{"gene":"PARP14","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2010,"finding":"PARP-14 functions as a transcriptional switch for STAT6-dependent gene activation: under non-stimulating conditions it 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, promotes STAT6 binding to target promoters, and allows replacement by HAT-containing coactivators.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, ADP-ribosylation assays, luciferase reporter assays, loss-of-function studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, enzymatic assay) in single lab with strong mechanistic model","pmids":["21081493"],"is_preprint":false},{"year":2009,"finding":"PARP-14 is a binding partner of the IL-4-induced transcription factor STAT6 and mediates IL-4-dependent protection against apoptosis in primary B cells, regulating gene products controlling cell survival, proliferation, and lymphomagenesis.","method":"PARP-14 knockout mice, co-immunoprecipitation, apoptosis assays, gene expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic KO model with defined phenotype, binding partner identified by Co-IP, replicated in primary cells","pmids":["19147789"],"is_preprint":false},{"year":2011,"finding":"PARP-14 is required for IL-4-induced enhancement of glycolysis in B cells; this glycolytic activity is central to IL-4-mediated prosurvival signaling, and PARP14 deficiency delays B lymphomagenesis driven by the Myc oncogene.","method":"Parp14 knockout mice, glycolysis assays, AMPK activity measurement, Myc-driven lymphoma model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple cellular readouts, in vivo oncogenesis model, pathway placement via AMPK epistasis","pmids":["21911376"],"is_preprint":false},{"year":2012,"finding":"PARP14 is a critical effector of JNK2-dependent prosurvival signaling in multiple myeloma: constitutively active JNK2 maintains PARP14 expression, PARP14 binds and inhibits pro-apoptotic JNK1, and PARP14 overexpression rescues myeloma cells from apoptosis induced by JNK2 knockdown.","method":"Loss-of-function (siRNA), overexpression rescue experiments, co-immunoprecipitation (PARP14-JNK1 binding), apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP demonstrating PARP14-JNK1 interaction, epistasis rescue experiment, multiple myeloma cell lines and primary tumors","pmids":["23045269"],"is_preprint":false},{"year":2013,"finding":"PARP14 macrodomains 2 and 3 (ARTD8/PARP14) function as readers of mono-ADP-ribosylated substrates: crystal structures of these macrodomains confirmed ADP-ribose binding, they recognized mono-ADP-ribosylated ARTD10 and its substrate Ran but not poly-ADP-ribosylated ARTD1, and ARTD10 colocalized with ARTD8 in cells.","method":"Crystal structure determination, isothermal titration calorimetry, in vitro binding assays, cell colocalization","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structures combined with ITC and in vitro functional validation of macrodomain reader activity","pmids":["23473667"],"is_preprint":false},{"year":2014,"finding":"PARP14 forms a ribonucleoprotein complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved AU-rich element in the tissue factor (TF) mRNA 3′UTR, selectively regulating TF mRNA stability in macrophages; PARP14 deficiency increases TF mRNA stability, TF expression, and coagulation activity in vitro and in vivo.","method":"Ribonucleoprotein complex immunoprecipitation, biotinylated RNA pull-down, Parp14 knockout mice, mRNA stability assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — direct RNA-protein interaction demonstrated by RIP and RNA pull-down, confirmed in vivo with KO mice","pmids":["25293769"],"is_preprint":false},{"year":2014,"finding":"PARP14 (ARTD8) forms complexes with DTX3L and ARTD9 in metastatic prostate cancer cells, and its enzymatic (ADP-ribosyltransferase) activity is required for survival of these cells; the complex also regulates IRF1 expression.","method":"Co-immunoprecipitation, immunofluorescence, siRNA loss-of-function, cell survival and proliferation assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP confirms complex formation, catalytic activity requirement shown by KD, single lab","pmids":["24886089"],"is_preprint":false},{"year":2015,"finding":"PARP14 promotes aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by maintaining low PKM2 activity: PARP14 inhibits pro-apoptotic JNK1 kinase, which would otherwise phosphorylate PKM2 at Thr365 and activate it; loss of PARP14 leads to JNK1 activation, PKM2 phosphorylation, and reduced glycolysis/increased apoptosis.","method":"Loss-of-function studies (siRNA/shRNA) in vitro and in vivo (xenografts), PKM2 phosphorylation assays, glycolysis measurements, JNK1 activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (PARP14→JNK1→PKM2-Thr365) validated in vitro and in vivo with multiple orthogonal methods","pmids":["26258887"],"is_preprint":false},{"year":2015,"finding":"PARP14 (mono-ADP-ribosyltransferase) interacts with PCNA and promotes homologous recombination DNA repair; PARP14 depletion results in reduced HR, persistent RAD51 foci, hypersensitivity to DNA-damaging agents, and accumulation of DNA strand breaks, establishing a role in replication fork stability and common fragile site replication.","method":"Co-immunoprecipitation (PARP14-PCNA interaction), siRNA knockdown, DNA damage sensitivity assays, RAD51 foci analysis, comet assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction shown by Co-IP, multiple DNA repair phenotypes in KD cells, two orthogonal readouts","pmids":["25753673"],"is_preprint":false},{"year":2016,"finding":"PARP14 and PARP9 cross-regulate macrophage activation: PARP14 directly ADP-ribosylates STAT1, which suppresses STAT1 phosphorylation; PARP9 counteracts this modification. Mutations at PARP14-dependent ADP-ribosylation sites on STAT1 lead to increased STAT1 phosphorylation. PARP14 also promotes STAT6 phosphorylation and anti-inflammatory gene expression in M(IL-4) macrophages.","method":"Global proteomics, siRNA knockdown, ADP-ribosylation assays, site-directed mutagenesis of STAT1 ADP-ribosylation sites, phosphorylation analysis, primary macrophages","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — direct ADP-ribosylation of STAT1 demonstrated biochemically; mutagenesis of modification sites shows functional consequence; replicated across M1/M2 contexts","pmids":["27796300"],"is_preprint":false},{"year":2018,"finding":"Using a chemical genetics approach (orthogonal NAD+ analog) combined with BioID proximity labeling, PARP14 was shown to MARylate 114 specific protein substrates, several of which are RNA regulatory proteins; PARP13 is directly MARylated by PARP14 on several acidic amino acids, revealing crosstalk between PARP family members.","method":"Chemical genetics (engineered PARP14 with orthogonal NAD+ analog), BioID proximity labeling, mass spectrometry, in vitro MARylation assays","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 — chemical genetics plus proximity labeling provides direct, selective substrate identification; in vitro validation of PARP13 MARylation","pmids":["30247868"],"is_preprint":false},{"year":2018,"finding":"PARP14 translocates into the nucleus of macrophages stimulated with inflammatory stimuli, binds a group of IFN-stimulated gene (ISG)-encoded proteins (identified by quantitative mass spectrometry), and is required for their nuclear accumulation; PARP14 depletion also attenuates transcription of primary antiviral response genes including Ifnb1, reducing IFN-β production.","method":"Nuclear fractionation/translocation assays, quantitative mass spectrometry, siRNA knockdown, gene expression analysis, Salmonella infection assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization experiment with functional consequence, MS-defined interactome, loss-of-function phenotype","pmids":["29500242"],"is_preprint":false},{"year":2020,"finding":"PARP14 suppresses microglial activation post-stroke by transcriptionally repressing the Lpar5 (lysophosphatidic acid receptor 5) gene; overexpression of PARP14 reduces LPAR5 expression and alleviates microglial activation, while PARP14 knockdown increases activation and worsens stroke outcomes.","method":"Photothrombotic stroke mouse model, PARP14 overexpression/knockdown, microglial activation assays, gene expression analysis, pharmacological inhibition","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function and gain-of-function with defined mechanistic target (LPAR5 transcription); single lab","pmids":["33317392"],"is_preprint":false},{"year":2020,"finding":"Genome-wide CRISPR screen in PARP14-deficient cells identified the ATR-CHK1 pathway as synthetically lethal with PARP14 loss; PARP14 modulates DNA replication dynamics, and its loss sensitizes cells to ATR-CHK1 pathway inhibitors.","method":"Genome-wide CRISPR knockout screen, DNA fiber assay (replication dynamics), ATR/CHK1 inhibitor sensitivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — unbiased genome-wide genetic screen with orthogonal mechanistic validation of replication dynamics","pmids":["32542389"],"is_preprint":false},{"year":2021,"finding":"PARP14 regulates cyclin D1 mRNA stability through the cyclin D1 3′UTR, controlling cyclin D1 protein levels; depletion of PARP14 reduces cyclin D1, causes G1 cell-cycle arrest dependent on an intact RB pathway, and requires the p53-p21 pathway for arrest.","method":"siRNA knockdown, luciferase 3′UTR stability assays, cell cycle analysis (flow cytometry), Western blot","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — luciferase assay directly demonstrates 3′UTR-mediated mRNA stability control; genetic epistasis with RB and p53 pathways","pmids":["34158578"],"is_preprint":false},{"year":2022,"finding":"PARP14 is a critical cofactor of MRE11 at stalled 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, promoting fork degradation and ssDNA gap accumulation; the KU complex recruits the PARP14-MRE11 complex to initiate partial resection.","method":"DNA fiber assay, iPOND (isolation of proteins on nascent DNA), siRNA/catalytic inhibitor studies, proximity ligation assay, Co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating PARP14-MRE11 interaction at nascent DNA; catalytic activity requirement shown; KU epistasis established","pmids":["36030235"],"is_preprint":false},{"year":2023,"finding":"PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase (de-MARylase) activities: the PARP14 macrodomain 1 is an active ADP-ribosyl glycohydrolase acting on protein and nucleic acid substrates; inactivation of macrodomain 1 causes marked accumulation of MARylation (including on PARP14 itself and PARP13) in human cells; SARS-CoV-2 Mac1 reverses PARP14-mediated ADP-ribosylation in vitro and in cells.","method":"In vitro ADP-ribosylhydrolase activity assays, site-directed mutagenesis (macrodomain 1 inactivation), cell-based MARylation detection, reconstitution with SARS-CoV-2 Mac1","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of hydrolase activity, mutagenesis confirming active site, cellular phenotype validation","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; PARP14 macrodomain 1 cannot degrade poly(ADP-ribose); the F926A mutation of PARP14 macrodomain 1 strongly reduces hydrolase activity, mechanistically analogous to SARS-CoV-2 Nsp3 Mac1.","method":"Biochemical ADP-ribosylation/hydrolysis assays, site-directed mutagenesis (F926A), comparison with Mac1 domain","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis confirming catalytic residue; mechanistic characterization of hydrolase activity","pmids":["37507011"],"is_preprint":false},{"year":2024,"finding":"Interferon-γ-induced ADP-ribosylation in macrophages depends on PARP14 as the major catalytic enzyme; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms and modulates PARP14 ADP-ribosylation activity; PARP14 and DTX3L localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins; SARS-CoV-2 Mac1 reverses PARP14-dependent ADP-ribosylation.","method":"Improved mono-ADP-ribosylation antibody detection, PARP14/PARP9/DTX3L knockdown, immunofluorescence localization, in vitro hydrolysis by Mac1, mass spectrometry","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches; PARP14 identified as major IFN-induced ART; PARP9/DTX3L regulation confirmed; corroborated by companion paper (PMID:38834852)","pmids":["38834853","38834852"],"is_preprint":false},{"year":2024,"finding":"KH-like domains in PARP14 and in PARP9/DTX3L mediate protein-protein interactions: KH domains coordinate PARP9-DTX3L and PARP14-DTX3L interactions; DTX3L homodimerization is coordinated by its KH-like domain; in vitro, DTX3L interaction suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.","method":"Co-immunoprecipitation, site-directed mutagenesis of KH domain, in vitro ADP-ribosylation assays, cell survival assays with truncation constructs","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction and enzymatic consequence demonstrated in vitro; single lab","pmids":["38182103"],"is_preprint":false},{"year":2024,"finding":"Interferon-induced PARP14 mono-ADP-ribosylates SQSTM1/p62 at cysteine residues 113, 289/290, and 331; this modification occurs in cytoplasmic p62 foci that colocalize with ubiquitin and PARP14 but not LC3 (autophagosome marker); SARS-CoV-2 macrodomain prevents this p62 modification, and TRIM21 prevents autophagic degradation of ADP-ribosylated p62.","method":"Site-specific mutagenesis of p62 cysteine residues, immunofluorescence colocalization, in vitro MARylation, SARS-CoV-2 macrodomain treatment, TRIM21 knockdown","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro MARylation with site-specific mutagenesis; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.06.29.601315"],"is_preprint":true},{"year":2024,"finding":"Interferon-induced PARP14-mediated ADP-ribosylation occurs in p62 body condensates: PARP14 physical presence and catalytic activity are both required for condensate formation; these condensates contain p62, NBR1, TAX1BP1, and K48/K63-linked polyubiquitin chains but lack LC3B; condensate formation requires an active ubiquitin-proteasome system but not autophagy.","method":"PARP14 knockdown/catalytic mutant, immunofluorescence colocalization, p62 knockdown, autophagy inhibitors, proteasome inhibitors, ubiquitin pathway perturbations","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological perturbations define condensate requirements; catalytic activity and physical presence distinguished; peer-reviewed","pmids":["40195501"],"is_preprint":false},{"year":2024,"finding":"PARP14 mono-ADP-ribosylates RACK1 (an integral ribosome component) on three acidic residues, promoting stress granule formation and colocalization of RACK1 with G3BP1, eIF3η, and 40S ribosomal proteins; MARylation of RACK1 reduces translation of a subset of mRNAs including AKT; the ADP-ribosyl hydrolase TARG1 de-MARylates RACK1 to disassemble stress granules and restore translation.","method":"In vitro MARylation assay, site-directed mutagenesis of RACK1 acceptor residues, PARP14 inhibitor treatment, stress granule imaging, polysome profiling, in vivo tumor growth assays","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution and mutagenesis of modification sites; functional cellular and in vivo validation; preprint","pmids":["37873085"],"is_preprint":true},{"year":2022,"finding":"PARP14 promotes EP4 receptor expression in colon cancer cells by mono-ADP-ribosylating HDAC1 and HDAC2; suppression of PARP14 by siRNA or inhibitors reduces EP4 receptor mRNA and protein expression.","method":"siRNA knockdown, PARP14 inhibitors, Western blot, RT-PCR for EP4 receptor expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — MARylation of HDACs proposed as mechanism but direct biochemical evidence of specific HDAC1/2 ribosylation limited; single lab","pmids":["35914351"],"is_preprint":false},{"year":2013,"finding":"PARP14 catalytic activity is required for Th17 cell differentiation downstream of T cell activation; PARP14 deficiency reduces IgE responses via a B cell-intrinsic process involving STAT6, and reduces IgA through B cell-extrinsic effects involving Th17 cells and CD103+ DCs; PARP14 enhances expression of RORα, Runx1, and Smad3 after T cell activation.","method":"PARP14 knockout mice, adoptive transfer experiments, antibody response measurements, T cell differentiation assays, catalytic activity requirement tested","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus catalytic activity requirement established in primary immune cells; multiple orthogonal immune readouts","pmids":["23956424"],"is_preprint":false},{"year":2026,"finding":"PARP14 RRM (RNA Recognition Motif) domains mediate recruitment of PARP14 to nascent DNA at reversed replication forks in BRCA2-deficient cells; these RRM domains are necessary for MRE11 recruitment to reversed forks, nascent strand degradation, and replication stress-induced double-strand break formation.","method":"iPOND (isolation of proteins on nascent DNA), RRM domain truncation/mutation analysis, MRE11 recruitment assays, DNA fiber assay, DSB formation assays in BRCA2-deficient cells","journal":"NAR cancer","confidence":"High","confidence_rationale":"Tier 2 — domain-specific mutagenesis with direct recruitment assay at nascent DNA; multiple mechanistic readouts in BRCA2-deficient system","pmids":["41684642"],"is_preprint":false},{"year":2022,"finding":"PARP14 promotes AML cell proliferation and glycolysis by activating NF-κB signaling to promote HIF-1α expression; HIF-1α silencing reverses the pro-cancer effects of PARP14, and PARP14 promotes tumor formation in vivo.","method":"siRNA knockdown, NF-κB inhibitor (BAY11-7082), Western blot, proliferation/apoptosis assays, glycolysis measurements, xenograft model","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement via NF-κB inhibitor and HIF-1α rescue; single lab without direct biochemical mechanism for NF-κB activation","pmids":["35944879"],"is_preprint":false},{"year":2025,"finding":"PARP14 catalytic activity enhances IFN-β and IFN-λ responses and independently restricts coronavirus (MHV and SARS-CoV-2 ARH-deficient) and HSV-1 replication; PARP14 also enhances VSV replication (proviral function); the effects on HSV-1 and VSV are independent of PARP14 catalytic activity.","method":"PARP14 KO cells, PARP14 active site inhibitor, viral replication assays (MHV, SARS-CoV-2, HSV-1, VSV, LCMV), IFN production measurement","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — KO genetic analysis combined with specific catalytic inhibitor to distinguish catalytic vs. non-catalytic functions; multiple viruses tested","pmids":["40937852"],"is_preprint":false},{"year":2024,"finding":"PARP14 inhibits GLUD1 (glutamate dehydrogenase 1) activity through mono-ADP-ribosylation, reducing alpha-ketoglutarate (α-KG) production and suppressing energy metabolism in granulosa cells; this PARP14-GLUD1-α-KG axis is involved in ovarian cell apoptosis regulation.","method":"Co-immunoprecipitation (PARP14-GLUD1 interaction), in vitro MARylation assay, GLUD1 activity assay, metabolite measurement (α-KG), PARP14 knockdown/overexpression","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct MARylation of GLUD1 shown in vitro with functional consequence; single lab","pmids":["41895093"],"is_preprint":false},{"year":2025,"finding":"PARP14 positively regulates NNT (nicotinamide nucleotide transhydrogenase) expression in microglia; NNT deficiency leads to ROS accumulation and microglial inflammation; PARP14 alleviates microglial activation and depressive-like behaviors in CUS mice via NNT-mediated ROS clearance.","method":"Hippocampal PARP14 overexpression (viral vector), NNT overexpression rescue, ROS inhibitor (N-Acetylcysteine), microglial activation assays, behavioral tests","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis between PARP14 and NNT with ROS pathway rescue; single lab, mechanism of NNT regulation not fully characterized","pmids":["39978699"],"is_preprint":false},{"year":2025,"finding":"PARP14 enhances SOCS2 mRNA stability in macrophages; overexpression of PARP14 restores M2 polarization suppressed by botulinum toxin A (BTXA), while SOCS2 silencing counteracts this; BTXA inhibits the PARP14-SOCS2 axis to reduce M2 macrophage polarization.","method":"RNA sequencing, mRNA stability assays, PARP14/SOCS2 overexpression and silencing, M2 polarization assays, mouse HS model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 3 — mRNA stabilization mechanism demonstrated but direct biochemical mechanism linking PARP14 enzymatic activity to SOCS2 mRNA not established; single lab","pmids":["40505894"],"is_preprint":false},{"year":2025,"finding":"YTHDF2 (m6A reader) binds Parp14 mRNA under oxygen-glucose deprivation conditions and reduces its stability via m6A-dependent mechanisms, decreasing PARP14 protein levels; YTHDF2 knockdown prevents PARP14 downregulation and promotes PARP14-driven microglial M1→M2 phenotypic switch.","method":"RIP (YTHDF2-Parp14 mRNA interaction), mRNA stability assays, siRNA knockdown of YTHDF2, microglial polarization assays","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 3 — RIP demonstrates YTHDF2-Parp14 mRNA interaction; m6A-dependent regulation; single lab with moderate functional follow-up","pmids":["40383033"],"is_preprint":false}],"current_model":"PARP14 is a large multidomain mono-ADP-ribosyltransferase (MARylase) whose macrodomain 1 also functions as an ADP-ribosyl hydrolase (de-MARylase), making it a writer, reader, and eraser of mono-ADP-ribosylation; it acts as a bimodal transcriptional switch downstream of STAT6 (ADP-ribosylating and releasing HDAC2/3 upon IL-4 stimulation) and cross-regulates macrophage activation by directly ADP-ribosylating STAT1 to suppress its phosphorylation; PARP14 inhibits JNK1 to promote tumor cell survival and the Warburg effect, interacts with PCNA and uses its RRM domains to recruit MRE11 to reversed replication forks in BRCA-deficient cells, forms IFNγ-induced cytoplasmic condensates (p62 bodies) where it ADP-ribosylates substrates including SQSTM1/p62 and RACK1, and its activity is counteracted by coronavirus macrodomain hydrolases."},"narrative":{"teleology":[{"year":2009,"claim":"Before this work, the biological role of PARP14 was unknown; this study established it as a STAT6 binding partner that mediates IL-4-dependent survival in B cells and influences lymphomagenesis, placing it in adaptive immune signaling.","evidence":"PARP14 knockout mice, co-immunoprecipitation with STAT6, apoptosis assays in primary B cells","pmids":["19147789"],"confidence":"High","gaps":["Enzymatic activity not yet linked to STAT6 function","Downstream transcriptional mechanism unknown"]},{"year":2010,"claim":"Resolving how PARP14 controls transcription, this work showed it acts as a bimodal switch: recruiting HDAC2/3 to repress IL-4-responsive promoters basally, then ADP-ribosylating those HDACs upon IL-4 stimulation to derepress gene expression and enable STAT6 binding.","evidence":"ChIP, co-immunoprecipitation, ADP-ribosylation assays, luciferase reporters","pmids":["21081493"],"confidence":"High","gaps":["Specific HDAC residues modified not identified","Whether other STAT6-target promoters use the same switch unknown"]},{"year":2011,"claim":"Extending PARP14's role beyond transcription, its requirement for IL-4-induced glycolysis in B cells was established, linking its activity to metabolic reprogramming and Myc-driven lymphomagenesis.","evidence":"PARP14 KO mice, glycolysis assays, AMPK activity measurement, E-Myc lymphoma model","pmids":["21911376"],"confidence":"High","gaps":["Direct enzymatic substrates mediating glycolytic control not identified","Relationship to JNK1 axis not yet established"]},{"year":2012,"claim":"PARP14 was identified as a JNK2-dependent pro-survival effector in multiple myeloma that directly binds and inhibits pro-apoptotic JNK1, revealing a non-catalytic scaffolding function in tumor cell survival.","evidence":"Reciprocal co-IP of PARP14-JNK1, siRNA knockdown, overexpression rescue in myeloma cells","pmids":["23045269"],"confidence":"High","gaps":["Whether JNK1 inhibition requires PARP14 catalytic activity unknown","Structural basis of PARP14-JNK1 interaction not determined"]},{"year":2013,"claim":"Two advances defined PARP14 as both a reader of mono-ADP-ribosylation and an immune regulator beyond B cells: crystal structures showed macrodomains 2/3 selectively bind mono-ADP-ribosylated substrates, and KO studies revealed PARP14 catalytic activity drives Th17 differentiation and IgE responses.","evidence":"X-ray crystallography and ITC of macrodomains 2/3; PARP14 KO mice with T cell differentiation assays and antibody measurements","pmids":["23473667","23956424"],"confidence":"High","gaps":["In vivo reader substrates not identified","How macrodomain reading integrates with transferase activity unclear"]},{"year":2014,"claim":"PARP14 was shown to regulate mRNA stability by forming an RNP complex with tristetraprolin on the tissue factor 3′UTR, and to form a functional complex with DTX3L and PARP9/ARTD9 in cancer cells, broadening its molecular partnerships.","evidence":"RIP and RNA pull-down for TTP-TF mRNA interaction with KO mouse validation; Co-IP of PARP14-DTX3L-ARTD9 in prostate cancer cells","pmids":["25293769","24886089"],"confidence":"High","gaps":["Whether PARP14 catalytic activity is needed for mRNA regulation not tested","Stoichiometry and structural basis of the DTX3L/PARP9/PARP14 complex unresolved"]},{"year":2015,"claim":"Two parallel advances established PARP14 in genome maintenance and metabolic signaling: PARP14 interacts with PCNA and promotes homologous recombination at replication forks, and it sustains the Warburg effect by inhibiting JNK1 to prevent PKM2 Thr365 phosphorylation.","evidence":"Co-IP of PARP14-PCNA, RAD51 foci and DNA damage sensitivity in KD cells; JNK1-PKM2 phosphorylation epistasis in HCC cells and xenografts","pmids":["25753673","26258887"],"confidence":"High","gaps":["Whether PCNA interaction requires PARP14 catalytic activity not determined","Direct MARylation targets at replication forks unknown"]},{"year":2016,"claim":"PARP14 was shown to directly ADP-ribosylate STAT1, suppressing its phosphorylation and thereby cross-regulating macrophage polarization between pro- and anti-inflammatory states, with PARP9 acting as its functional antagonist.","evidence":"Proteomics, site-directed mutagenesis of STAT1 ADP-ribosylation sites, phosphorylation analysis in primary macrophages","pmids":["27796300"],"confidence":"High","gaps":["Precise STAT1 modification sites not fully mapped","How PARP9 reverses the modification mechanistically unresolved"]},{"year":2018,"claim":"Chemical genetic substrate identification revealed PARP14 MARylates >100 proteins enriched for RNA regulatory functions, including direct modification of PARP13, while nuclear translocation studies showed PARP14 promotes accumulation of ISG-encoded proteins and IFN-β transcription in macrophages.","evidence":"Orthogonal NAD+ analog chemical genetics with BioID and MS; nuclear fractionation and MS interactomics with siRNA knockdown in macrophages","pmids":["30247868","29500242"],"confidence":"High","gaps":["Functional consequence of PARP13 MARylation unknown","How PARP14 promotes nuclear accumulation of ISG products mechanistically unclear"]},{"year":2020,"claim":"Genome-wide CRISPR screening identified synthetic lethality between PARP14 loss and ATR-CHK1 pathway inhibition, defining PARP14 as a modulator of replication dynamics and a potential therapeutic vulnerability.","evidence":"Genome-wide CRISPR KO screen, DNA fiber assays, ATR/CHK1 inhibitor sensitivity","pmids":["32542389"],"confidence":"High","gaps":["Whether synthetic lethality depends on PARP14 catalytic or structural function not resolved","Patient-relevant contexts not tested"]},{"year":2021,"claim":"PARP14 was found to stabilize cyclin D1 mRNA via its 3′UTR, controlling G1/S cell cycle progression through the RB and p53-p21 pathways, establishing it as a cell cycle regulator.","evidence":"Luciferase 3′UTR reporter, siRNA knockdown, cell cycle analysis by flow cytometry","pmids":["34158578"],"confidence":"High","gaps":["Direct RNA-binding domain responsible not mapped","Whether MARylation of an RNA-binding protein mediates this effect unknown"]},{"year":2022,"claim":"PARP14's replication fork role was mechanistically refined: it is recruited to nascent DNA upon replication stress in BRCA-deficient cells and its catalytic activity mediates MRE11 engagement via the KU complex, promoting fork degradation and ssDNA gap formation.","evidence":"iPOND, DNA fiber assay, proximity ligation assay, catalytic inhibitor and siRNA in BRCA-deficient cells","pmids":["36030235"],"confidence":"High","gaps":["Direct MARylation substrates at the fork not identified","Which domain recruits to nascent DNA not yet mapped"]},{"year":2023,"claim":"The discovery that PARP14 macrodomain 1 is an active ADP-ribosylhydrolase established PARP14 as a dual writer-eraser enzyme, and revealed that coronavirus macrodomains (e.g., SARS-CoV-2 Mac1) functionally mimic this eraser activity to counteract host MARylation.","evidence":"In vitro hydrolase assays, F926A mutagenesis ablating activity, cellular MARylation accumulation upon macrodomain 1 inactivation, reconstitution with SARS-CoV-2 Mac1","pmids":["37703374","37507011"],"confidence":"High","gaps":["Physiological substrates preferentially de-MARylated by macrodomain 1 not identified","Structural basis for substrate selectivity of macrodomain 1 vs. viral Mac1 not resolved"]},{"year":2024,"claim":"Multiple studies converged to show that IFN-γ-induced PARP14 is the dominant MARylase in macrophages, regulated post-translationally by PARP9/DTX3L, and that its activity and physical presence drive formation of p62 body condensates containing ADP-ribosylated substrates including p62 itself, polyubiquitin, and selective autophagy receptors—structures counteracted by SARS-CoV-2 Mac1.","evidence":"Improved MAR antibodies, PARP14/PARP9/DTX3L KD, immunofluorescence, site-directed mutagenesis of p62 cysteine acceptor residues, proteasome/autophagy inhibitors","pmids":["38834853","38834852","40195501"],"confidence":"High","gaps":["Functional consequence of p62 body condensates for antiviral defense not established","Whether condensate formation occurs in vivo during infection unknown","Cysteine-directed MARylation specificity mechanism not structurally resolved"]},{"year":2024,"claim":"KH-like domains were identified as the structural determinants mediating PARP14-DTX3L and PARP9-DTX3L protein-protein interactions, with DTX3L binding shifting PARP14 activity from auto- to trans-MARylation.","evidence":"Co-IP with KH domain mutagenesis, in vitro ADP-ribosylation assays","pmids":["38182103"],"confidence":"Medium","gaps":["Structural model of the ternary PARP14-PARP9-DTX3L complex absent","In vivo relevance of the auto- to trans-MARylation switch unconfirmed"]},{"year":2025,"claim":"Domain-specific analysis showed PARP14's RRM domains are necessary and sufficient for recruitment to reversed replication forks in BRCA2-deficient cells and for subsequent MRE11 engagement, resolving the structural basis of its replication fork function.","evidence":"iPOND with RRM truncation/mutation, MRE11 recruitment and DNA fiber assays in BRCA2-deficient cells","pmids":["41684642"],"confidence":"High","gaps":["Whether RRM domains bind DNA or RNA at the fork not distinguished","RRM-mediated interaction partners beyond MRE11 not mapped"]},{"year":2025,"claim":"PARP14 was shown to restrict coronavirus (MHV, SARS-CoV-2 with Mac1 mutation) and HSV-1 replication while paradoxically enhancing VSV replication, with antiviral effects on coronaviruses depending on catalytic activity and others being catalytic-activity-independent.","evidence":"PARP14 KO cells, catalytic inhibitor, viral replication assays across five viruses, IFN production measurement","pmids":["40937852"],"confidence":"High","gaps":["Direct antiviral MARylation substrates not identified","Mechanism of catalytic-activity-independent HSV-1 restriction unknown","Basis for proviral activity toward VSV not characterized"]},{"year":null,"claim":"Major open questions include the full catalog of physiological MARylation substrates that drive specific PARP14 functions, the structural basis for how PARP14 macrodomain 1 hydrolase and catalytic domain transferase activities are coordinated, and whether PARP14-dependent p62 body condensates serve a direct antiviral effector function in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length PARP14","In vivo antiviral mechanism through MARylation not demonstrated","Coordination between hydrolase and transferase domains within the same polypeptide not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,9,10,15,16,18,20,22,28]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[16,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,10,14,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[20,21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,11,18,24,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,9,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,13,15,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,7,26,28]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7,26]}],"complexes":["PARP14-PARP9-DTX3L complex"],"partners":["STAT6","STAT1","DTX3L","PARP9","PCNA","MRE11","JNK1","HDAC2"],"other_free_text":[]},"mechanistic_narrative":"PARP14 is a multidomain mono-ADP-ribosyltransferase (MARylase) that integrates innate immune signaling, transcriptional regulation, metabolic reprogramming, and genome maintenance through its enzymatic writer, reader, and eraser activities. Its catalytic domain MARylates STAT1, HDAC2/3, RACK1, GLUD1, and SQSTM1/p62, while macrodomains 2 and 3 read mono-ADP-ribosylation marks and macrodomain 1 functions as an ADP-ribosylhydrolase whose activity is mimicked and counteracted by coronavirus macrodomains [PMID:37703374, PMID:23473667, PMID:21081493, PMID:27796300, PMID:40195501]. PARP14 acts as a transcriptional switch downstream of IL-4/STAT6 by ADP-ribosylating HDACs to derepress target promoters, cross-regulates macrophage polarization by suppressing STAT1 phosphorylation, promotes Th17 differentiation, and upon IFN-γ stimulation drives formation of cytoplasmic p62 body condensates enriched in ADP-ribosylated substrates and polyubiquitin chains [PMID:21081493, PMID:27796300, PMID:23956424, PMID:38834853, PMID:40195501]. In genome maintenance, PARP14 interacts with PCNA and uses its RRM domains to recruit MRE11 to reversed replication forks in BRCA-deficient cells, promoting nascent strand degradation, while its loss creates synthetic lethality with the ATR-CHK1 pathway; PARP14 also stabilizes cyclin D1 and tissue factor mRNAs through 3′UTR-dependent mechanisms and inhibits JNK1 to sustain aerobic glycolysis and tumor cell survival [PMID:36030235, PMID:41684642, PMID:32542389, PMID:34158578, PMID:25293769, PMID:25258887]."},"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 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vitro expression of TMEM154 and PARP14 genes and restriction of SRLV infection in primary skin cells of Carpathian goats.","date":"2025","source":"Journal of veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/41497468","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.01.630990","title":"Exacerbated salmonellosis in poly(ADP-ribose) polymerase 14 deficient mice","date":"2025-01-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.01.630990","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.08.674862","title":"Tumor-myeloid crosstalk drives therapy resistance in localized bladder cancer","date":"2025-09-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674862","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.27.25333852","title":"Ultrarare Variants in DNA Damage Repair and Mitochondrial Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome and Acute Behavioral 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\"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, ADP-ribosylation assays, luciferase reporter assays, loss-of-function studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, Co-IP, enzymatic assay) in single lab with strong mechanistic model\",\n      \"pmids\": [\"21081493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PARP-14 is a binding partner of the IL-4-induced transcription factor STAT6 and mediates IL-4-dependent protection against apoptosis in primary B cells, regulating gene products controlling cell survival, proliferation, and lymphomagenesis.\",\n      \"method\": \"PARP-14 knockout mice, co-immunoprecipitation, apoptosis assays, gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with defined phenotype, binding partner identified by Co-IP, replicated in primary cells\",\n      \"pmids\": [\"19147789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PARP-14 is required for IL-4-induced enhancement of glycolysis in B cells; this glycolytic activity is central to IL-4-mediated prosurvival signaling, and PARP14 deficiency delays B lymphomagenesis driven by the Myc oncogene.\",\n      \"method\": \"Parp14 knockout mice, glycolysis assays, AMPK activity measurement, Myc-driven lymphoma model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple cellular readouts, in vivo oncogenesis model, pathway placement via AMPK epistasis\",\n      \"pmids\": [\"21911376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PARP14 is a critical effector of JNK2-dependent prosurvival signaling in multiple myeloma: constitutively active JNK2 maintains PARP14 expression, PARP14 binds and inhibits pro-apoptotic JNK1, and PARP14 overexpression rescues myeloma cells from apoptosis induced by JNK2 knockdown.\",\n      \"method\": \"Loss-of-function (siRNA), overexpression rescue experiments, co-immunoprecipitation (PARP14-JNK1 binding), apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP demonstrating PARP14-JNK1 interaction, epistasis rescue experiment, multiple myeloma cell lines and primary tumors\",\n      \"pmids\": [\"23045269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP14 macrodomains 2 and 3 (ARTD8/PARP14) function as readers of mono-ADP-ribosylated substrates: crystal structures of these macrodomains confirmed ADP-ribose binding, they recognized mono-ADP-ribosylated ARTD10 and its substrate Ran but not poly-ADP-ribosylated ARTD1, and ARTD10 colocalized with ARTD8 in cells.\",\n      \"method\": \"Crystal structure determination, isothermal titration calorimetry, in vitro binding assays, cell colocalization\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures combined with ITC and in vitro functional validation of macrodomain reader activity\",\n      \"pmids\": [\"23473667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PARP14 forms a ribonucleoprotein complex with the mRNA-destabilizing protein tristetraprolin (TTP) and a conserved AU-rich element in the tissue factor (TF) mRNA 3′UTR, selectively regulating TF mRNA stability in macrophages; PARP14 deficiency increases TF mRNA stability, TF expression, and coagulation activity in vitro and in vivo.\",\n      \"method\": \"Ribonucleoprotein complex immunoprecipitation, biotinylated RNA pull-down, Parp14 knockout mice, mRNA stability assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein interaction demonstrated by RIP and RNA pull-down, confirmed in vivo with KO mice\",\n      \"pmids\": [\"25293769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PARP14 (ARTD8) forms complexes with DTX3L and ARTD9 in metastatic prostate cancer cells, and its enzymatic (ADP-ribosyltransferase) activity is required for survival of these cells; the complex also regulates IRF1 expression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA loss-of-function, cell survival and proliferation assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP confirms complex formation, catalytic activity requirement shown by KD, single lab\",\n      \"pmids\": [\"24886089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP14 promotes aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by maintaining low PKM2 activity: PARP14 inhibits pro-apoptotic JNK1 kinase, which would otherwise phosphorylate PKM2 at Thr365 and activate it; loss of PARP14 leads to JNK1 activation, PKM2 phosphorylation, and reduced glycolysis/increased apoptosis.\",\n      \"method\": \"Loss-of-function studies (siRNA/shRNA) in vitro and in vivo (xenografts), PKM2 phosphorylation assays, glycolysis measurements, JNK1 activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (PARP14→JNK1→PKM2-Thr365) validated in vitro and in vivo with multiple orthogonal methods\",\n      \"pmids\": [\"26258887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PARP14 (mono-ADP-ribosyltransferase) interacts with PCNA and promotes homologous recombination DNA repair; PARP14 depletion results in reduced HR, persistent RAD51 foci, hypersensitivity to DNA-damaging agents, and accumulation of DNA strand breaks, establishing a role in replication fork stability and common fragile site replication.\",\n      \"method\": \"Co-immunoprecipitation (PARP14-PCNA interaction), siRNA knockdown, DNA damage sensitivity assays, RAD51 foci analysis, comet assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction shown by Co-IP, multiple DNA repair phenotypes in KD cells, two orthogonal readouts\",\n      \"pmids\": [\"25753673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PARP14 and PARP9 cross-regulate macrophage activation: PARP14 directly ADP-ribosylates STAT1, which suppresses STAT1 phosphorylation; PARP9 counteracts this modification. Mutations at PARP14-dependent ADP-ribosylation sites on STAT1 lead to increased STAT1 phosphorylation. PARP14 also promotes STAT6 phosphorylation and anti-inflammatory gene expression in M(IL-4) macrophages.\",\n      \"method\": \"Global proteomics, siRNA knockdown, ADP-ribosylation assays, site-directed mutagenesis of STAT1 ADP-ribosylation sites, phosphorylation analysis, primary macrophages\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct ADP-ribosylation of STAT1 demonstrated biochemically; mutagenesis of modification sites shows functional consequence; replicated across M1/M2 contexts\",\n      \"pmids\": [\"27796300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using a chemical genetics approach (orthogonal NAD+ analog) combined with BioID proximity labeling, PARP14 was shown to MARylate 114 specific protein substrates, several of which are RNA regulatory proteins; PARP13 is directly MARylated by PARP14 on several acidic amino acids, revealing crosstalk between PARP family members.\",\n      \"method\": \"Chemical genetics (engineered PARP14 with orthogonal NAD+ analog), BioID proximity labeling, mass spectrometry, in vitro MARylation assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chemical genetics plus proximity labeling provides direct, selective substrate identification; in vitro validation of PARP13 MARylation\",\n      \"pmids\": [\"30247868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP14 translocates into the nucleus of macrophages stimulated with inflammatory stimuli, binds a group of IFN-stimulated gene (ISG)-encoded proteins (identified by quantitative mass spectrometry), and is required for their nuclear accumulation; PARP14 depletion also attenuates transcription of primary antiviral response genes including Ifnb1, reducing IFN-β production.\",\n      \"method\": \"Nuclear fractionation/translocation assays, quantitative mass spectrometry, siRNA knockdown, gene expression analysis, Salmonella infection assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization experiment with functional consequence, MS-defined interactome, loss-of-function phenotype\",\n      \"pmids\": [\"29500242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PARP14 suppresses microglial activation post-stroke by transcriptionally repressing the Lpar5 (lysophosphatidic acid receptor 5) gene; overexpression of PARP14 reduces LPAR5 expression and alleviates microglial activation, while PARP14 knockdown increases activation and worsens stroke outcomes.\",\n      \"method\": \"Photothrombotic stroke mouse model, PARP14 overexpression/knockdown, microglial activation assays, gene expression analysis, pharmacological inhibition\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function and gain-of-function with defined mechanistic target (LPAR5 transcription); single lab\",\n      \"pmids\": [\"33317392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genome-wide CRISPR screen in PARP14-deficient cells identified the ATR-CHK1 pathway as synthetically lethal with PARP14 loss; PARP14 modulates DNA replication dynamics, and its loss sensitizes cells to ATR-CHK1 pathway inhibitors.\",\n      \"method\": \"Genome-wide CRISPR knockout screen, DNA fiber assay (replication dynamics), ATR/CHK1 inhibitor sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genome-wide genetic screen with orthogonal mechanistic validation of replication dynamics\",\n      \"pmids\": [\"32542389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP14 regulates cyclin D1 mRNA stability through the cyclin D1 3′UTR, controlling cyclin D1 protein levels; depletion of PARP14 reduces cyclin D1, causes G1 cell-cycle arrest dependent on an intact RB pathway, and requires the p53-p21 pathway for arrest.\",\n      \"method\": \"siRNA knockdown, luciferase 3′UTR stability assays, cell cycle analysis (flow cytometry), Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — luciferase assay directly demonstrates 3′UTR-mediated mRNA stability control; genetic epistasis with RB and p53 pathways\",\n      \"pmids\": [\"34158578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP14 is a critical cofactor of MRE11 at stalled 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, promoting fork degradation and ssDNA gap accumulation; the KU complex recruits the PARP14-MRE11 complex to initiate partial resection.\",\n      \"method\": \"DNA fiber assay, iPOND (isolation of proteins on nascent DNA), siRNA/catalytic inhibitor studies, proximity ligation assay, Co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating PARP14-MRE11 interaction at nascent DNA; catalytic activity requirement shown; KU epistasis established\",\n      \"pmids\": [\"36030235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP14 is a dual-function enzyme with both ADP-ribosyl transferase and hydrolase (de-MARylase) activities: the PARP14 macrodomain 1 is an active ADP-ribosyl glycohydrolase acting on protein and nucleic acid substrates; inactivation of macrodomain 1 causes marked accumulation of MARylation (including on PARP14 itself and PARP13) in human cells; SARS-CoV-2 Mac1 reverses PARP14-mediated ADP-ribosylation in vitro and in cells.\",\n      \"method\": \"In vitro ADP-ribosylhydrolase activity assays, site-directed mutagenesis (macrodomain 1 inactivation), cell-based MARylation detection, reconstitution with SARS-CoV-2 Mac1\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of hydrolase activity, mutagenesis confirming active site, cellular phenotype validation\",\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; PARP14 macrodomain 1 cannot degrade poly(ADP-ribose); the F926A mutation of PARP14 macrodomain 1 strongly reduces hydrolase activity, mechanistically analogous to SARS-CoV-2 Nsp3 Mac1.\",\n      \"method\": \"Biochemical ADP-ribosylation/hydrolysis assays, site-directed mutagenesis (F926A), comparison with Mac1 domain\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis confirming catalytic residue; mechanistic characterization of hydrolase activity\",\n      \"pmids\": [\"37507011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Interferon-γ-induced ADP-ribosylation in macrophages depends on PARP14 as the major catalytic enzyme; the PARP9/DTX3L complex regulates PARP14 protein levels via post-translational mechanisms and modulates PARP14 ADP-ribosylation activity; PARP14 and DTX3L localize to IFNγ-induced cytoplasmic inclusions containing ADP-ribosylated proteins; SARS-CoV-2 Mac1 reverses PARP14-dependent ADP-ribosylation.\",\n      \"method\": \"Improved mono-ADP-ribosylation antibody detection, PARP14/PARP9/DTX3L knockdown, immunofluorescence localization, in vitro hydrolysis by Mac1, mass spectrometry\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches; PARP14 identified as major IFN-induced ART; PARP9/DTX3L regulation confirmed; corroborated by companion paper (PMID:38834852)\",\n      \"pmids\": [\"38834853\", \"38834852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KH-like domains in PARP14 and in PARP9/DTX3L mediate protein-protein interactions: KH domains coordinate PARP9-DTX3L and PARP14-DTX3L interactions; DTX3L homodimerization is coordinated by its KH-like domain; in vitro, DTX3L interaction suppresses PARP14 auto-ADP-ribosylation and promotes trans-ADP-ribosylation of PARP9 and DTX3L.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of KH domain, in vitro ADP-ribosylation assays, cell survival assays with truncation constructs\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction and enzymatic consequence demonstrated in vitro; single lab\",\n      \"pmids\": [\"38182103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Interferon-induced PARP14 mono-ADP-ribosylates SQSTM1/p62 at cysteine residues 113, 289/290, and 331; this modification occurs in cytoplasmic p62 foci that colocalize with ubiquitin and PARP14 but not LC3 (autophagosome marker); SARS-CoV-2 macrodomain prevents this p62 modification, and TRIM21 prevents autophagic degradation of ADP-ribosylated p62.\",\n      \"method\": \"Site-specific mutagenesis of p62 cysteine residues, immunofluorescence colocalization, in vitro MARylation, SARS-CoV-2 macrodomain treatment, TRIM21 knockdown\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro MARylation with site-specific mutagenesis; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.29.601315\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Interferon-induced PARP14-mediated ADP-ribosylation occurs in p62 body condensates: PARP14 physical presence and catalytic activity are both required for condensate formation; these condensates contain p62, NBR1, TAX1BP1, and K48/K63-linked polyubiquitin chains but lack LC3B; condensate formation requires an active ubiquitin-proteasome system but not autophagy.\",\n      \"method\": \"PARP14 knockdown/catalytic mutant, immunofluorescence colocalization, p62 knockdown, autophagy inhibitors, proteasome inhibitors, ubiquitin pathway perturbations\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological perturbations define condensate requirements; catalytic activity and physical presence distinguished; peer-reviewed\",\n      \"pmids\": [\"40195501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP14 mono-ADP-ribosylates RACK1 (an integral ribosome component) on three acidic residues, promoting stress granule formation and colocalization of RACK1 with G3BP1, eIF3η, and 40S ribosomal proteins; MARylation of RACK1 reduces translation of a subset of mRNAs including AKT; the ADP-ribosyl hydrolase TARG1 de-MARylates RACK1 to disassemble stress granules and restore translation.\",\n      \"method\": \"In vitro MARylation assay, site-directed mutagenesis of RACK1 acceptor residues, PARP14 inhibitor treatment, stress granule imaging, polysome profiling, in vivo tumor growth assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution and mutagenesis of modification sites; functional cellular and in vivo validation; preprint\",\n      \"pmids\": [\"37873085\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP14 promotes EP4 receptor expression in colon cancer cells by mono-ADP-ribosylating HDAC1 and HDAC2; suppression of PARP14 by siRNA or inhibitors reduces EP4 receptor mRNA and protein expression.\",\n      \"method\": \"siRNA knockdown, PARP14 inhibitors, Western blot, RT-PCR for EP4 receptor expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — MARylation of HDACs proposed as mechanism but direct biochemical evidence of specific HDAC1/2 ribosylation limited; single lab\",\n      \"pmids\": [\"35914351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PARP14 catalytic activity is required for Th17 cell differentiation downstream of T cell activation; PARP14 deficiency reduces IgE responses via a B cell-intrinsic process involving STAT6, and reduces IgA through B cell-extrinsic effects involving Th17 cells and CD103+ DCs; PARP14 enhances expression of RORα, Runx1, and Smad3 after T cell activation.\",\n      \"method\": \"PARP14 knockout mice, adoptive transfer experiments, antibody response measurements, T cell differentiation assays, catalytic activity requirement tested\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus catalytic activity requirement established in primary immune cells; multiple orthogonal immune readouts\",\n      \"pmids\": [\"23956424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PARP14 RRM (RNA Recognition Motif) domains mediate recruitment of PARP14 to nascent DNA at reversed replication forks in BRCA2-deficient cells; these RRM domains are necessary for MRE11 recruitment to reversed forks, nascent strand degradation, and replication stress-induced double-strand break formation.\",\n      \"method\": \"iPOND (isolation of proteins on nascent DNA), RRM domain truncation/mutation analysis, MRE11 recruitment assays, DNA fiber assay, DSB formation assays in BRCA2-deficient cells\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific mutagenesis with direct recruitment assay at nascent DNA; multiple mechanistic readouts in BRCA2-deficient system\",\n      \"pmids\": [\"41684642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP14 promotes AML cell proliferation and glycolysis by activating NF-κB signaling to promote HIF-1α expression; HIF-1α silencing reverses the pro-cancer effects of PARP14, and PARP14 promotes tumor formation in vivo.\",\n      \"method\": \"siRNA knockdown, NF-κB inhibitor (BAY11-7082), Western blot, proliferation/apoptosis assays, glycolysis measurements, xenograft model\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement via NF-κB inhibitor and HIF-1α rescue; single lab without direct biochemical mechanism for NF-κB activation\",\n      \"pmids\": [\"35944879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 catalytic activity enhances IFN-β and IFN-λ responses and independently restricts coronavirus (MHV and SARS-CoV-2 ARH-deficient) and HSV-1 replication; PARP14 also enhances VSV replication (proviral function); the effects on HSV-1 and VSV are independent of PARP14 catalytic activity.\",\n      \"method\": \"PARP14 KO cells, PARP14 active site inhibitor, viral replication assays (MHV, SARS-CoV-2, HSV-1, VSV, LCMV), IFN production measurement\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO genetic analysis combined with specific catalytic inhibitor to distinguish catalytic vs. non-catalytic functions; multiple viruses tested\",\n      \"pmids\": [\"40937852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP14 inhibits GLUD1 (glutamate dehydrogenase 1) activity through mono-ADP-ribosylation, reducing alpha-ketoglutarate (α-KG) production and suppressing energy metabolism in granulosa cells; this PARP14-GLUD1-α-KG axis is involved in ovarian cell apoptosis regulation.\",\n      \"method\": \"Co-immunoprecipitation (PARP14-GLUD1 interaction), in vitro MARylation assay, GLUD1 activity assay, metabolite measurement (α-KG), PARP14 knockdown/overexpression\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct MARylation of GLUD1 shown in vitro with functional consequence; single lab\",\n      \"pmids\": [\"41895093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 positively regulates NNT (nicotinamide nucleotide transhydrogenase) expression in microglia; NNT deficiency leads to ROS accumulation and microglial inflammation; PARP14 alleviates microglial activation and depressive-like behaviors in CUS mice via NNT-mediated ROS clearance.\",\n      \"method\": \"Hippocampal PARP14 overexpression (viral vector), NNT overexpression rescue, ROS inhibitor (N-Acetylcysteine), microglial activation assays, behavioral tests\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis between PARP14 and NNT with ROS pathway rescue; single lab, mechanism of NNT regulation not fully characterized\",\n      \"pmids\": [\"39978699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP14 enhances SOCS2 mRNA stability in macrophages; overexpression of PARP14 restores M2 polarization suppressed by botulinum toxin A (BTXA), while SOCS2 silencing counteracts this; BTXA inhibits the PARP14-SOCS2 axis to reduce M2 macrophage polarization.\",\n      \"method\": \"RNA sequencing, mRNA stability assays, PARP14/SOCS2 overexpression and silencing, M2 polarization assays, mouse HS model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mRNA stabilization mechanism demonstrated but direct biochemical mechanism linking PARP14 enzymatic activity to SOCS2 mRNA not established; single lab\",\n      \"pmids\": [\"40505894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF2 (m6A reader) binds Parp14 mRNA under oxygen-glucose deprivation conditions and reduces its stability via m6A-dependent mechanisms, decreasing PARP14 protein levels; YTHDF2 knockdown prevents PARP14 downregulation and promotes PARP14-driven microglial M1→M2 phenotypic switch.\",\n      \"method\": \"RIP (YTHDF2-Parp14 mRNA interaction), mRNA stability assays, siRNA knockdown of YTHDF2, microglial polarization assays\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RIP demonstrates YTHDF2-Parp14 mRNA interaction; m6A-dependent regulation; single lab with moderate functional follow-up\",\n      \"pmids\": [\"40383033\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARP14 is a large multidomain mono-ADP-ribosyltransferase (MARylase) whose macrodomain 1 also functions as an ADP-ribosyl hydrolase (de-MARylase), making it a writer, reader, and eraser of mono-ADP-ribosylation; it acts as a bimodal transcriptional switch downstream of STAT6 (ADP-ribosylating and releasing HDAC2/3 upon IL-4 stimulation) and cross-regulates macrophage activation by directly ADP-ribosylating STAT1 to suppress its phosphorylation; PARP14 inhibits JNK1 to promote tumor cell survival and the Warburg effect, interacts with PCNA and uses its RRM domains to recruit MRE11 to reversed replication forks in BRCA-deficient cells, forms IFNγ-induced cytoplasmic condensates (p62 bodies) where it ADP-ribosylates substrates including SQSTM1/p62 and RACK1, and its activity is counteracted by coronavirus macrodomain hydrolases.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PARP14 is a multidomain mono-ADP-ribosyltransferase (MARylase) that integrates innate immune signaling, transcriptional regulation, metabolic reprogramming, and genome maintenance through its enzymatic writer, reader, and eraser activities. Its catalytic domain MARylates STAT1, HDAC2/3, RACK1, GLUD1, and SQSTM1/p62, while macrodomains 2 and 3 read mono-ADP-ribosylation marks and macrodomain 1 functions as an ADP-ribosylhydrolase whose activity is mimicked and counteracted by coronavirus macrodomains [PMID:37703374, PMID:23473667, PMID:21081493, PMID:27796300, PMID:40195501]. PARP14 acts as a transcriptional switch downstream of IL-4/STAT6 by ADP-ribosylating HDACs to derepress target promoters, cross-regulates macrophage polarization by suppressing STAT1 phosphorylation, promotes Th17 differentiation, and upon IFN-γ stimulation drives formation of cytoplasmic p62 body condensates enriched in ADP-ribosylated substrates and polyubiquitin chains [PMID:21081493, PMID:27796300, PMID:23956424, PMID:38834853, PMID:40195501]. In genome maintenance, PARP14 interacts with PCNA and uses its RRM domains to recruit MRE11 to reversed replication forks in BRCA-deficient cells, promoting nascent strand degradation, while its loss creates synthetic lethality with the ATR-CHK1 pathway; PARP14 also stabilizes cyclin D1 and tissue factor mRNAs through 3′UTR-dependent mechanisms and inhibits JNK1 to sustain aerobic glycolysis and tumor cell survival [PMID:36030235, PMID:41684642, PMID:32542389, PMID:34158578, PMID:25293769, PMID:25258887].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Before this work, the biological role of PARP14 was unknown; this study established it as a STAT6 binding partner that mediates IL-4-dependent survival in B cells and influences lymphomagenesis, placing it in adaptive immune signaling.\",\n      \"evidence\": \"PARP14 knockout mice, co-immunoprecipitation with STAT6, apoptosis assays in primary B cells\",\n      \"pmids\": [\"19147789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity not yet linked to STAT6 function\", \"Downstream transcriptional mechanism unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolving how PARP14 controls transcription, this work showed it acts as a bimodal switch: recruiting HDAC2/3 to repress IL-4-responsive promoters basally, then ADP-ribosylating those HDACs upon IL-4 stimulation to derepress gene expression and enable STAT6 binding.\",\n      \"evidence\": \"ChIP, co-immunoprecipitation, ADP-ribosylation assays, luciferase reporters\",\n      \"pmids\": [\"21081493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific HDAC residues modified not identified\", \"Whether other STAT6-target promoters use the same switch unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extending PARP14's role beyond transcription, its requirement for IL-4-induced glycolysis in B cells was established, linking its activity to metabolic reprogramming and Myc-driven lymphomagenesis.\",\n      \"evidence\": \"PARP14 KO mice, glycolysis assays, AMPK activity measurement, E-Myc lymphoma model\",\n      \"pmids\": [\"21911376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrates mediating glycolytic control not identified\", \"Relationship to JNK1 axis not yet established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"PARP14 was identified as a JNK2-dependent pro-survival effector in multiple myeloma that directly binds and inhibits pro-apoptotic JNK1, revealing a non-catalytic scaffolding function in tumor cell survival.\",\n      \"evidence\": \"Reciprocal co-IP of PARP14-JNK1, siRNA knockdown, overexpression rescue in myeloma cells\",\n      \"pmids\": [\"23045269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether JNK1 inhibition requires PARP14 catalytic activity unknown\", \"Structural basis of PARP14-JNK1 interaction not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two advances defined PARP14 as both a reader of mono-ADP-ribosylation and an immune regulator beyond B cells: crystal structures showed macrodomains 2/3 selectively bind mono-ADP-ribosylated substrates, and KO studies revealed PARP14 catalytic activity drives Th17 differentiation and IgE responses.\",\n      \"evidence\": \"X-ray crystallography and ITC of macrodomains 2/3; PARP14 KO mice with T cell differentiation assays and antibody measurements\",\n      \"pmids\": [\"23473667\", \"23956424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo reader substrates not identified\", \"How macrodomain reading integrates with transferase activity unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PARP14 was shown to regulate mRNA stability by forming an RNP complex with tristetraprolin on the tissue factor 3′UTR, and to form a functional complex with DTX3L and PARP9/ARTD9 in cancer cells, broadening its molecular partnerships.\",\n      \"evidence\": \"RIP and RNA pull-down for TTP-TF mRNA interaction with KO mouse validation; Co-IP of PARP14-DTX3L-ARTD9 in prostate cancer cells\",\n      \"pmids\": [\"25293769\", \"24886089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PARP14 catalytic activity is needed for mRNA regulation not tested\", \"Stoichiometry and structural basis of the DTX3L/PARP9/PARP14 complex unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two parallel advances established PARP14 in genome maintenance and metabolic signaling: PARP14 interacts with PCNA and promotes homologous recombination at replication forks, and it sustains the Warburg effect by inhibiting JNK1 to prevent PKM2 Thr365 phosphorylation.\",\n      \"evidence\": \"Co-IP of PARP14-PCNA, RAD51 foci and DNA damage sensitivity in KD cells; JNK1-PKM2 phosphorylation epistasis in HCC cells and xenografts\",\n      \"pmids\": [\"25753673\", \"26258887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PCNA interaction requires PARP14 catalytic activity not determined\", \"Direct MARylation targets at replication forks unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PARP14 was shown to directly ADP-ribosylate STAT1, suppressing its phosphorylation and thereby cross-regulating macrophage polarization between pro- and anti-inflammatory states, with PARP9 acting as its functional antagonist.\",\n      \"evidence\": \"Proteomics, site-directed mutagenesis of STAT1 ADP-ribosylation sites, phosphorylation analysis in primary macrophages\",\n      \"pmids\": [\"27796300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise STAT1 modification sites not fully mapped\", \"How PARP9 reverses the modification mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Chemical genetic substrate identification revealed PARP14 MARylates >100 proteins enriched for RNA regulatory functions, including direct modification of PARP13, while nuclear translocation studies showed PARP14 promotes accumulation of ISG-encoded proteins and IFN-β transcription in macrophages.\",\n      \"evidence\": \"Orthogonal NAD+ analog chemical genetics with BioID and MS; nuclear fractionation and MS interactomics with siRNA knockdown in macrophages\",\n      \"pmids\": [\"30247868\", \"29500242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PARP13 MARylation unknown\", \"How PARP14 promotes nuclear accumulation of ISG products mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide CRISPR screening identified synthetic lethality between PARP14 loss and ATR-CHK1 pathway inhibition, defining PARP14 as a modulator of replication dynamics and a potential therapeutic vulnerability.\",\n      \"evidence\": \"Genome-wide CRISPR KO screen, DNA fiber assays, ATR/CHK1 inhibitor sensitivity\",\n      \"pmids\": [\"32542389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether synthetic lethality depends on PARP14 catalytic or structural function not resolved\", \"Patient-relevant contexts not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PARP14 was found to stabilize cyclin D1 mRNA via its 3′UTR, controlling G1/S cell cycle progression through the RB and p53-p21 pathways, establishing it as a cell cycle regulator.\",\n      \"evidence\": \"Luciferase 3′UTR reporter, siRNA knockdown, cell cycle analysis by flow cytometry\",\n      \"pmids\": [\"34158578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding domain responsible not mapped\", \"Whether MARylation of an RNA-binding protein mediates this effect unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"PARP14's replication fork role was mechanistically refined: it is recruited to nascent DNA upon replication stress in BRCA-deficient cells and its catalytic activity mediates MRE11 engagement via the KU complex, promoting fork degradation and ssDNA gap formation.\",\n      \"evidence\": \"iPOND, DNA fiber assay, proximity ligation assay, catalytic inhibitor and siRNA in BRCA-deficient cells\",\n      \"pmids\": [\"36030235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MARylation substrates at the fork not identified\", \"Which domain recruits to nascent DNA not yet mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The discovery that PARP14 macrodomain 1 is an active ADP-ribosylhydrolase established PARP14 as a dual writer-eraser enzyme, and revealed that coronavirus macrodomains (e.g., SARS-CoV-2 Mac1) functionally mimic this eraser activity to counteract host MARylation.\",\n      \"evidence\": \"In vitro hydrolase assays, F926A mutagenesis ablating activity, cellular MARylation accumulation upon macrodomain 1 inactivation, reconstitution with SARS-CoV-2 Mac1\",\n      \"pmids\": [\"37703374\", \"37507011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates preferentially de-MARylated by macrodomain 1 not identified\", \"Structural basis for substrate selectivity of macrodomain 1 vs. viral Mac1 not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies converged to show that IFN-γ-induced PARP14 is the dominant MARylase in macrophages, regulated post-translationally by PARP9/DTX3L, and that its activity and physical presence drive formation of p62 body condensates containing ADP-ribosylated substrates including p62 itself, polyubiquitin, and selective autophagy receptors—structures counteracted by SARS-CoV-2 Mac1.\",\n      \"evidence\": \"Improved MAR antibodies, PARP14/PARP9/DTX3L KD, immunofluorescence, site-directed mutagenesis of p62 cysteine acceptor residues, proteasome/autophagy inhibitors\",\n      \"pmids\": [\"38834853\", \"38834852\", \"40195501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of p62 body condensates for antiviral defense not established\", \"Whether condensate formation occurs in vivo during infection unknown\", \"Cysteine-directed MARylation specificity mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KH-like domains were identified as the structural determinants mediating PARP14-DTX3L and PARP9-DTX3L protein-protein interactions, with DTX3L binding shifting PARP14 activity from auto- to trans-MARylation.\",\n      \"evidence\": \"Co-IP with KH domain mutagenesis, in vitro ADP-ribosylation assays\",\n      \"pmids\": [\"38182103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of the ternary PARP14-PARP9-DTX3L complex absent\", \"In vivo relevance of the auto- to trans-MARylation switch unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Domain-specific analysis showed PARP14's RRM domains are necessary and sufficient for recruitment to reversed replication forks in BRCA2-deficient cells and for subsequent MRE11 engagement, resolving the structural basis of its replication fork function.\",\n      \"evidence\": \"iPOND with RRM truncation/mutation, MRE11 recruitment and DNA fiber assays in BRCA2-deficient cells\",\n      \"pmids\": [\"41684642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RRM domains bind DNA or RNA at the fork not distinguished\", \"RRM-mediated interaction partners beyond MRE11 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PARP14 was shown to restrict coronavirus (MHV, SARS-CoV-2 with Mac1 mutation) and HSV-1 replication while paradoxically enhancing VSV replication, with antiviral effects on coronaviruses depending on catalytic activity and others being catalytic-activity-independent.\",\n      \"evidence\": \"PARP14 KO cells, catalytic inhibitor, viral replication assays across five viruses, IFN production measurement\",\n      \"pmids\": [\"40937852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct antiviral MARylation substrates not identified\", \"Mechanism of catalytic-activity-independent HSV-1 restriction unknown\", \"Basis for proviral activity toward VSV not characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the full catalog of physiological MARylation substrates that drive specific PARP14 functions, the structural basis for how PARP14 macrodomain 1 hydrolase and catalytic domain transferase activities are coordinated, and whether PARP14-dependent p62 body condensates serve a direct antiviral effector function in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length PARP14\", \"In vivo antiviral mechanism through MARylation not demonstrated\", \"Coordination between hydrolase and transferase domains within the same polypeptide not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 9, 10, 15, 16, 18, 20, 22, 28]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 10, 14, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [20, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 11, 18, 24, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 9, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 13, 15, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 7, 26, 28]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7, 26]}\n    ],\n    \"complexes\": [\n      \"PARP14-PARP9-DTX3L complex\"\n    ],\n    \"partners\": [\n      \"STAT6\",\n      \"STAT1\",\n      \"DTX3L\",\n      \"PARP9\",\n      \"PCNA\",\n      \"MRE11\",\n      \"JNK1\",\n      \"HDAC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}