{"gene":"PARP12","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2014,"finding":"PARP12 is an interferon-stimulated gene (ISG) that localizes to stress granules upon ectopic expression or oxidative stress, where it blocks mRNA translation. Both the N-terminal RNA-binding domain (five CCCH-type Zn-fingers) and an intact catalytic domain are required for translational suppression. Upon LPS stimulation, PARP12 instead localizes to p62/SQSTM1-containing structures, and deletion of the N-terminal domain promotes this association, correlating with increased NF-κB signaling.","method":"Ectopic expression, stress granule co-localization, deletion mutagenesis, translational reporter assays, co-immunoprecipitation with p62/SQSTM1, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal methods (localization, mutagenesis, reporter assays) in a single lab; functional consequences of localization established but reconstitution not performed","pmids":["25086041"],"is_preprint":false},{"year":2017,"finding":"PARP12 is a Golgi-localized mono-ADP-ribosyltransferase that reversibly translocates from the trans-Golgi network to stress granules under stress. PARP1 activation in the nucleus produces poly-ADP-ribose (PAR) polymers that directly bind the PARP12 WWE domain, driving this translocation. PARP12 departure from the Golgi causes Golgi membrane disassembly and a block in anterograde membrane traffic, which is reversible upon stress removal.","method":"Live-cell imaging, PARP1 inhibition/activation, PAR-binding assay via WWE domain, Golgi morphology analysis, anterograde traffic assay, drug wash-out rescue experiment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments, direct PAR-binding via WWE domain, rescue by drug wash-out, multiple orthogonal methods in single study with clear mechanistic linkage","pmids":["29070863"],"is_preprint":false},{"year":2018,"finding":"PARP12 restricts Zika virus replication by mediating ADP-ribosylation of the viral nonstructural proteins NS1 and NS3, which triggers their proteasome-dependent degradation. Knockout of PARP12 in A549 cells enhanced Zika virus replication.","method":"CRISPR knockout screen (21 ISGs), individual ISG knockout in A549 cells, western blot for NS1/NS3 protein levels, proteasome inhibitor rescue experiment, ADP-ribosylation assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-scale screen plus functional validation with KO, proteasome inhibitor rescue, and ADP-ribosylation assay; multiple orthogonal methods","pmids":["29921658"],"is_preprint":false},{"year":2018,"finding":"PARP12 interacts with four-and-a-half LIM-only protein 2 (FHL2) via protein affinity purification. PARP12 stabilizes FHL2 protein by protecting it from ubiquitin-mediated proteasomal degradation, and this stabilization is independent of PARP12 enzymatic activity. PARP12 deficiency increases TGF-β1 expression and promotes epithelial-mesenchymal transition, increasing migration and invasion of hepatocellular carcinoma cells.","method":"Protein affinity purification, co-immunoprecipitation, ubiquitination assay, in vitro ADP-ribosylation assay (negative for FHL2), siRNA knockdown, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP plus ubiquitination assay and in vitro ADP-ribosylation (negative result for FHL2 as direct substrate); single lab","pmids":["30154409"],"is_preprint":false},{"year":2021,"finding":"PARP11 physically interacts with PARP12 (confirmed by co-immunoprecipitation) and promotes PARP12-mediated ADP-ribosylation and proteasomal degradation of Zika virus NS1 and NS3 proteins. In PARP11/PARP12 double-knockout cells, NS1/NS3 degradation is further impaired relative to single knockouts, demonstrating synergistic anti-Zika activity.","method":"PARP11/PARP12 single and double knockout HEK293T lines, co-immunoprecipitation, western blot for NS1/NS3 levels, immunofluorescence","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus double-KO epistasis experiment; single lab, orthogonal approaches","pmids":["34187568"],"is_preprint":false},{"year":2022,"finding":"PARP12 mono-ADP-ribosylates Golgin-97 at an acidic cluster in its coiled-coil domain at the trans-Golgi network. This modification is required for the formation and fission of carriers transporting specific basolateral cargoes (E-cadherin and VSVG). PARP12 depletion or mutation of the Golgin-97 modification site causes accumulation of these cargoes in a trans-Golgi/Rab11-positive intermediate compartment, delaying their transport to the plasma membrane. PARP12 enzymatic activity depends on its direct phosphorylation by protein kinase D (PKD) at the TGN.","method":"In vitro ADP-ribosylation assay, site-directed mutagenesis of Golgin-97 acidic cluster, PARP12 depletion (siRNA/KO), cargo transport assay (E-cadherin, VSVG, TNFα), Rab11 colocalization, PKD kinase assay, PKD inhibition, phosphorylation mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, substrate identification, upstream kinase (PKD) identified with phosphorylation assay, multiple cargo/compartment readouts; single lab but multiple orthogonal methods","pmids":["34969853"],"is_preprint":false},{"year":2023,"finding":"PARP12 knockout in mice increases replication of a coronavirus (MHV) Mac1 mutant in bone-marrow-derived macrophages and in vivo, and worsens liver pathology in A59-infected mice. This establishes PARP12 as a required innate immune restriction factor against coronavirus infection in cell culture and in animals, acting via its ADP-ribosyltransferase activity that is counteracted by the viral Mac1 macrodomain.","method":"PARP12-/- mouse generation, siRNA screen in BMDMs, viral replication assay, liver pathology assessment, lethality study","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in mice (in vivo), siRNA screen validation, multiple cell/tissue types, replicated in both peer-reviewed and preprint forms","pmids":["37695054","37398292"],"is_preprint":false},{"year":2023,"finding":"PARP12 localizes near spindle poles during meiotic metaphase I and II in mouse oocytes. PARP12 depletion causes spindle disorganization, chromosome misalignment, aneuploidy, spindle assembly checkpoint activation (BubR1 signal), and reduction of F-actin in metaphase I oocytes, demonstrating a required role in meiotic spindle integrity and asymmetric division.","method":"Immunofluorescence (localization at GV, MI, MII), morpholino/siRNA knockdown, spindle morphology analysis, chromosome spread and aneuploidy scoring, BubR1 immunostaining, F-actin staining, transcriptomic analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with multiple cellular phenotype readouts (spindle, chromosome, SAC, actin); localization tied to functional consequence; single lab","pmids":["37305966"],"is_preprint":false},{"year":2022,"finding":"PARP12 is highly expressed in brown adipose tissue and localizes primarily to mitochondria. Knockdown of PARP12 reduces UCP1 expression and decreases mitochondrial respiration in thermogenic adipocytes, while overexpression reverses these effects.","method":"qRT-PCR, western blot, subcellular fractionation/immunofluorescence (mitochondrial localization), siRNA knockdown and overexpression, mitochondrial oxygen consumption assay (Seahorse)","journal":"Adipocyte","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/OE with phenotype but no molecular mechanism connecting PARP12 to UCP1 or respiration identified; localization not functionally dissected","pmids":["35916471"],"is_preprint":false},{"year":2024,"finding":"PARP12 interacts with ISG15 (identified by mass spectrometry and co-immunoprecipitation) and upregulates ISGylation of mitofusin 1 and 2 (MFN1/2), which decreases MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent mitophagy in chondrocytes. IRF1, activated by inflammatory cytokines, directly binds the PARP12 promoter to drive PARP12 transcription.","method":"Mass spectrometry, co-immunoprecipitation, ISGylation assay, ubiquitination assay, SUMOylation assay, ChIP (IRF1-PARP12 promoter), PINK1/Parkin pathway analysis, rat OA model","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — MS-identified interaction confirmed by co-IP, multiple PTM assays, ChIP for transcriptional regulation; single lab, several orthogonal methods","pmids":["39465252"],"is_preprint":false},{"year":2025,"finding":"PARP12 catalyzes mono-ADP-ribosylation (MARylation) of RIPK1 (in both its intermediate domain and kinase domain) and RIPK3 in cells stimulated by IFNγ and TNFα. PARP12-mediated MARylation of RIPK1 promotes RIPK1 kinase activation and its interaction with RIPK3 to promote necroptosis, while inhibiting RIPK1–caspase-8 binding to suppress apoptosis. PARP12 deficiency reduces necroptosis, sensitizes cells to apoptosis, and also promotes expression of a subset of ISGs, conferring protection against influenza A virus lethality in mice.","method":"Co-immunoprecipitation, in vitro MARylation assay, RIPK1/RIPK3 kinase activity assay, PARP12-/- cells and mice, necroptosis/apoptosis assays, influenza A virus infection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro MARylation assay identifying substrates and domains, genetic KO in cells and mice, multiple functional readouts (necroptosis, apoptosis, ISG induction, viral mortality), single lab with multiple orthogonal methods","pmids":["40489618"],"is_preprint":false},{"year":2025,"finding":"PARP12 mono-ADP-ribosylates AKT, which is required for AKT activation in oestrogen receptor-positive breast cancer cells. Transcriptional inhibition of PARP12 reduces AKT activity, increases DNA damage, augments p53 nuclear localization, promotes p53–AKT interaction, and increases FOXO1 protein levels leading to apoptotic cell death.","method":"ADP-ribosylation assay (AKT as substrate), PARP12 siRNA knockdown, AKT activity assay (phospho-substrate readouts), FOXO1/p53 western blot, immunofluorescence (p53 localization), co-immunoprecipitation (p53-AKT), apoptosis assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ADP-ribosylation assay identifying AKT as substrate, KD with multiple downstream readouts; single lab","pmids":["39847113"],"is_preprint":false},{"year":2025,"finding":"PARP12 ADP-ribosylates viral RNA of chikungunya virus (positive-strand RNA virus), which inhibits translation in cell-free systems and infected fibroblasts, promotes more rapid viral RNA decay, and induces antiviral host response gene expression (acting as a novel pathogen-associated molecular pattern, PAMP). The viral macrodomain counteracts this RNA ribosylation.","method":"RNA ribosylation assay (PARP12), cell-free translation system, infected fibroblast translation assay, viral RNA decay assay, antiviral gene expression (qRT-PCR/RNA-seq), chikungunya virus infection model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution (cell-free translation, RNA ribosylation assay) plus cell-based validation; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.07.18.665567"],"is_preprint":true},{"year":2025,"finding":"PARP12 ADP-ribosylates approximately 150 mRNAs, including insulin mRNA, in MIN6 insulin-producing cells during inflammation. This mRNA ADP-ribosylation modifies transcript localization and halts translation, suggesting a post-transcriptional regulatory role in insulin production during insulitis.","method":"Proteomics/mass spectrometry, RNA ADP-ribosylation mapping (proteomics of RNA machinery), mRNA localization assay, translation assay, PARP12 induction by cytokines","journal":"Research square (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, RNA ribosylation mapping without full mechanistic validation, functional translation link established only partially","pmids":["40470236"],"is_preprint":true},{"year":2024,"finding":"In RA fibroblast-like synoviocytes, elevated trans-Golgi NAD+ (resulting from QPRT deficiency) suppresses TGN-resident PARP12, leading to mTORC1-mediated protein translation and Golgi expansion. This places PARP12 downstream of TGN NAD+ availability as a regulator of protein secretion.","method":"QPRT knockdown, NAD+ compartment measurement, mTORC1 activity assay, Golgi morphology analysis, RA mouse model with QPRT gene therapy","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, PARP12 role inferred from QPRT-KD phenotype rescue; PARP12 not directly manipulated in all experiments; single lab","pmids":["bio_10.1101_2024.10.27.24316032"],"is_preprint":true}],"current_model":"PARP12 is an interferon-stimulated, Golgi-resident mono-ADP-ribosyltransferase (MARylating enzyme) that, upon activation, modifies a diverse set of substrates—including the TGN protein Golgin-97 (regulating E-cadherin/VSVG basolateral traffic), viral nonstructural proteins NS1 and NS3 (triggering their proteasomal degradation to restrict Zika and coronavirus replication), RIPK1 and RIPK3 (promoting necroptosis and suppressing apoptosis downstream of IFNγ/TNFα), viral and cellular mRNAs (inhibiting their translation and stability), and AKT (required for AKT activation in breast cancer cells); PARP12's own catalytic activity is controlled by PKD-mediated phosphorylation at the TGN and by nuclear PAR produced by PARP1, which binds the PARP12 WWE domain to drive Golgi-to-stress-granule translocation, thereby coupling nuclear stress sensing to cytoplasmic translation arrest and intracellular traffic blockade."},"narrative":{"mechanistic_narrative":"PARP12 is an interferon-stimulated mono-ADP-ribosyltransferase that couples nuclear and cytoplasmic stress sensing to the control of membrane traffic, mRNA translation, and innate antiviral defense [PMID:25086041, PMID:29070863]. At the trans-Golgi network its catalytic activity is switched on by direct phosphorylation from protein kinase D, where it mono-ADP-ribosylates Golgin-97 on an acidic cluster to drive the formation and fission of carriers delivering basolateral cargoes such as E-cadherin and VSVG to the plasma membrane [PMID:34969853]. Upon stress, nuclear PARP1 activation generates poly-ADP-ribose that binds the PARP12 WWE domain, triggering reversible translocation from the Golgi to stress granules; this departure disassembles the Golgi, blocks anterograde traffic, and—via its N-terminal CCCH Zn-finger RNA-binding domain together with an intact catalytic domain—suppresses mRNA translation [PMID:25086041, PMID:29070863]. As an antiviral effector, PARP12 ADP-ribosylates the viral nonstructural proteins NS1 and NS3 to trigger their proteasomal degradation and restrict Zika virus, an activity potentiated by its partner PARP11 [PMID:29921658, PMID:34187568], and it restricts coronavirus replication in mice through ADP-ribosyltransferase activity opposed by the viral Mac1 macrodomain [PMID:37695054, PMID:37398292]. PARP12 also MARylates signaling and survival regulators: it modifies RIPK1 and RIPK3 downstream of IFNγ/TNFα to promote necroptosis while suppressing apoptosis [PMID:40489618], and modifies AKT to sustain its activation in breast cancer cells [PMID:39847113]. Independent of catalysis, PARP12 stabilizes FHL2 against proteasomal degradation to restrain TGF-β1-driven epithelial-mesenchymal transition [PMID:30154409], and it engages ISG15 to promote MFN1/2 ISGylation and limit mitophagy [PMID:39465252].","teleology":[{"year":2014,"claim":"Established PARP12 as an interferon-stimulated gene whose subcellular targeting dictates function, linking its RNA-binding and catalytic domains to translational arrest at stress granules.","evidence":"Ectopic expression, stress granule co-localization, deletion mutagenesis, translational reporters and NF-κB assays in cells","pmids":["25086041"],"confidence":"Medium","gaps":["Direct RNA or protein substrates of the translational block not identified","Reconstitution of the catalytic requirement not performed","Mechanism linking p62/SQSTM1 association to NF-κB not resolved"]},{"year":2017,"claim":"Defined the trigger for PARP12 relocalization: nuclear PARP1-generated PAR binds the WWE domain to drive Golgi-to-stress-granule translocation, coupling nuclear stress to a reversible Golgi/traffic block.","evidence":"Live-cell imaging, PARP1 modulation, WWE PAR-binding assay, Golgi morphology and anterograde traffic assays with wash-out rescue","pmids":["29070863"],"confidence":"High","gaps":["Golgi substrates mediating traffic block not yet identified at this stage","Structural basis of WWE-PAR recognition not resolved"]},{"year":2018,"claim":"Demonstrated a direct antiviral catalytic mechanism: PARP12 ADP-ribosylates Zika NS1 and NS3 to trigger their proteasomal degradation and restrict viral replication.","evidence":"CRISPR ISG knockout screen, A549 KO, NS1/NS3 western blot, proteasome inhibitor rescue and ADP-ribosylation assay","pmids":["29921658"],"confidence":"High","gaps":["Modified residues on NS1/NS3 not mapped","E3 ligase coupling MARylation to degradation unknown"]},{"year":2018,"claim":"Revealed a catalysis-independent role: PARP12 binds and stabilizes FHL2 against ubiquitin-mediated degradation to restrain TGF-β1-driven EMT and tumor invasion.","evidence":"Affinity purification, reciprocal co-IP, ubiquitination assay, negative in vitro ADP-ribosylation of FHL2, siRNA and in vivo metastasis model","pmids":["30154409"],"confidence":"Medium","gaps":["Mechanism by which PARP12 shields FHL2 from ubiquitination unknown","Single lab; reciprocal validation in independent systems lacking"]},{"year":2021,"claim":"Identified PARP11 as a physical partner that potentiates PARP12-mediated ADP-ribosylation and degradation of Zika NS1/NS3, defining cooperative anti-viral PARP activity.","evidence":"Single and double KO HEK293T lines, co-IP, NS1/NS3 western blot, immunofluorescence","pmids":["34187568"],"confidence":"Medium","gaps":["Whether PARP11 modifies PARP12 or co-modifies substrates unresolved","Structural basis of the interaction unknown"]},{"year":2022,"claim":"Pinpointed Golgin-97 as the TGN substrate and PKD as the upstream activating kinase, mechanistically explaining how PARP12 controls basolateral cargo carrier formation.","evidence":"In vitro ADP-ribosylation with site-directed mutagenesis, PARP12 depletion, cargo transport and Rab11 colocalization assays, PKD kinase assay and inhibition","pmids":["34969853"],"confidence":"High","gaps":["Reader of ADP-ribosylated Golgin-97 driving fission not identified","Generality across other cargoes beyond E-cadherin/VSVG not defined"]},{"year":2022,"claim":"Reported a mitochondrial localization and a role supporting UCP1 expression and respiration in thermogenic adipocytes.","evidence":"qRT-PCR, western blot, fractionation/immunofluorescence, siRNA and overexpression, Seahorse respiration assay","pmids":["35916471"],"confidence":"Low","gaps":["No molecular mechanism connecting PARP12 to UCP1 or respiration identified","Mitochondrial localization not functionally dissected","Single lab, not independently confirmed"]},{"year":2023,"claim":"Extended antiviral function to coronaviruses in vivo, showing PARP12 is a genetically required restriction factor whose ADP-ribosyltransferase activity is counteracted by the viral Mac1 macrodomain.","evidence":"PARP12-/- mice, BMDM siRNA screen, viral replication and liver pathology assays, lethality study","pmids":["37695054","37398292"],"confidence":"High","gaps":["Coronavirus substrates of PARP12 not defined","Cell types responsible for in vivo restriction not delineated"]},{"year":2023,"claim":"Uncovered a meiotic role: PARP12 localizes near spindle poles and is required for spindle integrity, chromosome alignment, and asymmetric division in mouse oocytes.","evidence":"Immunofluorescence across meiotic stages, knockdown, spindle/chromosome/aneuploidy scoring, BubR1 and F-actin staining","pmids":["37305966"],"confidence":"Medium","gaps":["Spindle/actin substrates of PARP12 not identified","Whether catalytic activity is required not tested"]},{"year":2024,"claim":"Connected PARP12 to PTM cross-talk and transcriptional control: it engages ISG15 to drive MFN1/2 ISGylation, limiting mitophagy, and is transcriptionally induced by IRF1.","evidence":"Mass spectrometry, co-IP, ISGylation/ubiquitination/SUMOylation assays, ChIP of IRF1 on PARP12 promoter, PINK1/Parkin analysis, rat OA model","pmids":["39465252"],"confidence":"Medium","gaps":["Whether PARP12 catalysis is required for ISG15 effect unclear","Direct MFN1/2 modification by PARP12 not established"]},{"year":2025,"claim":"Defined PARP12 as a regulator of cell-death fate, MARylating RIPK1/RIPK3 to promote necroptosis and suppress apoptosis downstream of IFNγ/TNFα with in vivo antiviral consequences.","evidence":"In vitro MARylation assay mapping RIPK1 domains, RIPK kinase assays, PARP12-/- cells and mice, necroptosis/apoptosis assays, influenza A model","pmids":["40489618"],"confidence":"High","gaps":["Modified RIPK1/RIPK3 residues not pinpointed","Reader/eraser of these marks unknown"]},{"year":2025,"claim":"Identified AKT as a substrate, with PARP12 MARylation required for AKT activation and survival signaling in ER-positive breast cancer cells.","evidence":"ADP-ribosylation assay with AKT, siRNA, AKT activity and downstream p53/FOXO1 readouts, p53-AKT co-IP, apoptosis assay","pmids":["39847113"],"confidence":"Medium","gaps":["AKT modification site not mapped","Single lab; in vivo relevance not tested"]},{"year":2025,"claim":"Extended ADP-ribosylation to RNA itself: PARP12 modifies chikungunya and cellular mRNAs (including insulin mRNA) to block translation, alter localization, accelerate decay, and trigger antiviral gene expression.","evidence":"RNA ribosylation assays, cell-free and infected-cell translation assays, viral RNA decay, antiviral gene expression, RNA localization in MIN6 cells (preprints)","pmids":["bio_10.1101_2025.07.18.665567","40470236"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Chemistry/site of RNA modification not fully defined","Mechanism linking RNA mark to decay/localization unresolved"]},{"year":null,"claim":"How PARP12's distinct localization-defined activities (TGN traffic, stress-granule translation arrest, mitochondrial/spindle roles, cell-death control) are integrated and selectively engaged remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate selection across compartments","Readers/erasers of PARP12-deposited marks largely unknown","Relative contribution of catalytic vs scaffolding functions unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,10,11]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,5,10]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[12,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,12,13]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,6,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,12]}],"complexes":[],"partners":["PARP11","FHL2","ISG15","RIPK1","RIPK3","AKT","GOLGIN-97"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0J9","full_name":"Protein mono-ADP-ribosyltransferase PARP12","aliases":["ADP-ribosyltransferase diphtheria toxin-like 12","ARTD12","Poly [ADP-ribose] polymerase 12","PARP-12","Zinc finger CCCH domain-containing protein 1"],"length_aa":701,"mass_kda":79.1,"function":"Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins (PubMed:25043379, PubMed:34969853). Acts as an antiviral factor by cooperating with PARP11 to suppress Zika virus replication (PubMed:34187568). Displays anti-alphavirus activity during IFN-gamma immune activation by directly ADP-ribosylating the alphaviral non-structural proteins nsP3 and nsP4 (PubMed:39888989). Acts as a component of the PRKD1-driven regulatory cascade that selectively controls a major branch of the basolateral transport pathway by catalyzing the MARylation of GOLGA1 (PubMed:34969853). Acts also as a key regulator of mitochondrial function, protein translation, and inflammation. Inhibits PINK1/Parkin-dependent mitophagy and promotes cartilage degeneration by inhibiting the ubiquitination and SUMOylation of MFN1/2 by upregulating ISG15 and ISGylation (PubMed:39465252)","subcellular_location":"Nucleus; Golgi apparatus, trans-Golgi network; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9H0J9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARP12","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/PARP12","total_profiled":1310},"omim":[{"mim_id":"612481","title":"POLY(ADP-RIBOSE) POLYMERASE FAMILY, MEMBER 12; PARP12","url":"https://www.omim.org/entry/612481"},{"mim_id":"612480","title":"TCDD-INDUCIBLE POLY(ADP-RIBOSE) POLYMERASE; TIPARP","url":"https://www.omim.org/entry/612480"},{"mim_id":"607312","title":"ZINC FINGER CCCH DOMAIN-CONTAINING ANTIVIRAL PROTEIN 1; ZC3HAV1","url":"https://www.omim.org/entry/607312"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PARP12"},"hgnc":{"alias_symbol":["FLJ22693","PARP-12","ZC3H1","ARTD12"],"prev_symbol":["ZC3HDC1"]},"alphafold":{"accession":"Q9H0J9","domains":[{"cath_id":"-","chopping":"75-236","consensus_level":"medium","plddt":89.0513,"start":75,"end":236},{"cath_id":"3.30.720.50","chopping":"377-459","consensus_level":"medium","plddt":89.1429,"start":377,"end":459},{"cath_id":"3.90.228.10","chopping":"498-677","consensus_level":"high","plddt":90.3646,"start":498,"end":677}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0J9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0J9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0J9-F1-predicted_aligned_error_v6.png","plddt_mean":83.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARP12","jax_strain_url":"https://www.jax.org/strain/search?query=PARP12"},"sequence":{"accession":"Q9H0J9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0J9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0J9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0J9"}},"corpus_meta":[{"pmid":"23881923","id":"PMC_23881923","title":"BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23881923","citation_count":412,"is_preprint":false},{"pmid":"24240700","id":"PMC_24240700","title":"Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24240700","citation_count":305,"is_preprint":false},{"pmid":"25117293","id":"PMC_25117293","title":"Combined inhibition of Wee1 and PARP1/2 for radiosensitization in pancreatic cancer.","date":"2014","source":"Clinical cancer research : an official journal of the American Association for Cancer 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Tolerability, and Pharmacokinetics of Senaparib, a Novel PARP1/2 Inhibitor, in Chinese Patients With Advanced Solid Tumors: A Phase I Trial.","date":"2023","source":"The oncologist","url":"https://pubmed.ncbi.nlm.nih.gov/37338150","citation_count":6,"is_preprint":false},{"pmid":"35916471","id":"PMC_35916471","title":"PARP12 is required for mitochondrial function maintenance in thermogenic adipocytes.","date":"2022","source":"Adipocyte","url":"https://pubmed.ncbi.nlm.nih.gov/35916471","citation_count":5,"is_preprint":false},{"pmid":"39201718","id":"PMC_39201718","title":"Leveraging PARP-1/2 to Target Distant Metastasis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201718","citation_count":3,"is_preprint":false},{"pmid":"39847113","id":"PMC_39847113","title":"PARP12-mediated ADP-ribosylation contributes to breast cancer cell fate by regulating AKT activation and DNA-damage response.","date":"2025","source":"Cellular and 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Both the N-terminal RNA-binding domain (five CCCH-type Zn-fingers) and an intact catalytic domain are required for translational suppression. Upon LPS stimulation, PARP12 instead localizes to p62/SQSTM1-containing structures, and deletion of the N-terminal domain promotes this association, correlating with increased NF-κB signaling.\",\n      \"method\": \"Ectopic expression, stress granule co-localization, deletion mutagenesis, translational reporter assays, co-immunoprecipitation with p62/SQSTM1, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal methods (localization, mutagenesis, reporter assays) in a single lab; functional consequences of localization established but reconstitution not performed\",\n      \"pmids\": [\"25086041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PARP12 is a Golgi-localized mono-ADP-ribosyltransferase that reversibly translocates from the trans-Golgi network to stress granules under stress. PARP1 activation in the nucleus produces poly-ADP-ribose (PAR) polymers that directly bind the PARP12 WWE domain, driving this translocation. PARP12 departure from the Golgi causes Golgi membrane disassembly and a block in anterograde membrane traffic, which is reversible upon stress removal.\",\n      \"method\": \"Live-cell imaging, PARP1 inhibition/activation, PAR-binding assay via WWE domain, Golgi morphology analysis, anterograde traffic assay, drug wash-out rescue experiment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments, direct PAR-binding via WWE domain, rescue by drug wash-out, multiple orthogonal methods in single study with clear mechanistic linkage\",\n      \"pmids\": [\"29070863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP12 restricts Zika virus replication by mediating ADP-ribosylation of the viral nonstructural proteins NS1 and NS3, which triggers their proteasome-dependent degradation. Knockout of PARP12 in A549 cells enhanced Zika virus replication.\",\n      \"method\": \"CRISPR knockout screen (21 ISGs), individual ISG knockout in A549 cells, western blot for NS1/NS3 protein levels, proteasome inhibitor rescue experiment, ADP-ribosylation assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-scale screen plus functional validation with KO, proteasome inhibitor rescue, and ADP-ribosylation assay; multiple orthogonal methods\",\n      \"pmids\": [\"29921658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PARP12 interacts with four-and-a-half LIM-only protein 2 (FHL2) via protein affinity purification. PARP12 stabilizes FHL2 protein by protecting it from ubiquitin-mediated proteasomal degradation, and this stabilization is independent of PARP12 enzymatic activity. PARP12 deficiency increases TGF-β1 expression and promotes epithelial-mesenchymal transition, increasing migration and invasion of hepatocellular carcinoma cells.\",\n      \"method\": \"Protein affinity purification, co-immunoprecipitation, ubiquitination assay, in vitro ADP-ribosylation assay (negative for FHL2), siRNA knockdown, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP plus ubiquitination assay and in vitro ADP-ribosylation (negative result for FHL2 as direct substrate); single lab\",\n      \"pmids\": [\"30154409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PARP11 physically interacts with PARP12 (confirmed by co-immunoprecipitation) and promotes PARP12-mediated ADP-ribosylation and proteasomal degradation of Zika virus NS1 and NS3 proteins. In PARP11/PARP12 double-knockout cells, NS1/NS3 degradation is further impaired relative to single knockouts, demonstrating synergistic anti-Zika activity.\",\n      \"method\": \"PARP11/PARP12 single and double knockout HEK293T lines, co-immunoprecipitation, western blot for NS1/NS3 levels, immunofluorescence\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus double-KO epistasis experiment; single lab, orthogonal approaches\",\n      \"pmids\": [\"34187568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP12 mono-ADP-ribosylates Golgin-97 at an acidic cluster in its coiled-coil domain at the trans-Golgi network. This modification is required for the formation and fission of carriers transporting specific basolateral cargoes (E-cadherin and VSVG). PARP12 depletion or mutation of the Golgin-97 modification site causes accumulation of these cargoes in a trans-Golgi/Rab11-positive intermediate compartment, delaying their transport to the plasma membrane. PARP12 enzymatic activity depends on its direct phosphorylation by protein kinase D (PKD) at the TGN.\",\n      \"method\": \"In vitro ADP-ribosylation assay, site-directed mutagenesis of Golgin-97 acidic cluster, PARP12 depletion (siRNA/KO), cargo transport assay (E-cadherin, VSVG, TNFα), Rab11 colocalization, PKD kinase assay, PKD inhibition, phosphorylation mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, substrate identification, upstream kinase (PKD) identified with phosphorylation assay, multiple cargo/compartment readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34969853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP12 knockout in mice increases replication of a coronavirus (MHV) Mac1 mutant in bone-marrow-derived macrophages and in vivo, and worsens liver pathology in A59-infected mice. This establishes PARP12 as a required innate immune restriction factor against coronavirus infection in cell culture and in animals, acting via its ADP-ribosyltransferase activity that is counteracted by the viral Mac1 macrodomain.\",\n      \"method\": \"PARP12-/- mouse generation, siRNA screen in BMDMs, viral replication assay, liver pathology assessment, lethality study\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in mice (in vivo), siRNA screen validation, multiple cell/tissue types, replicated in both peer-reviewed and preprint forms\",\n      \"pmids\": [\"37695054\", \"37398292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PARP12 localizes near spindle poles during meiotic metaphase I and II in mouse oocytes. PARP12 depletion causes spindle disorganization, chromosome misalignment, aneuploidy, spindle assembly checkpoint activation (BubR1 signal), and reduction of F-actin in metaphase I oocytes, demonstrating a required role in meiotic spindle integrity and asymmetric division.\",\n      \"method\": \"Immunofluorescence (localization at GV, MI, MII), morpholino/siRNA knockdown, spindle morphology analysis, chromosome spread and aneuploidy scoring, BubR1 immunostaining, F-actin staining, transcriptomic analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with multiple cellular phenotype readouts (spindle, chromosome, SAC, actin); localization tied to functional consequence; single lab\",\n      \"pmids\": [\"37305966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP12 is highly expressed in brown adipose tissue and localizes primarily to mitochondria. Knockdown of PARP12 reduces UCP1 expression and decreases mitochondrial respiration in thermogenic adipocytes, while overexpression reverses these effects.\",\n      \"method\": \"qRT-PCR, western blot, subcellular fractionation/immunofluorescence (mitochondrial localization), siRNA knockdown and overexpression, mitochondrial oxygen consumption assay (Seahorse)\",\n      \"journal\": \"Adipocyte\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/OE with phenotype but no molecular mechanism connecting PARP12 to UCP1 or respiration identified; localization not functionally dissected\",\n      \"pmids\": [\"35916471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PARP12 interacts with ISG15 (identified by mass spectrometry and co-immunoprecipitation) and upregulates ISGylation of mitofusin 1 and 2 (MFN1/2), which decreases MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent mitophagy in chondrocytes. IRF1, activated by inflammatory cytokines, directly binds the PARP12 promoter to drive PARP12 transcription.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, ISGylation assay, ubiquitination assay, SUMOylation assay, ChIP (IRF1-PARP12 promoter), PINK1/Parkin pathway analysis, rat OA model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — MS-identified interaction confirmed by co-IP, multiple PTM assays, ChIP for transcriptional regulation; single lab, several orthogonal methods\",\n      \"pmids\": [\"39465252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP12 catalyzes mono-ADP-ribosylation (MARylation) of RIPK1 (in both its intermediate domain and kinase domain) and RIPK3 in cells stimulated by IFNγ and TNFα. PARP12-mediated MARylation of RIPK1 promotes RIPK1 kinase activation and its interaction with RIPK3 to promote necroptosis, while inhibiting RIPK1–caspase-8 binding to suppress apoptosis. PARP12 deficiency reduces necroptosis, sensitizes cells to apoptosis, and also promotes expression of a subset of ISGs, conferring protection against influenza A virus lethality in mice.\",\n      \"method\": \"Co-immunoprecipitation, in vitro MARylation assay, RIPK1/RIPK3 kinase activity assay, PARP12-/- cells and mice, necroptosis/apoptosis assays, influenza A virus infection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro MARylation assay identifying substrates and domains, genetic KO in cells and mice, multiple functional readouts (necroptosis, apoptosis, ISG induction, viral mortality), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40489618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP12 mono-ADP-ribosylates AKT, which is required for AKT activation in oestrogen receptor-positive breast cancer cells. Transcriptional inhibition of PARP12 reduces AKT activity, increases DNA damage, augments p53 nuclear localization, promotes p53–AKT interaction, and increases FOXO1 protein levels leading to apoptotic cell death.\",\n      \"method\": \"ADP-ribosylation assay (AKT as substrate), PARP12 siRNA knockdown, AKT activity assay (phospho-substrate readouts), FOXO1/p53 western blot, immunofluorescence (p53 localization), co-immunoprecipitation (p53-AKT), apoptosis assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ADP-ribosylation assay identifying AKT as substrate, KD with multiple downstream readouts; single lab\",\n      \"pmids\": [\"39847113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP12 ADP-ribosylates viral RNA of chikungunya virus (positive-strand RNA virus), which inhibits translation in cell-free systems and infected fibroblasts, promotes more rapid viral RNA decay, and induces antiviral host response gene expression (acting as a novel pathogen-associated molecular pattern, PAMP). The viral macrodomain counteracts this RNA ribosylation.\",\n      \"method\": \"RNA ribosylation assay (PARP12), cell-free translation system, infected fibroblast translation assay, viral RNA decay assay, antiviral gene expression (qRT-PCR/RNA-seq), chikungunya virus infection model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution (cell-free translation, RNA ribosylation assay) plus cell-based validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.18.665567\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARP12 ADP-ribosylates approximately 150 mRNAs, including insulin mRNA, in MIN6 insulin-producing cells during inflammation. This mRNA ADP-ribosylation modifies transcript localization and halts translation, suggesting a post-transcriptional regulatory role in insulin production during insulitis.\",\n      \"method\": \"Proteomics/mass spectrometry, RNA ADP-ribosylation mapping (proteomics of RNA machinery), mRNA localization assay, translation assay, PARP12 induction by cytokines\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, RNA ribosylation mapping without full mechanistic validation, functional translation link established only partially\",\n      \"pmids\": [\"40470236\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In RA fibroblast-like synoviocytes, elevated trans-Golgi NAD+ (resulting from QPRT deficiency) suppresses TGN-resident PARP12, leading to mTORC1-mediated protein translation and Golgi expansion. This places PARP12 downstream of TGN NAD+ availability as a regulator of protein secretion.\",\n      \"method\": \"QPRT knockdown, NAD+ compartment measurement, mTORC1 activity assay, Golgi morphology analysis, RA mouse model with QPRT gene therapy\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, PARP12 role inferred from QPRT-KD phenotype rescue; PARP12 not directly manipulated in all experiments; single lab\",\n      \"pmids\": [\"bio_10.1101_2024.10.27.24316032\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PARP12 is an interferon-stimulated, Golgi-resident mono-ADP-ribosyltransferase (MARylating enzyme) that, upon activation, modifies a diverse set of substrates—including the TGN protein Golgin-97 (regulating E-cadherin/VSVG basolateral traffic), viral nonstructural proteins NS1 and NS3 (triggering their proteasomal degradation to restrict Zika and coronavirus replication), RIPK1 and RIPK3 (promoting necroptosis and suppressing apoptosis downstream of IFNγ/TNFα), viral and cellular mRNAs (inhibiting their translation and stability), and AKT (required for AKT activation in breast cancer cells); PARP12's own catalytic activity is controlled by PKD-mediated phosphorylation at the TGN and by nuclear PAR produced by PARP1, which binds the PARP12 WWE domain to drive Golgi-to-stress-granule translocation, thereby coupling nuclear stress sensing to cytoplasmic translation arrest and intracellular traffic blockade.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PARP12 is an interferon-stimulated mono-ADP-ribosyltransferase that couples nuclear and cytoplasmic stress sensing to the control of membrane traffic, mRNA translation, and innate antiviral defense [#0, #1]. At the trans-Golgi network its catalytic activity is switched on by direct phosphorylation from protein kinase D, where it mono-ADP-ribosylates Golgin-97 on an acidic cluster to drive the formation and fission of carriers delivering basolateral cargoes such as E-cadherin and VSVG to the plasma membrane [#5]. Upon stress, nuclear PARP1 activation generates poly-ADP-ribose that binds the PARP12 WWE domain, triggering reversible translocation from the Golgi to stress granules; this departure disassembles the Golgi, blocks anterograde traffic, and—via its N-terminal CCCH Zn-finger RNA-binding domain together with an intact catalytic domain—suppresses mRNA translation [#0, #1]. As an antiviral effector, PARP12 ADP-ribosylates the viral nonstructural proteins NS1 and NS3 to trigger their proteasomal degradation and restrict Zika virus, an activity potentiated by its partner PARP11 [#2, #4], and it restricts coronavirus replication in mice through ADP-ribosyltransferase activity opposed by the viral Mac1 macrodomain [#6]. PARP12 also MARylates signaling and survival regulators: it modifies RIPK1 and RIPK3 downstream of IFN\\u03b3/TNF\\u03b1 to promote necroptosis while suppressing apoptosis [#10], and modifies AKT to sustain its activation in breast cancer cells [#11]. Independent of catalysis, PARP12 stabilizes FHL2 against proteasomal degradation to restrain TGF-\\u03b21-driven epithelial-mesenchymal transition [#3], and it engages ISG15 to promote MFN1/2 ISGylation and limit mitophagy [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established PARP12 as an interferon-stimulated gene whose subcellular targeting dictates function, linking its RNA-binding and catalytic domains to translational arrest at stress granules.\",\n      \"evidence\": \"Ectopic expression, stress granule co-localization, deletion mutagenesis, translational reporters and NF-\\u03baB assays in cells\",\n      \"pmids\": [\"25086041\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct RNA or protein substrates of the translational block not identified\", \"Reconstitution of the catalytic requirement not performed\", \"Mechanism linking p62/SQSTM1 association to NF-\\u03baB not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the trigger for PARP12 relocalization: nuclear PARP1-generated PAR binds the WWE domain to drive Golgi-to-stress-granule translocation, coupling nuclear stress to a reversible Golgi/traffic block.\",\n      \"evidence\": \"Live-cell imaging, PARP1 modulation, WWE PAR-binding assay, Golgi morphology and anterograde traffic assays with wash-out rescue\",\n      \"pmids\": [\"29070863\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Golgi substrates mediating traffic block not yet identified at this stage\", \"Structural basis of WWE-PAR recognition not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a direct antiviral catalytic mechanism: PARP12 ADP-ribosylates Zika NS1 and NS3 to trigger their proteasomal degradation and restrict viral replication.\",\n      \"evidence\": \"CRISPR ISG knockout screen, A549 KO, NS1/NS3 western blot, proteasome inhibitor rescue and ADP-ribosylation assay\",\n      \"pmids\": [\"29921658\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Modified residues on NS1/NS3 not mapped\", \"E3 ligase coupling MARylation to degradation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a catalysis-independent role: PARP12 binds and stabilizes FHL2 against ubiquitin-mediated degradation to restrain TGF-\\u03b21-driven EMT and tumor invasion.\",\n      \"evidence\": \"Affinity purification, reciprocal co-IP, ubiquitination assay, negative in vitro ADP-ribosylation of FHL2, siRNA and in vivo metastasis model\",\n      \"pmids\": [\"30154409\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which PARP12 shields FHL2 from ubiquitination unknown\", \"Single lab; reciprocal validation in independent systems lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PARP11 as a physical partner that potentiates PARP12-mediated ADP-ribosylation and degradation of Zika NS1/NS3, defining cooperative anti-viral PARP activity.\",\n      \"evidence\": \"Single and double KO HEK293T lines, co-IP, NS1/NS3 western blot, immunofluorescence\",\n      \"pmids\": [\"34187568\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether PARP11 modifies PARP12 or co-modifies substrates unresolved\", \"Structural basis of the interaction unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pinpointed Golgin-97 as the TGN substrate and PKD as the upstream activating kinase, mechanistically explaining how PARP12 controls basolateral cargo carrier formation.\",\n      \"evidence\": \"In vitro ADP-ribosylation with site-directed mutagenesis, PARP12 depletion, cargo transport and Rab11 colocalization assays, PKD kinase assay and inhibition\",\n      \"pmids\": [\"34969853\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Reader of ADP-ribosylated Golgin-97 driving fission not identified\", \"Generality across other cargoes beyond E-cadherin/VSVG not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported a mitochondrial localization and a role supporting UCP1 expression and respiration in thermogenic adipocytes.\",\n      \"evidence\": \"qRT-PCR, western blot, fractionation/immunofluorescence, siRNA and overexpression, Seahorse respiration assay\",\n      \"pmids\": [\"35916471\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No molecular mechanism connecting PARP12 to UCP1 or respiration identified\", \"Mitochondrial localization not functionally dissected\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended antiviral function to coronaviruses in vivo, showing PARP12 is a genetically required restriction factor whose ADP-ribosyltransferase activity is counteracted by the viral Mac1 macrodomain.\",\n      \"evidence\": \"PARP12-/- mice, BMDM siRNA screen, viral replication and liver pathology assays, lethality study\",\n      \"pmids\": [\"37695054\", \"37398292\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Coronavirus substrates of PARP12 not defined\", \"Cell types responsible for in vivo restriction not delineated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a meiotic role: PARP12 localizes near spindle poles and is required for spindle integrity, chromosome alignment, and asymmetric division in mouse oocytes.\",\n      \"evidence\": \"Immunofluorescence across meiotic stages, knockdown, spindle/chromosome/aneuploidy scoring, BubR1 and F-actin staining\",\n      \"pmids\": [\"37305966\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Spindle/actin substrates of PARP12 not identified\", \"Whether catalytic activity is required not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected PARP12 to PTM cross-talk and transcriptional control: it engages ISG15 to drive MFN1/2 ISGylation, limiting mitophagy, and is transcriptionally induced by IRF1.\",\n      \"evidence\": \"Mass spectrometry, co-IP, ISGylation/ubiquitination/SUMOylation assays, ChIP of IRF1 on PARP12 promoter, PINK1/Parkin analysis, rat OA model\",\n      \"pmids\": [\"39465252\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether PARP12 catalysis is required for ISG15 effect unclear\", \"Direct MFN1/2 modification by PARP12 not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined PARP12 as a regulator of cell-death fate, MARylating RIPK1/RIPK3 to promote necroptosis and suppress apoptosis downstream of IFN\\u03b3/TNF\\u03b1 with in vivo antiviral consequences.\",\n      \"evidence\": \"In vitro MARylation assay mapping RIPK1 domains, RIPK kinase assays, PARP12-/- cells and mice, necroptosis/apoptosis assays, influenza A model\",\n      \"pmids\": [\"40489618\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Modified RIPK1/RIPK3 residues not pinpointed\", \"Reader/eraser of these marks unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified AKT as a substrate, with PARP12 MARylation required for AKT activation and survival signaling in ER-positive breast cancer cells.\",\n      \"evidence\": \"ADP-ribosylation assay with AKT, siRNA, AKT activity and downstream p53/FOXO1 readouts, p53-AKT co-IP, apoptosis assay\",\n      \"pmids\": [\"39847113\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"AKT modification site not mapped\", \"Single lab; in vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ADP-ribosylation to RNA itself: PARP12 modifies chikungunya and cellular mRNAs (including insulin mRNA) to block translation, alter localization, accelerate decay, and trigger antiviral gene expression.\",\n      \"evidence\": \"RNA ribosylation assays, cell-free and infected-cell translation assays, viral RNA decay, antiviral gene expression, RNA localization in MIN6 cells (preprints)\",\n      \"pmids\": [\"bio_10.1101_2025.07.18.665567\", \"40470236\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Chemistry/site of RNA modification not fully defined\", \"Mechanism linking RNA mark to decay/localization unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PARP12's distinct localization-defined activities (TGN traffic, stress-granule translation arrest, mitochondrial/spindle roles, cell-death control) are integrated and selectively engaged remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying model for substrate selection across compartments\", \"Readers/erasers of PARP12-deposited marks largely unknown\", \"Relative contribution of catalytic vs scaffolding functions unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 10, 11]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 5, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 12, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 6, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP11\", \"FHL2\", \"ISG15\", \"RIPK1\", \"RIPK3\", \"AKT\", \"Golgin-97\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}