dependent B-cell survival rather than leaving it an orphan ADP-ribosyltransferase.","evidence":"Parp14-knockout mice, apoptosis and gene expression assays, STAT6 binding assays in primary B cells","pmids":["19147789"],"confidence":"High","gaps":["Did not define whether catalytic activity is required for the STAT6 interaction","Molecular mechanism of survival gene induction not resolved"]},{"year":2010,"claim":"Answered how PARP14 switches transcription by showing it represses via HDAC recruitment at baseline and de-represses by ADP-ribosylating the HDACs upon IL-4 stimulation, defining a bimodal enzymatic transcriptional switch.","evidence":"ChIP, co-IP, promoter reporter and ADP-ribosylation assays in T/B cells","pmids":["21081493"],"confidence":"High","gaps":["Direct biochemical reconstitution of HDAC ADP-ribosylation not shown","Specific modified residues on HDAC2/3 not mapped"]},{"year":2011,"claim":"Connected PARP14 to metabolic reprogramming by showing IL-4-induced glycolysis underlies its pro-survival and lymphomagenic function, with AMPK as a rescuing node.","evidence":"Parp14-knockout mice, glycolysis and AMPK activity assays, Myc-driven lymphoma models","pmids":["21911376"],"confidence":"High","gaps":["Direct enzymatic substrate linking PARP14 to glycolytic control not identified","Relationship between AMPK rescue and ADP-ribosylation unclear"]},{"year":2012,"claim":"Identified a non-transcriptional survival mechanism: PARP14 physically binds and inhibits pro-apoptotic JNK1, placing it downstream of JNK2 in myeloma survival signaling.","evidence":"siRNA/shRNA, overexpression rescue, PARP14-JNK1 co-IP, apoptosis assays in myeloma lines","pmids":["23045269"],"confidence":"High","gaps":["Whether JNK1 is an ADP-ribosylation substrate not established","Structural basis of inhibition unknown"]},{"year":2013,"claim":"Defined PARP14 macrodomains 2 and 3 as readers of mono-ADP-ribose with substrate selectivity, establishing PARP14 as both writer and reader of MARylation.","evidence":"Crystal structures, ITC, binding/co-localization assays with MARylated ARTD10 and Ran","pmids":["23473667"],"confidence":"High","gaps":["In vivo MARylated ligands recognized by these macrodomains not defined","Functional consequence of reading in cells not tested"]},{"year":2013,"claim":"Showed PARP14 catalytic activity shapes adaptive immunity, driving Th17 differentiation and IL-4-dependent IgE/IgA responses through transcription-factor expression.","evidence":"Parp14-deficient and catalytic-mutant mice, antibody isotype and flow-cytometric analyses","pmids":["23956424"],"confidence":"High","gaps":["Direct substrates mediating RORα/Runx1/Smad3 induction unknown","B-cell-intrinsic vs extrinsic mechanisms incompletely separated"]},{"year":2015,"claim":"Linked the JNK1-inhibitory function to metabolism by defining the PARP14-JNK1-PKM2 axis controlling aerobic glycolysis in hepatocellular carcinoma.","evidence":"In vitro/in vivo loss-of-function, PKM2 Thr365 phosphorylation and glycolysis assays","pmids":["26258887"],"confidence":"High","gaps":["Catalytic requirement of PARP14 for JNK1 inhibition not resolved"]},{"year":2015,"claim":"Placed PARP14 in genome maintenance by demonstrating its PCNA interaction and requirement for homologous recombination and replication of difficult loci.","evidence":"PARP14-PCNA co-IP, siRNA, RAD51 foci, HR reporter and comet assays","pmids":["25753673"],"confidence":"High","gaps":["Domain mediating PCNA interaction not mapped here","Whether catalytic activity is required not yet tested"]},{"year":2016,"claim":"Identified STAT1 as a direct ADP-ribosylation substrate whose modification suppresses phosphorylation, defining the PARP14/PARP9 cross-regulatory axis of macrophage activation.","evidence":"Proteomics, STAT1 site mutagenesis, PARP14/PARP9 silencing in primary macrophages","pmids":["27796300"],"confidence":"High","gaps":["Structural basis of STAT1 ADP-ribose-mediated phospho-suppression unknown"]},{"year":2014,"claim":"Demonstrated a post-transcriptional role: PARP14 forms an RNP with tristetraprolin to control tissue factor mRNA stability with transcript selectivity.","evidence":"RNP-IP, biotinylated RNA pulldown, knockout macrophages, mRNA stability and coagulation assays","pmids":["25293769"],"confidence":"High","gaps":["Whether ADP-ribosylation drives the mRNA stabilization not established","Basis of transcript selectivity unknown"]},{"year":2014,"claim":"Defined a stable PARP14-PARP9-DTX3L complex required for cancer-cell survival, establishing physical assembly of these ADP-ribosylation machinery components.","evidence":"Reciprocal co-IP, immunofluorescence, siRNA, catalytic-mutant survival assays in prostate cancer cells","pmids":["24886089"],"confidence":"Medium","gaps":["Single-lab study","Stoichiometry and architecture of the complex not resolved"]},{"year":2017,"claim":"Provided structural and enzymatic characterization of PARP14 auto-ADP-ribosylation and NAD+-competitive inhibition, enabling pharmacological targeting.","evidence":"Purified protein, RapidFire MS and [3H]NAD+ auto-ribosylation assays, co-crystal structures with inhibitors","pmids":["28315326"],"confidence":"High","gaps":["Physiological consequences of auto-modification not addressed here"]},{"year":2018,"claim":"Showed PARP14 translocates to the nucleus on inflammatory stimulation, binds ISG-encoded proteins, and is required for IRF3-dependent antiviral transcription including IFN-β.","evidence":"Fractionation, quantitative MS interactome, siRNA, RT-qPCR, Salmonella infection assays","pmids":["29500242"],"confidence":"High","gaps":["Whether catalytic activity drives ISG-protein nuclear accumulation not resolved"]},{"year":2018,"claim":"Defined the PARP14-specific MARylation substrate landscape via chemical genetics and proximity labeling, revealing enrichment for RNA-regulatory proteins and identifying PARP13 as a direct substrate.","evidence":"Orthogonal NAD+ analog with engineered PARP14, BioID, MS substrate ID, in vitro validation","pmids":["30247868"],"confidence":"High","gaps":["Functional consequences of most identified substrates untested","Modified residues on most substrates not mapped"]},{"year":2019,"claim":"Provided first direct mapping of IFNγ-induced ADP-ribosylation on PARP14 and PARP9 in macrophages, establishing these PARPs as auto/cross-modification targets in interferon signaling.","evidence":"Af1521 enrichment, EThcD/HCD MS/MS of IFNγ-treated THP-1 macrophages","pmids":["30848916"],"confidence":"Medium","gaps":["No mutagenesis validation of specific sites","Functional role of identified sites untested"]},{"year":2020,"claim":"Revealed PARP14 as a critical co-factor of MRE11 at reversed forks in BRCA-deficient cells, defining a KU-PARP14-MRE11-EXO1 resection pathway dependent on catalytic activity.","evidence":"iPOND, PLA, DNA fiber and S1 nuclease assays, MRE11/KU co-IP, PARP14 inhibition/knockout","pmids":["36030235"],"confidence":"High","gaps":["Direct ADP-ribosylation substrate enabling MRE11 engagement not identified"]},{"year":2020,"claim":"Identified ATR-CHK1 as synthetically lethal with PARP14 loss, mechanistically tying PARP14 to replication-dynamics control and nominating a therapeutic vulnerability.","evidence":"Genome-wide CRISPR knockout screen, ATR/CHK1 inhibitor treatment, DNA fiber assays","pmids":["32542389"],"confidence":"Medium","gaps":["Single lab","Molecular mechanism linking PARP14 to ATR-CHK1 dependence incompletely defined"]},{"year":2020,"claim":"Extended PARP14 function to CNS injury, showing it limits microglial activation and promotes post-stroke recovery via suppression of LPAR5 transcription.","evidence":"Photothrombotic stroke model with PARP14 knockdown/overexpression, pharmacological inhibition, LPAR5 promoter analysis","pmids":["33317392"],"confidence":"Medium","gaps":["Single lab","Direct link between ADP-ribosylation and LPAR5 transcription unresolved"]},{"year":2021,"claim":"Showed PARP14 controls cyclin D1 expression via 3'UTR mRNA stability, governing G1 progression through the RB and p53-p21 pathways.","evidence":"siRNA depletion, luciferase 3'UTR reporters, cell-cycle and western analyses","pmids":["34158578"],"confidence":"Medium","gaps":["Single lab","Whether ADP-ribosylation mediates the 3'UTR effect not shown"]},{"year":2022,"claim":"Connected PARP14 transcriptional regulation to EP4 receptor expression in colon cancer through MARylation of HDAC1/HDAC2.","evidence":"siRNA, PARP14 inhibitor, RT-qPCR, western, HDAC ADP-ribosylation assays","pmids":["35914351"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of HDAC1/2 modification","Single lab"]},{"year":2022,"claim":"Implicated PARP14 in AML glycolysis through an NF-κB/HIF-1α axis, extending its metabolic role to myeloid leukemia.","evidence":"siRNA/overexpression, NF-κB inhibitor, HIF-1α siRNA rescue, glycolysis assays, xenografts","pmids":["35944879"],"confidence":"Medium","gaps":["Single lab","Mechanism by which PARP14 activates NF-κB not defined"]},{"year":2023,"claim":"Reclassified PARP14 as a dual-function enzyme by demonstrating its macrodomain 1 is an active de-MARylase, with viral Nsp3 Mac1 reversing PARP14 modifications.","evidence":"In vitro reconstitution, macrodomain-1 mutagenesis, cellular MARylation detection, SARS-CoV-2 Mac1 reversal","pmids":["37703374"],"confidence":"High","gaps":["Physiological balance between writer and eraser activities not quantified"]},{"year":2023,"claim":"Characterized PARP14 (and PARP9) macrodomain-1 as ADP-ribosyl glycohydrolases not directed to specific side chains and inactive on poly(ADP-ribose), revealing mechanistic homology to SARS-CoV-2 Mac1.","evidence":"In vitro hydrolysis assays, F926A/F244A mutagenesis, PARP1 poly-ADP-ribose comparison","pmids":["37507011"],"confidence":"High","gaps":["Single lab","Endogenous substrates of the glycohydrolase activity not defined"]},{"year":2024,"claim":"Showed IFNγ-induced cellular ADP-ribosylation depends on PARP14 catalysis and that PARP9/DTX3L post-translationally control PARP14 levels and co-localize at cytoplasmic ADPr inclusions.","evidence":"IFNγ treatment with anti-mono-ADPr detection, catalytic mutant, PARP9/DTX3L siRNA, immunofluorescence, Nsp3 Mac1 reversal (two convergent papers)","pmids":["38834853","38834852"],"confidence":"High","gaps":["Mechanism of post-translational PARP14 level control by PARP9/DTX3L not detailed"]},{"year":2024,"claim":"Defined KH-like domains as the structural basis for PARP14-DTX3L-PARP9 interactions, with DTX3L binding suppressing PARP14 auto-modification and redirecting it to trans-modification.","evidence":"Co-IP, KH-domain mutagenesis, PARP14 truncation rescue, in vitro ADP-ribosylation assays","pmids":["38182103"],"confidence":"Medium","gaps":["Single lab","Cellular consequence of DTX3L-redirected activity not established"]},{"year":2024,"claim":"Identified RACK1 as a PARP14 MARylation substrate whose modification drives stress-granule formation and selective translational repression, reversed by TARG1.","evidence":"MS site mapping, RACK1 mutagenesis, stress-granule imaging, polysome profiling, xenograft (preprint)","pmids":["37873085"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Generality beyond ovarian cancer cells untested"]},{"year":2025,"claim":"Showed PARP14 catalytic activity enhances IFN-β/IFN-γ responses and restricts ARH-deficient coronaviruses and HSV-1 while being pro-viral for VSV, separating catalytic from non-catalytic antiviral roles.","evidence":"CRISPR-knockout A549 cells, multi-virus replication assays, active-site inhibitor, IFN ELISA","pmids":["40937852"],"confidence":"Medium","gaps":["Single lab","Catalytic substrates underlying virus restriction not identified"]},{"year":2025,"claim":"Demonstrated that PARP14 both physically scaffolds and catalytically maintains interferon-induced p62-body condensates containing selective autophagy receptors and polyubiquitin but lacking LC3B.","evidence":"PARP14/p62 siRNA, catalytic mutant, immunofluorescence, autophagy/proteasome/ubiquitination inhibitors","pmids":["40195501"],"confidence":"High","gaps":["Functional output of these condensates incompletely defined","p62 cysteine-MARylation role within condensates not fully linked"]},{"year":2026,"claim":"Identified PARP14 RRM domains as the recruitment module to reversed forks required for MRE11 engagement and nascent-strand degradation in BRCA2-deficient cells, refining the structural basis of its replication-stress role.","evidence":"iPOND, domain truncation/deletion constructs, DNA fiber, γH2AX and MRE11 foci assays","pmids":["41684642"],"confidence":"High","gaps":["RNA ligand, if any, bound by the RRMs at forks unknown","Single lab"]},{"year":2026,"claim":"Extended PARP14 substrate repertoire to metabolic enzyme GLUD1, whose MARylation inhibits glutamate dehydrogenase activity and suppresses mitochondrial energy metabolism.","evidence":"Co-IP, in vitro ADP-ribosylation, GLUD1 activity and α-KG measurements in granulosa cells","pmids":["41895093"],"confidence":"Medium","gaps":["Single lab","Modified residues on GLUD1 not mapped"]},{"year":null,"claim":"It remains unresolved which direct ADP-ribosylation substrates mediate PARP14's transcriptional, replication-fork, and antiviral phenotypes, and how the balance between its transferase and macrodomain-1 hydrolase activities is regulated in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["Causal substrate-to-phenotype links largely inferential","In vivo regulation of writer/eraser balance unquantified","Structural basis of many substrate interactions undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,10,13,22,27]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[12,13,29]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[13,14]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,10,17]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,22,25]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,15,26]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,9,11,23]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,15,26,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,5,27,30]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,17,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,7]}],"complexes":["PARP14-PARP9-DTX3L complex","PARP14-tristetraprolin (TTP) ribonucleoprotein complex","p62-body condensate"],"partners":["STAT6","JNK1","PCNA","MRE11","DTX3L","PARP9","STAT1","PARP13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q460N5","full_name":"Protein mono-ADP-ribosyltransferase PARP14","aliases":["ADP-ribosyltransferase diphtheria toxin-like 8","ARTD8","B aggressive lymphoma protein 2","Poly [ADP-ribose] polymerase 14","PARP-14"],"length_aa":1801,"mass_kda":202.8,"function":"ADP-ribosyltransferase that mediates mono-ADP-ribosylation of glutamate residues on target proteins (PubMed:16061477, PubMed:18851833, PubMed:25043379, PubMed:27796300). In contrast to PARP1 and PARP2, it is not able to mediate poly-ADP-ribosylation (PubMed:25043379). Has been shown to catalyze the mono-ADP-ribosylation of STAT1 at 'Glu-657' and 'Glu-705', thus decreasing STAT1 phosphorylation which negatively regulates pro-inflammatory cytokine production in macrophages in response to IFNG stimulation (PubMed:27796300). However, the role of ADP-ribosylation in the prevention of STAT1 phosphorylation has been called into question and it has been suggested that the inhibition of phosphorylation may be the result of sumoylation of STAT1 'Lys-703' (PubMed:29858569). Mono-ADP-ribosylates STAT6; enhancing STAT6-dependent transcription (PubMed:27796300). In macrophages, positively regulates MRC1 expression in response to IL4 stimulation by promoting STAT6 phosphorylation (PubMed:27796300). Mono-ADP-ribosylates PARP9 (PubMed:27796300)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q460N5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARP14","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PARP14","total_profiled":1310},"omim":[{"mim_id":"612066","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 15; PARP15","url":"https://www.omim.org/entry/612066"},{"mim_id":"612065","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 9; PARP9","url":"https://www.omim.org/entry/612065"},{"mim_id":"610028","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 14; PARP14","url":"https://www.omim.org/entry/610028"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARP14"},"hgnc":{"alias_symbol":["KIAA1268","pART8","ARTD8","BAL2"],"prev_symbol":[]},"alphafold":{"accession":"Q460N5","domains":[{"cath_id":"3.30.70,3.30.70","chopping":"8-89","consensus_level":"high","plddt":85.9298,"start":8,"end":89},{"cath_id":"3.30.70.330","chopping":"151-308","consensus_level":"medium","plddt":83.1008,"start":151,"end":308},{"cath_id":"-","chopping":"325-463","consensus_level":"medium","plddt":78.5312,"start":325,"end":463},{"cath_id":"-","chopping":"466-668","consensus_level":"medium","plddt":84.7921,"start":466,"end":668},{"cath_id":"3.40.220.10","chopping":"792-979","consensus_level":"medium","plddt":91.8084,"start":792,"end":979},{"cath_id":"3.40.220.10","chopping":"1008-1174","consensus_level":"high","plddt":93.2654,"start":1008,"end":1174},{"cath_id":"3.40.220.10","chopping":"1211-1387","consensus_level":"high","plddt":89.3553,"start":1211,"end":1387},{"cath_id":"3.90.228.10","chopping":"1619-1801","consensus_level":"high","plddt":89.0862,"start":1619,"end":1801}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q460N5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q460N5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q460N5-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARP14","jax_strain_url":"https://www.jax.org/strain/search?query=PARP14"},"sequence":{"accession":"Q460N5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q460N5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q460N5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q460N5"}},"corpus_meta":[{"pmid":"27796300","id":"PMC_27796300","title":"PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27796300","citation_count":238,"is_preprint":false},{"pmid":"26258887","id":"PMC_26258887","title":"PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26258887","citation_count":190,"is_preprint":false},{"pmid":"21081493","id":"PMC_21081493","title":"PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21081493","citation_count":123,"is_preprint":false},{"pmid":"23473667","id":"PMC_23473667","title":"Recognition of mono-ADP-ribosylated ARTD10 substrates by ARTD8 macrodomains.","date":"2013","source":"Structure (London, England : 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with both ADP-ribosyl transferase and hydrolase activities.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37703374","citation_count":62,"is_preprint":false},{"pmid":"25293769","id":"PMC_25293769","title":"PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/25293769","citation_count":62,"is_preprint":false},{"pmid":"26032162","id":"PMC_26032162","title":"Identification of a novel PARP14-TFE3 gene fusion from 10-year-old FFPE tissue by RNA-seq.","date":"2015","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26032162","citation_count":57,"is_preprint":false},{"pmid":"30247868","id":"PMC_30247868","title":"Combining Chemical Genetics with Proximity-Dependent Labeling Reveals Cellular Targets of Poly(ADP-ribose) Polymerase 14 (PARP14).","date":"2018","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30247868","citation_count":55,"is_preprint":false},{"pmid":"25753673","id":"PMC_25753673","title":"A novel role for the mono-ADP-ribosyltransferase PARP14/ARTD8 in promoting homologous recombination and protecting against replication stress.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25753673","citation_count":53,"is_preprint":false},{"pmid":"34158578","id":"PMC_34158578","title":"PARP14 regulates cyclin D1 expression to promote cell-cycle progression.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34158578","citation_count":46,"is_preprint":false},{"pmid":"38834853","id":"PMC_38834853","title":"PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/38834853","citation_count":43,"is_preprint":false},{"pmid":"30890936","id":"PMC_30890936","title":"Research Progress on PARP14 as a Drug Target.","date":"2019","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30890936","citation_count":42,"is_preprint":false},{"pmid":"36030235","id":"PMC_36030235","title":"The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36030235","citation_count":41,"is_preprint":false},{"pmid":"23956424","id":"PMC_23956424","title":"B cell-intrinsic and -extrinsic regulation of antibody responses by PARP14, an intracellular (ADP-ribosyl)transferase.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23956424","citation_count":32,"is_preprint":false},{"pmid":"37752135","id":"PMC_37752135","title":"PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37752135","citation_count":31,"is_preprint":false},{"pmid":"35944879","id":"PMC_35944879","title":"PARP14 promotes the growth and glycolysis of acute myeloid leukemia cells by regulating HIF-1α expression.","date":"2022","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/35944879","citation_count":31,"is_preprint":false},{"pmid":"30848916","id":"PMC_30848916","title":"A Study into the ADP-Ribosylome of IFN-γ-Stimulated THP-1 Human Macrophage-like Cells Identifies ARTD8/PARP14 and ARTD9/PARP9 ADP-Ribosylation.","date":"2019","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/30848916","citation_count":31,"is_preprint":false},{"pmid":"30968979","id":"PMC_30968979","title":"PARP14 promotes the proliferation and gemcitabine chemoresistance of pancreatic cancer cells through activation of NF-κB 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promoters, and enabling coactivator with HAT activity to replace the repressor complex.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, promoter reporter assays, ADP-ribosylation assays in T cells/B cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, and functional reporter assays in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"21081493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP14 (ARTD8) macrodomains 2 and 3 act as readers of mono-ADP-ribosylation: crystal structures and isothermal titration calorimetry confirmed their interaction with ADP-ribose, and they specifically recognized mono-ADP-ribosylated ARTD10 and its substrate Ran, but not poly-ADP-ribosylated ARTD1, distinguishing them from the macroH2A1.1 macrodomain.\",\n      \"method\": \"Crystal structure determination, isothermal titration calorimetry, co-localization and binding assays in vitro and in cells\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with ITC and cellular validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23473667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PARP-14 mediates IL-4-dependent survival signaling in primary B cells: PARP-14-deficient mice show increased apoptosis in IL-4-treated B cells including after DNA damage, and PARP-14 regulates IL-4-induced expression of gene products controlling survival, proliferation, and lymphomagenesis. PARP-14 physically interacts with the IL-4-induced transcription factor STAT6.\",\n      \"method\": \"Knockout mouse studies, apoptosis assays, gene expression analysis, binding assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with defined cellular phenotype, replicated across multiple assays\",\n      \"pmids\": [\"19147789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PARP14 is required for IL-4-induced enhancement of glycolysis in B cells, and this glycolytic activity mediates IL-4-dependent pro-survival signaling. PARP14 deficiency delayed B lymphomagenesis and reversed the block to B-cell maturation driven by the Myc oncogene; restoration of AMP-activated protein kinase activity rescued glycolytic activity and prosurvival signaling in Parp14-deficient B cells.\",\n      \"method\": \"Parp14 knockout mice, glycolysis assays, AMPK activity assays, lymphoma mouse models, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple in vivo and in vitro functional readouts, epistasis via AMPK rescue\",\n      \"pmids\": [\"21911376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP14 is a downstream effector of JNK2-dependent pro-survival signaling in multiple myeloma: JNK2 constitutive activation maintains PARP14 expression; PARP14 promotes myeloma cell survival by physically binding and inhibiting the pro-apoptotic kinase JNK1; overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown.\",\n      \"method\": \"Loss-of-function (siRNA/shRNA) studies, overexpression rescue experiments, co-immunoprecipitation (PARP14-JNK1 interaction), apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating PARP14-JNK1 interaction, genetic epistasis via rescue experiments, multiple cell lines\",\n      \"pmids\": [\"23045269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1: PARP14 suppresses JNK1 kinase activity, which prevents JNK1-mediated phosphorylation of PKM2 at Thr365 that would otherwise activate PKM2 and reduce aerobic glycolysis. This PARP14-JNK1-PKM2 axis links anti-apoptotic signaling to metabolic reprogramming.\",\n      \"method\": \"Loss-of-function studies (siRNA/shRNA) in vitro and in vivo (xenograft), PKM2 phosphorylation assays, glycolysis measurements, apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro loss-of-function, specific phosphorylation site identified, multiple orthogonal methods\",\n      \"pmids\": [\"26258887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP14 promotes homologous recombination DNA repair and protects against replication stress: PARP14 interacts with PCNA and promotes replication of DNA lesions and common fragile sites; PARP14 depletion results in reduced homologous recombination, persistent RAD51 foci, hypersensitivity to DNA damaging agents, and accumulation of DNA strand breaks.\",\n      \"method\": \"Co-immunoprecipitation (PARP14-PCNA), siRNA knockdown, RAD51 foci assays, HR reporter assays, comet assays, sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional HR assays, and multiple phenotypic readouts in a single focused study\",\n      \"pmids\": [\"25753673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PARP14 induces ADP-ribosylation of STAT1, which suppresses STAT1 phosphorylation; PARP9 antagonizes this by suppressing PARP14-mediated ADP-ribosylation of STAT1. Mutations at the PARP14-dependent ADP-ribosylation sites on STAT1 lead to increased STAT1 phosphorylation. PARP14 and PARP9 thus cross-regulate macrophage activation via opposing effects on STAT1 activity.\",\n      \"method\": \"Global proteomic analysis, ADP-ribosylation assays, site-directed mutagenesis of STAT1, PARP14/PARP9 silencing in primary macrophages, phosphorylation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ADP-ribosylation site mapping with mutagenesis validation, multiple macrophage models, orthogonal proteomic and biochemical methods\",\n      \"pmids\": [\"27796300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PARP-14 selectively regulates macrophage tissue factor (TF) mRNA stability by forming a ribonucleoprotein complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved AU-rich element in the TF mRNA 3' UTR; PARP-14 deficiency leads to increased TF mRNA stability, TF expression, and TF activity in macrophages, while TNFα mRNA (also regulated by TTP) is unaffected.\",\n      \"method\": \"Ribonucleoprotein immunoprecipitation, biotinylated RNA pulldown, PARP14-knockout macrophages (in vitro and in vivo), mRNA stability assays, TF functional coagulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNP-IP and RNA pulldown demonstrate direct complex, validated in vivo in knockout mice with functional readout\",\n      \"pmids\": [\"25293769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP14 translocates into the nucleus of macrophages upon inflammatory stimulation, binds a group of IFN-stimulated gene (ISG)-encoded proteins by quantitative mass spectrometry, and is required for their nuclear accumulation. PARP14 depletion attenuates IFN regulatory factor 3-dependent antiviral gene transcription including Ifnb1, reducing IFN-β production.\",\n      \"method\": \"Nuclear/cytoplasmic fractionation, quantitative mass spectrometry for interactors, siRNA knockdown, RT-qPCR, Salmonella infection assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation/localization with functional consequence, quantitative MS interactome, multiple orthogonal methods\",\n      \"pmids\": [\"29500242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using a chemical genetics approach (orthogonal NAD+ analog with engineered PARP14 variant) combined with BioID proximity-dependent labeling, 114 PARP14-specific MARylation substrates were identified, enriched for RNA regulatory proteins. PARP13 was identified as a direct PARP14 MARylation substrate, modified on several acidic amino acids.\",\n      \"method\": \"Chemical genetics (orthogonal NAD+ analog), BioID proximity labeling, mass spectrometry substrate identification, in vitro ADP-ribosylation assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — two orthogonal unbiased methods for substrate identification, in vitro validation of PARP13 as substrate\",\n      \"pmids\": [\"30247868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP14 catalytic activity promotes Th17 cell differentiation and is required for IL-4-dependent IgE antibody responses (B cell-intrinsic) and IgA antibody responses (predominantly B cell-extrinsic involving Th17 cells and CD103+ dendritic cells). PARP14 enhances expression of RORα, Runx1, and Smad3 after T cell activation.\",\n      \"method\": \"PARP14-deficient mice, antibody isotype measurements, flow cytometric analysis of Th17 cells and DC populations, gene expression analysis, catalytic mutant studies\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mice with multiple functional immune readouts, direct evidence for catalytic activity requirement\",\n      \"pmids\": [\"23956424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PARP14 catalyzes auto-ADP-ribosylation (auto-ribosylation), and co-crystal structures of PARP14 with inhibitor compounds showed that small-molecule inhibitors bind to the NAD+-binding site of the catalytic domain, acting as NAD+-competitive inhibitors.\",\n      \"method\": \"Purified PARP14 protein, RapidFire high-throughput mass spectrometry auto-ribosylation assay, [3H]NAD+ immunoradiometric assay, co-crystal structure determination, cell-based protein stabilization assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of PARP14 catalytic domain with inhibitors, in vitro enzymatic assays, single laboratory\",\n      \"pmids\": [\"28315326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP14 is a dual-function enzyme with both mono-ADP-ribosyl transferase and ADP-ribosyl hydrolase activities: the macrodomain 1 of PARP14 acts as an active ADP-ribosyl hydrolase (de-MARylase). Inactivation of macrodomain 1 (hydrolase-dead mutant) results in marked increase of protein mono-ADP-ribosylation in human cells, including auto-MARylation of PARP14 and MARylation of antiviral PARP13. The SARS-CoV-2 Nsp3 Mac1 macrodomain efficiently reverses PARP14 ADP-ribosylation in vitro and in cells.\",\n      \"method\": \"In vitro ADP-ribosylation and hydrolysis assays, macrodomain 1 mutagenesis, cellular MARylation detection with improved antibodies, SARS-CoV-2 Mac1 reversal assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with mutagenesis validation, cellular phenotype confirmation, multiple orthogonal methods across substrates\",\n      \"pmids\": [\"37703374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP14 macrodomain 1 and PARP9 macrodomain 1 both display ADP-ribosyl glycohydrolase activity that is not directed toward specific protein side chains; this activity does not degrade poly(ADP-ribose). The F926A mutation of PARP14 and F244A of PARP9 strongly reduced glycohydrolase activity, revealing mechanistic homology to the SARS-CoV-2 Nsp3 Mac1 domain.\",\n      \"method\": \"Biochemical ADP-ribosylation hydrolysis assays, site-directed mutagenesis (F926A PARP14, F244A PARP9), comparison with PARP1 poly-ADP-ribose substrate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis, mechanistically informative negative result (no poly-ADP-ribose degradation), single lab\",\n      \"pmids\": [\"37507011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PARP14 is a critical co-factor of MRE11 at reversed replication forks in BRCA-deficient cells: PARP14 is recruited to nascent DNA upon replication stress, and through its catalytic (mono-ADP-ribosyltransferase) activity mediates MRE11 engagement. The KU complex binds reversed forks and recruits the PARP14-MRE11 complex, which initiates partial resection to release KU and allow long-range resection by EXO1. Loss or inhibition of PARP14 suppresses MRE11-mediated fork degradation and ssDNA gap accumulation.\",\n      \"method\": \"iPOND (isolation of proteins on nascent DNA), proximity ligation assays, PARP14 inhibition/knockout, DNA fiber assays, S1 nuclease gap assays, MRE11 co-immunoprecipitation, KU interaction assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iPOND for direct nascent DNA recruitment, Co-IP for complex formation, catalytic inhibitor validation, multiple epistatic relationships established\",\n      \"pmids\": [\"36030235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFNγ-induced ADP-ribosylation in cells depends on PARP14 catalytic activity; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms (not transcriptional) and both localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins. PARP14 itself and DTX3L are ADP-ribosylation targets; the SARS-CoV-2 Nsp3 macrodomain reverses these modifications.\",\n      \"method\": \"IFNγ treatment with mono-ADPr antibody detection, PARP14 catalytic mutant, siRNA knockdown of PARP9/DTX3L, immunofluorescence, western blot for protein levels, Nsp3 Mac1 reversal\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, two independent simultaneous publications (PMID 38834853 and 38834852) with convergent findings\",\n      \"pmids\": [\"38834853\", \"38834852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP14 regulates cyclin D1 expression at the mRNA level via cyclin D1 3'UTR stability: depletion of PARP14 decreases cyclin D1 protein levels, leading to G1 cell-cycle arrest in cells with functional RB pathway, dependent on an intact p53-p21 pathway.\",\n      \"method\": \"PARP14 siRNA depletion, luciferase 3'UTR reporter assays, cell cycle analysis (flow cytometry), western blot for cyclin D1/RB/p53 pathway components\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase 3'UTR assay and cell cycle analysis provide mechanistic evidence, single lab study\",\n      \"pmids\": [\"34158578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genome-wide CRISPR knockout screen in PARP14-deficient cells identified the ATR-CHK1 pathway as synthetically lethal with PARP14 loss, and mechanistically linked this to regulation of DNA replication dynamics; inhibition of the ATR-CHK1 pathway in PARP14-deficient cells leads to cell death through replication stress.\",\n      \"method\": \"Genome-wide CRISPR knockout genetic screen, ATR/CHK1 inhibitor treatment of PARP14-deficient cells, DNA fiber assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genome-wide screen with mechanistic follow-up, single lab\",\n      \"pmids\": [\"32542389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DTX3L (BBAP) forms a protein complex with PARP14 (ARTD8) and PARP9 (ARTD9) in metastatic prostate cancer cells; the enzymatic activity of PARP14 is required for survival of these cells, and the complex mediates proliferation, chemo-resistance, and survival.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, cell proliferation/survival assays, catalytic mutant analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP for complex formation, catalytic activity requirement established, single lab\",\n      \"pmids\": [\"24886089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP14 regulates EP4 receptor expression in colon cancer cells through mono-ADP-ribosylation of HDAC1 and HDAC2; suppression of PARP14 activity by siRNA or inhibitors reduced EP4 receptor mRNA and protein expression.\",\n      \"method\": \"siRNA knockdown, PARP14 inhibitor treatment, RT-qPCR, western blot, HDAC ADP-ribosylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mono-ADP-ribosylation of HDAC1/2 proposed mechanistically with siRNA and inhibitor data, single lab without direct biochemical reconstitution\",\n      \"pmids\": [\"35914351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KH-like domains in PARP14 and PARP9/DTX3L coordinate protein-protein interactions important to pro-survival signaling: KH-like domains mediate PARP9-DTX3L and PARP14-DTX3L interactions; homodimerization of DTX3L is also coordinated by a KH-like domain. In vitro, DTX3L interaction with PARP14 suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of KH domain, PARP14 truncation rescue experiments, in vitro ADP-ribosylation assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mutagenesis, in vitro enzymatic assays for regulation of activity, single lab\",\n      \"pmids\": [\"38182103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP14 mono-ADP-ribosylates RACK1 (an integral ribosome component) on three acidic residues in ovarian cancer cells; MARylation of RACK1 is required for stress granule formation and promotes colocalization of RACK1 with G3BP1, eIF3η, and 40S ribosomal subunits in stress granules, while reducing translation of a subset of mRNAs including AKT. The ADP-ribosyl hydrolase TARG1 reverses this modification, allowing stress granule dissociation and translation restoration.\",\n      \"method\": \"Mass spectrometry identification of MARylation sites, PARP14 inhibitor, site-directed mutagenesis of RACK1 MARylation sites, stress granule imaging, polysome profiling, in vivo tumor xenograft\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified sites with mutagenesis validation and in vivo confirmation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"37873085\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 catalytic activity enhances IFN-β and IFN-γ responses and restricts replication of ARH-deficient coronaviruses (MHV, SARS-CoV-2) and HSV-1. PARP14 has pro-viral function for VSV, as its knockout decreased VSV replication. The effects on HSV-1 and VSV were independent of PARP14 catalytic activity as demonstrated by an active site inhibitor having no effect.\",\n      \"method\": \"PARP14 knockout (CRISPR) A549 cells, viral replication assays for MHV, SARS-CoV-2, HSV-1, VSV, LCMV; PARP14 active site inhibitor treatment; IFN-β/IFN-γ ELISA\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple viral challenges and orthogonal catalytic inhibitor, single lab, peer-reviewed\",\n      \"pmids\": [\"40937852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Interferon induces PARP14-mediated mono-ADP-ribosylation of SQSTM1/p62 at cysteine residues 113, 289/290, and 331; this creates cytoplasmic p62 foci colocalizing with ubiquitin and PARP14 but lacking LC3, distinguishing them from autophagosomes. TRIM21 prevents autophagic degradation of ADP-ribosylated p62. The SARS-CoV-2 macrodomain reverses this p62 modification.\",\n      \"method\": \"Mass spectrometry for site identification, site-directed mutagenesis of p62 cysteines, immunofluorescence, PARP14 catalytic inhibition, SARS-CoV-2 macrodomain reversal assays, TRIM21 knockdown\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified cysteine sites with mutagenesis, viral macrodomain reversal, preprint stage\",\n      \"pmids\": [\"bio_10.1101_2024.06.29.601315\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Interferon-induced PARP14-mediated ADP-ribosylation occurs within p62 body condensates: PARP14 physical presence and catalytic activity are both required for condensate formation. These PARP14/ADPr condensates contain p62, NBR1, TAX1BP1, and K48/K63-linked polyubiquitin but lack LC3B; p62 knockdown disrupts condensate formation. Condensate integrity is independent of autophagy but requires ubiquitination and proteasome activity.\",\n      \"method\": \"siRNA knockdown of PARP14 and p62, PARP14 catalytic mutant expression, immunofluorescence, autophagy inhibitors (bafilomycin), proteasome inhibitors, ubiquitination inhibitors\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — catalytic mutant distinguishes physical vs enzymatic role, multiple genetic knockdowns with convergent results, peer-reviewed\",\n      \"pmids\": [\"40195501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PARP14 is recruited to nascent DNA at reversed replication forks in BRCA2-deficient cells via its RRM (RNA Recognition Motif) domains; these domains are necessary for MRE11 recruitment to reversed forks, for promotion of nascent strand degradation, and for replication stress-induced double-strand break formation in BRCA2-deficient cells.\",\n      \"method\": \"iPOND, PARP14 domain truncation/deletion constructs, DNA fiber assays, DSB (γH2AX) analysis, MRE11 foci assays in BRCA2-deficient cells\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPOND for direct nascent DNA recruitment, domain-specific rescue experiments, functional epistasis, single lab with multiple orthogonal assays\",\n      \"pmids\": [\"41684642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PARP14 mediates MARylation of GLUD1 (glutamate dehydrogenase 1), inhibiting GLUD1 enzyme activity via mono-ADP-ribosylation, which reduces alpha-ketoglutarate production and suppresses mitochondrial energy metabolism in granulosa cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ADP-ribosylation assay, GLUD1 enzyme activity measurement, metabolite (α-KG) quantification, PARP14 overexpression/knockdown\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — Co-IP and enzymatic activity assay support substrate relationship, single lab, single paper\",\n      \"pmids\": [\"41895093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PARP14 promotes post-stroke functional recovery by inhibiting microglial activation through suppression of LPAR5 (lysophosphatidic acid receptor 5) gene transcription; PARP14 overexpression in microglia attenuates post-stroke microglial activation possibly through modulation of macroautophagy.\",\n      \"method\": \"PARP14 genetic knockdown/overexpression in photothrombotic stroke mouse model, pharmacological PARP14 inhibition, microglial activation assays, LPAR5 promoter analysis, autophagy modulation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo loss/gain-of-function with defined molecular target (LPAR5 transcription), single lab\",\n      \"pmids\": [\"33317392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PARP14 ADP-ribosylates itself (auto-ribosylation); mass spectrometry detected IFNγ-induced ADP-ribosylation of PARP14 (ARTD8) along with PARP9 (ARTD9) in macrophages, providing first characterization of ADP-ribosylation on these PARP family members.\",\n      \"method\": \"Af1521 enrichment of ADP-ribosylated peptides, anti-poly-ADPr antibody enrichment, EThcD and HCD MS/MS, IFNγ treatment of THP-1 macrophages\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mass spectrometry identification of modification sites, single lab, no mutagenesis validation of specific sites\",\n      \"pmids\": [\"30848916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP14 promotes AML cell glycolysis by activating NF-κB signaling, which in turn promotes HIF-1α expression; HIF-1α silencing reverses the cancer-promoting effects of PARP14 overexpression.\",\n      \"method\": \"siRNA/overexpression of PARP14, NF-κB inhibitor (BAY11-7082), HIF-1α siRNA rescue, glycolysis assays (ECAR, glucose consumption, lactate production), xenograft tumor model\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway epistasis via rescue experiments and pharmacological inhibition, in vivo validation, single lab\",\n      \"pmids\": [\"35944879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 inhibits microglial activation and depressive-like behavior by positively regulating nicotinamide nucleotide transhydrogenase (NNT) expression in microglia; NNT deficiency leads to ROS accumulation and microglial inflammation, which PARP14 suppresses via NNT-mediated ROS clearance.\",\n      \"method\": \"CUS mouse model, hippocampal PARP14 knockdown/overexpression, microglial-targeted AAV overexpression, NNT overexpression rescue, ROS inhibitor (NAC) treatment, microglial activation assays\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis via NNT rescue, in vivo targeted overexpression, single lab\",\n      \"pmids\": [\"39978699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF2 (m6A reader) interacts with PARP14 mRNA under oxygen-glucose deprivation (OGD) conditions, promoting m6A-dependent degradation of PARP14 mRNA and reducing PARP14 protein levels; this mechanism enables YTHDF2-dependent suppression of PARP14-driven M2 microglial polarization.\",\n      \"method\": \"RIP (RNA immunoprecipitation) for YTHDF2-PARP14 mRNA interaction, siRNA knockdown of YTHDF2, mRNA stability assays, microglial phenotype assays\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP confirms mRNA-protein interaction, functional epistasis demonstrated, single lab\",\n      \"pmids\": [\"40383033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 enhances SOCS2 mRNA stability, promoting M2 macrophage polarization relevant to hypertrophic scarring; overexpression of PARP14 restored M2 polarization in macrophages treated with botulinum toxin A, which was counteracted by additional SOCS2 silencing.\",\n      \"method\": \"RNA sequencing, PARP14 overexpression, SOCS2 silencing rescue experiments, mRNA stability assays, in vivo mouse HS model, THP-1 M2 polarization model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA stability assay and epistasis rescue, single lab, limited mechanistic detail on how ADP-ribosylation mediates mRNA stabilization\",\n      \"pmids\": [\"40505894\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARP14 is a large multidomain mono-ADP-ribosyltransferase (and its macrodomain 1 a de-MARylase) that acts as a bimodal transcriptional switch—recruiting HDACs to repress IL-4/STAT6 target genes at baseline and ADP-ribosylating them upon IL-4 stimulation to enable STAT6-driven transcription—while also directly ADP-ribosylating STAT1 to suppress pro-inflammatory signaling, interacting with and inhibiting the pro-apoptotic kinase JNK1 to promote cell survival and the Warburg effect, acting as a critical co-factor for MRE11-dependent replication fork processing via its RRM domains, functioning as a major IFN-induced ADP-ribosyltransferase whose activity is targeted by viral macrodomains (e.g., SARS-CoV-2 Nsp3 Mac1), and regulating mRNA stability of select transcripts through ribonucleoprotein complexes with tristetraprolin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PARP14 is a large multidomain mono-ADP-ribosyltransferase that operates as a bimodal regulator of cytokine-driven transcription, innate immune signaling, and replication-stress responses [#0, #7, #15]. In IL-4 signaling it acts as a transcriptional switch: at baseline it recruits HDAC2/HDAC3 to IL-4-responsive promoters to repress transcription, and upon IL-4 stimulation it ADP-ribosylates these HDACs to release them and permit STAT6-driven gene activation, supporting B-cell survival, glycolysis, and lymphomagenesis [#0, #2, #3]. PARP14 catalytic activity also directly ADP-ribosylates STAT1 to suppress STAT1 phosphorylation and pro-inflammatory macrophage activation, an effect antagonized by PARP9 [#7]. Beyond transcription, PARP14 binds and inhibits the pro-apoptotic kinase JNK1, blocking JNK1-mediated phosphorylation of PKM2 to enforce the Warburg effect and promote tumor-cell survival [#4, #5]. In genome maintenance, PARP14 is recruited to nascent DNA at reversed replication forks via its RRM domains and, through its catalytic activity, drives MRE11 engagement and fork resection, promoting homologous recombination and rendering its loss synthetically lethal with ATR-CHK1 inhibition [#6, #15, #26, #18]. PARP14 is a major interferon-induced ADP-ribosyltransferase: it auto-MARylates and modifies substrates including PARP13, RACK1, and SQSTM1/p62, and its activity is reversed by its own macrodomain 1—an active de-MARylase (glycohydrolase)—and by the SARS-CoV-2 Nsp3 Mac1 macrodomain [#13, #14, #10, #29, #16]. PARP14 nucleates interferon-induced p62-body condensates and restricts replication of several viruses [#25, #23]. PARP14 additionally regulates the stability of select mRNAs, forming a ribonucleoprotein complex with tristetraprolin on tissue factor mRNA [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that PARP14 is a functional partner of STAT6 controlling cytokine-driven cell fate, linking the protein to IL-4-dependent B-cell survival rather than leaving it an orphan ADP-ribosyltransferase.\",\n      \"evidence\": \"Parp14-knockout mice, apoptosis and gene expression assays, STAT6 binding assays in primary B cells\",\n      \"pmids\": [\"19147789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define whether catalytic activity is required for the STAT6 interaction\", \"Molecular mechanism of survival gene induction not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Answered how PARP14 switches transcription by showing it represses via HDAC recruitment at baseline and de-represses by ADP-ribosylating the HDACs upon IL-4 stimulation, defining a bimodal enzymatic transcriptional switch.\",\n      \"evidence\": \"ChIP, co-IP, promoter reporter and ADP-ribosylation assays in T/B cells\",\n      \"pmids\": [\"21081493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical reconstitution of HDAC ADP-ribosylation not shown\", \"Specific modified residues on HDAC2/3 not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected PARP14 to metabolic reprogramming by showing IL-4-induced glycolysis underlies its pro-survival and lymphomagenic function, with AMPK as a rescuing node.\",\n      \"evidence\": \"Parp14-knockout mice, glycolysis and AMPK activity assays, Myc-driven lymphoma models\",\n      \"pmids\": [\"21911376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrate linking PARP14 to glycolytic control not identified\", \"Relationship between AMPK rescue and ADP-ribosylation unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a non-transcriptional survival mechanism: PARP14 physically binds and inhibits pro-apoptotic JNK1, placing it downstream of JNK2 in myeloma survival signaling.\",\n      \"evidence\": \"siRNA/shRNA, overexpression rescue, PARP14-JNK1 co-IP, apoptosis assays in myeloma lines\",\n      \"pmids\": [\"23045269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JNK1 is an ADP-ribosylation substrate not established\", \"Structural basis of inhibition unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined PARP14 macrodomains 2 and 3 as readers of mono-ADP-ribose with substrate selectivity, establishing PARP14 as both writer and reader of MARylation.\",\n      \"evidence\": \"Crystal structures, ITC, binding/co-localization assays with MARylated ARTD10 and Ran\",\n      \"pmids\": [\"23473667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo MARylated ligands recognized by these macrodomains not defined\", \"Functional consequence of reading in cells not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed PARP14 catalytic activity shapes adaptive immunity, driving Th17 differentiation and IL-4-dependent IgE/IgA responses through transcription-factor expression.\",\n      \"evidence\": \"Parp14-deficient and catalytic-mutant mice, antibody isotype and flow-cytometric analyses\",\n      \"pmids\": [\"23956424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates mediating RORα/Runx1/Smad3 induction unknown\", \"B-cell-intrinsic vs extrinsic mechanisms incompletely separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked the JNK1-inhibitory function to metabolism by defining the PARP14-JNK1-PKM2 axis controlling aerobic glycolysis in hepatocellular carcinoma.\",\n      \"evidence\": \"In vitro/in vivo loss-of-function, PKM2 Thr365 phosphorylation and glycolysis assays\",\n      \"pmids\": [\"26258887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic requirement of PARP14 for JNK1 inhibition not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed PARP14 in genome maintenance by demonstrating its PCNA interaction and requirement for homologous recombination and replication of difficult loci.\",\n      \"evidence\": \"PARP14-PCNA co-IP, siRNA, RAD51 foci, HR reporter and comet assays\",\n      \"pmids\": [\"25753673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain mediating PCNA interaction not mapped here\", \"Whether catalytic activity is required not yet tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified STAT1 as a direct ADP-ribosylation substrate whose modification suppresses phosphorylation, defining the PARP14/PARP9 cross-regulatory axis of macrophage activation.\",\n      \"evidence\": \"Proteomics, STAT1 site mutagenesis, PARP14/PARP9 silencing in primary macrophages\",\n      \"pmids\": [\"27796300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAT1 ADP-ribose-mediated phospho-suppression unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a post-transcriptional role: PARP14 forms an RNP with tristetraprolin to control tissue factor mRNA stability with transcript selectivity.\",\n      \"evidence\": \"RNP-IP, biotinylated RNA pulldown, knockout macrophages, mRNA stability and coagulation assays\",\n      \"pmids\": [\"25293769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADP-ribosylation drives the mRNA stabilization not established\", \"Basis of transcript selectivity unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a stable PARP14-PARP9-DTX3L complex required for cancer-cell survival, establishing physical assembly of these ADP-ribosylation machinery components.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, siRNA, catalytic-mutant survival assays in prostate cancer cells\",\n      \"pmids\": [\"24886089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Stoichiometry and architecture of the complex not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural and enzymatic characterization of PARP14 auto-ADP-ribosylation and NAD+-competitive inhibition, enabling pharmacological targeting.\",\n      \"evidence\": \"Purified protein, RapidFire MS and [3H]NAD+ auto-ribosylation assays, co-crystal structures with inhibitors\",\n      \"pmids\": [\"28315326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of auto-modification not addressed here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed PARP14 translocates to the nucleus on inflammatory stimulation, binds ISG-encoded proteins, and is required for IRF3-dependent antiviral transcription including IFN-β.\",\n      \"evidence\": \"Fractionation, quantitative MS interactome, siRNA, RT-qPCR, Salmonella infection assays\",\n      \"pmids\": [\"29500242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity drives ISG-protein nuclear accumulation not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the PARP14-specific MARylation substrate landscape via chemical genetics and proximity labeling, revealing enrichment for RNA-regulatory proteins and identifying PARP13 as a direct substrate.\",\n      \"evidence\": \"Orthogonal NAD+ analog with engineered PARP14, BioID, MS substrate ID, in vitro validation\",\n      \"pmids\": [\"30247868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of most identified substrates untested\", \"Modified residues on most substrates not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided first direct mapping of IFNγ-induced ADP-ribosylation on PARP14 and PARP9 in macrophages, establishing these PARPs as auto/cross-modification targets in interferon signaling.\",\n      \"evidence\": \"Af1521 enrichment, EThcD/HCD MS/MS of IFNγ-treated THP-1 macrophages\",\n      \"pmids\": [\"30848916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of specific sites\", \"Functional role of identified sites untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed PARP14 as a critical co-factor of MRE11 at reversed forks in BRCA-deficient cells, defining a KU-PARP14-MRE11-EXO1 resection pathway dependent on catalytic activity.\",\n      \"evidence\": \"iPOND, PLA, DNA fiber and S1 nuclease assays, MRE11/KU co-IP, PARP14 inhibition/knockout\",\n      \"pmids\": [\"36030235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ADP-ribosylation substrate enabling MRE11 engagement not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified ATR-CHK1 as synthetically lethal with PARP14 loss, mechanistically tying PARP14 to replication-dynamics control and nominating a therapeutic vulnerability.\",\n      \"evidence\": \"Genome-wide CRISPR knockout screen, ATR/CHK1 inhibitor treatment, DNA fiber assays\",\n      \"pmids\": [\"32542389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular mechanism linking PARP14 to ATR-CHK1 dependence incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PARP14 function to CNS injury, showing it limits microglial activation and promotes post-stroke recovery via suppression of LPAR5 transcription.\",\n      \"evidence\": \"Photothrombotic stroke model with PARP14 knockdown/overexpression, pharmacological inhibition, LPAR5 promoter analysis\",\n      \"pmids\": [\"33317392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct link between ADP-ribosylation and LPAR5 transcription unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PARP14 controls cyclin D1 expression via 3'UTR mRNA stability, governing G1 progression through the RB and p53-p21 pathways.\",\n      \"evidence\": \"siRNA depletion, luciferase 3'UTR reporters, cell-cycle and western analyses\",\n      \"pmids\": [\"34158578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether ADP-ribosylation mediates the 3'UTR effect not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected PARP14 transcriptional regulation to EP4 receptor expression in colon cancer through MARylation of HDAC1/HDAC2.\",\n      \"evidence\": \"siRNA, PARP14 inhibitor, RT-qPCR, western, HDAC ADP-ribosylation assays\",\n      \"pmids\": [\"35914351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of HDAC1/2 modification\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated PARP14 in AML glycolysis through an NF-κB/HIF-1α axis, extending its metabolic role to myeloid leukemia.\",\n      \"evidence\": \"siRNA/overexpression, NF-κB inhibitor, HIF-1α siRNA rescue, glycolysis assays, xenografts\",\n      \"pmids\": [\"35944879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which PARP14 activates NF-κB not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reclassified PARP14 as a dual-function enzyme by demonstrating its macrodomain 1 is an active de-MARylase, with viral Nsp3 Mac1 reversing PARP14 modifications.\",\n      \"evidence\": \"In vitro reconstitution, macrodomain-1 mutagenesis, cellular MARylation detection, SARS-CoV-2 Mac1 reversal\",\n      \"pmids\": [\"37703374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance between writer and eraser activities not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Characterized PARP14 (and PARP9) macrodomain-1 as ADP-ribosyl glycohydrolases not directed to specific side chains and inactive on poly(ADP-ribose), revealing mechanistic homology to SARS-CoV-2 Mac1.\",\n      \"evidence\": \"In vitro hydrolysis assays, F926A/F244A mutagenesis, PARP1 poly-ADP-ribose comparison\",\n      \"pmids\": [\"37507011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Endogenous substrates of the glycohydrolase activity not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed IFNγ-induced cellular ADP-ribosylation depends on PARP14 catalysis and that PARP9/DTX3L post-translationally control PARP14 levels and co-localize at cytoplasmic ADPr inclusions.\",\n      \"evidence\": \"IFNγ treatment with anti-mono-ADPr detection, catalytic mutant, PARP9/DTX3L siRNA, immunofluorescence, Nsp3 Mac1 reversal (two convergent papers)\",\n      \"pmids\": [\"38834853\", \"38834852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of post-translational PARP14 level control by PARP9/DTX3L not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined KH-like domains as the structural basis for PARP14-DTX3L-PARP9 interactions, with DTX3L binding suppressing PARP14 auto-modification and redirecting it to trans-modification.\",\n      \"evidence\": \"Co-IP, KH-domain mutagenesis, PARP14 truncation rescue, in vitro ADP-ribosylation assays\",\n      \"pmids\": [\"38182103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Cellular consequence of DTX3L-redirected activity not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified RACK1 as a PARP14 MARylation substrate whose modification drives stress-granule formation and selective translational repression, reversed by TARG1.\",\n      \"evidence\": \"MS site mapping, RACK1 mutagenesis, stress-granule imaging, polysome profiling, xenograft (preprint)\",\n      \"pmids\": [\"37873085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Generality beyond ovarian cancer cells untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PARP14 catalytic activity enhances IFN-β/IFN-γ responses and restricts ARH-deficient coronaviruses and HSV-1 while being pro-viral for VSV, separating catalytic from non-catalytic antiviral roles.\",\n      \"evidence\": \"CRISPR-knockout A549 cells, multi-virus replication assays, active-site inhibitor, IFN ELISA\",\n      \"pmids\": [\"40937852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Catalytic substrates underlying virus restriction not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that PARP14 both physically scaffolds and catalytically maintains interferon-induced p62-body condensates containing selective autophagy receptors and polyubiquitin but lacking LC3B.\",\n      \"evidence\": \"PARP14/p62 siRNA, catalytic mutant, immunofluorescence, autophagy/proteasome/ubiquitination inhibitors\",\n      \"pmids\": [\"40195501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of these condensates incompletely defined\", \"p62 cysteine-MARylation role within condensates not fully linked\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified PARP14 RRM domains as the recruitment module to reversed forks required for MRE11 engagement and nascent-strand degradation in BRCA2-deficient cells, refining the structural basis of its replication-stress role.\",\n      \"evidence\": \"iPOND, domain truncation/deletion constructs, DNA fiber, γH2AX and MRE11 foci assays\",\n      \"pmids\": [\"41684642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA ligand, if any, bound by the RRMs at forks unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended PARP14 substrate repertoire to metabolic enzyme GLUD1, whose MARylation inhibits glutamate dehydrogenase activity and suppresses mitochondrial energy metabolism.\",\n      \"evidence\": \"Co-IP, in vitro ADP-ribosylation, GLUD1 activity and α-KG measurements in granulosa cells\",\n      \"pmids\": [\"41895093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Modified residues on GLUD1 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which direct ADP-ribosylation substrates mediate PARP14's transcriptional, replication-fork, and antiviral phenotypes, and how the balance between its transferase and macrodomain-1 hydrolase activities is regulated in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Causal substrate-to-phenotype links largely inferential\", \"In vivo regulation of writer/eraser balance unquantified\", \"Structural basis of many substrate interactions undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 10, 13, 22, 27]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [12, 13, 29]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 10, 17]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 22, 25]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 15, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 9, 11, 23]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 15, 26, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 5, 27, 30]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 17, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 7]}\n    ],\n    \"complexes\": [\n      \"PARP14-PARP9-DTX3L complex\",\n      \"PARP14-tristetraprolin (TTP) ribonucleoprotein complex\",\n      \"p62-body condensate\"\n    ],\n    \"partners\": [\n      \"STAT6\",\n      \"JNK1\",\n      \"PCNA\",\n      \"MRE11\",\n      \"DTX3L\",\n      \"PARP9\",\n      \"STAT1\",\n      \"PARP13\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}