{"gene":"PADI6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2026,"finding":"PADI6 forms a conserved ternary complex (MPU: maternal PADI6-UHRF1-UBE2D) that regulates protein ubiquitination during oocyte maturation and early embryogenesis. Cryo-EM structure of MPU was determined. PADI6, assisted by UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to substrate proteins, thereby suppressing the ubiquitination cascade. 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly.","method":"Cryo-electron microscopy structure determination, Co-immunoprecipitation, biochemical reconstitution, mutational analysis of clinical variants","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure resolved, reconstituted complex, mechanistic biochemistry (ubiquitin transfer suppression), and clinical variant mapping all in a single rigorous study","pmids":["41772195"],"is_preprint":false},{"year":2008,"finding":"PADI6 is required for cytoplasmic lattice (CPL) formation in oocytes; in Padi6-/- oocytes, CPLs cannot be visualized. Ribosomal small subunit protein S6 sedimentation properties are dramatically altered in Padi6-/- oocytes, indicating that ribosomal components are stored in CPLs via PADI6. Padi6-/- two-cell embryos show reduced abundance and mislocalization of ribosomal components, dysregulated de novo protein synthesis, and defective embryonic genome activation (EGA).","method":"Padi6 knockout mouse model, sucrose gradient sedimentation, immunofluorescence, ribosome fractionation, metabolic labeling of protein synthesis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal biochemical readouts (sedimentation, protein synthesis, EGA), replicated across related studies","pmids":["18599511"],"is_preprint":false},{"year":2016,"finding":"PADI6 is required to anchor the mRNA-MSY2 complex to oocyte cytoplasmic lattices (CPLs). In Padi6 KO oocytes, rRNAs are dramatically decreased, mRNA abundance and localization are disrupted, and the association of the major RNA-binding protein MSY2 with the insoluble (CPL) fraction is markedly decreased. RNase A treatment impairs PADI6 and MSY2 localization in oocytes, suggesting mRNAs in complex with MSY2 and PADI6 are bound within CPLs.","method":"Padi6 knockout mouse model, Triton X-100 fractionation, RNase A treatment, immunofluorescence, western blotting","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple biochemical fractionation and localization methods in single lab","pmids":["27929740"],"is_preprint":false},{"year":2008,"finding":"PADI6 undergoes a dramatic increase in phosphorylation during oocyte maturation, and this phosphorylation-dependent modification leads to interaction of PADI6 with YWHA (14-3-3) proteins in the mature egg. GST-YWHA pulldown and tandem affinity purification/LC-MS confirmed the YWHA-PADI6 binding interaction.","method":"GST pulldown, transgenic tandem affinity purification with LC-MS, phosphorylation analysis during oocyte maturation","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and mass spectrometry confirmation, single lab, two orthogonal methods","pmids":["18463355"],"is_preprint":false},{"year":2024,"finding":"A Padi6 missense variant causes defective oocyte maturation including incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, and up-regulation of maternal decay genes. PADI6 controls cytoplasmic localization of epigenetic factors UHRF1 and DNMT1: UHRF1 levels are reduced in mutant oocytes and DNMT1/UHRF1 localization is abnormal in oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue developmental arrest, indicating cytoplasmic functions of PADI6 are separately required.","method":"Mouse knockin model, single-cell multiomic analysis (scRNA-seq + scBS-seq), western blotting, immunofluorescence, 5-azacytidine rescue experiment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knockin mouse model with single-cell multiomics, protein localization, and pharmacological rescue, multiple orthogonal methods in one rigorous study","pmids":["38453481"],"is_preprint":false},{"year":2026,"finding":"Maternal PADI6 depletion (Padi6P620A mutant oocytes) causes dramatic reduction of UHRF1 and DNMT1 protein levels, decreased H3K9me3, and whole-genome hypomethylation including imprinted loci and repetitive elements at the blastocyst stage. PADI6-deficient embryos show deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. These data establish PADI6 as a key regulator of epigenetic factor stability required for genomic imprinting maintenance in late preimplantation embryos.","method":"Combined single-blastocyst RNA-seq/BS-seq, immunostaining, Padi6 mutant mouse model","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with single-blastocyst multiomics and immunostaining validation, multiple orthogonal methods demonstrating imprinting and epigenetic factor mechanistic link","pmids":["41998711"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function PADI6 mutations in humans cause reduced phosphorylated RNA polymerase II and decreased expression of seven genes involved in zygotic genome activation in affected embryos, consistent with a role for PADI6 in zygotic genome activation.","method":"Immunostaining of affected patient oocytes and embryos, gene expression analysis in embryos from patients with PADI6 nonsense/frameshift mutations","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunostaining in human patient embryos with confirmed PADI6 mutations, single lab, limited sample size","pmids":["27545678"],"is_preprint":false},{"year":2021,"finding":"PADI6 co-localizes with and physically interacts with YAP1 in human trophoblast cells (cytotrophoblast). PADI6 positively regulates YAP1 expression. Overexpression of PADI6 promotes cell cycle progression, migration, invasion, proliferation, and apoptosis in trophoblast cells; knockdown has opposite effects. PADI6 regulates trophoblast cell behavior through the Hippo/YAP1 pathway.","method":"Co-immunoprecipitation, immunocytochemistry, siRNA knockdown, overexpression, wound healing, Transwell migration/invasion assays, EdU staining, flow cytometry, western blot","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP confirmed interaction, functional KD/OE with multiple cellular readouts, single lab","pmids":["34326657"],"is_preprint":false},{"year":2015,"finding":"Sp1 transcription factor binds directly to the -56/-47 region of the porcine PADI6 promoter and is required for basal PADI6 transcription. Overexpression of Sp1 increases PADI6 promoter activity and gene expression; siRNA-mediated Sp1 knockdown reduces both. Mithramycin A (Sp1 inhibitor) reduces PADI6 transcriptional activity in a dose-dependent manner.","method":"5'-RACE to map transcription start site, promoter deletion constructs, EMSA, Sp1 overexpression/siRNA knockdown, Mithramycin A treatment, luciferase reporter assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — EMSA and mutagenesis of promoter, functional rescue/knockdown, single lab, porcine model","pmids":["26403316"],"is_preprint":false},{"year":2025,"finding":"PADI6 null mutation inhibits embryonic genome activation and causes defective maternal mRNA degradation and disruption of protein storage on cytoplasmic lattices. Single-cell proteomics fractionation defined a CPL-enriched proteome that includes essential components of the endolysosomal vesicular assembly (ELVA), suggesting previously unknown functional interconnections between CPLs and ELVA. PADI6 performs a critical scaffolding function implicating CPLs as regulatory hubs for translation, respiration, and protein degradation in oocytes and early embryos.","method":"Single-cell transcriptomics, single-cell proteomics fractionation, Padi6 null and hypomorphic mouse models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal single-cell methods, two genetic mouse models, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2018,"finding":"PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos, establishing PADI6 as a member of the subcortical maternal complex (SCMC) alongside NLRP7 in humans.","method":"Immunofluorescence co-localization in human oocytes and preimplantation embryos","journal":"European journal of human genetics : EJHG","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunofluorescence co-localization, no biochemical interaction confirmation, single lab","pmids":["29693651"],"is_preprint":false},{"year":2023,"finding":"PADI6 has no reported catalytic (peptidylarginine deiminase) activity despite belonging to the PAD enzyme family; it is less conserved than other PADIs and its molecular mechanisms of function remain unknown according to the review of available literature.","method":"Review and synthesis of published literature","journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — review conclusion based on absence of reported activity across multiple studies; negative finding","pmids":["37778376"],"is_preprint":false}],"current_model":"PADI6 is a core scaffolding component of oocyte cytoplasmic lattices (CPLs) that forms a ternary MPU complex with UHRF1 and UBE2D (E2 ubiquitin-conjugating enzyme) to suppress ubiquitination cascades during oocyte maturation; it also sequesters ribosomal subunits and mRNA-MSY2 complexes in CPLs for translational control, controls cytoplasmic localization of epigenetic factors UHRF1 and DNMT1 to maintain genomic imprinting, supports zygotic genome activation, and interacts with YWHA (14-3-3) proteins in a phosphorylation-dependent manner—with loss of function causing early embryonic arrest at the two-cell stage."},"narrative":{"mechanistic_narrative":"PADI6 is a maternal-effect scaffolding protein essential for the formation and function of oocyte cytoplasmic lattices (CPLs), the storage hubs that organize translation, protein degradation, and epigenetic factor stability during oocyte maturation and early embryogenesis [PMID:18599511]. Despite belonging to the peptidylarginine deiminase family, PADI6 has no reported catalytic deiminase activity, and its function is structural rather than enzymatic [PMID:37778376]. PADI6 nucleates a conserved ternary complex (MPU) in which it, assisted by UHRF1, sequesters the E2 ubiquitin-conjugating enzyme UBE2D to block ubiquitin transfer to substrates and thereby suppress the ubiquitination cascade; most clinically identified PADI6 missense variants disrupt assembly of this complex [PMID:18599511]. Beyond ubiquitin control, PADI6 anchors ribosomal subunits and the mRNA-MSY2 complex within CPLs, and its loss alters ribosomal sedimentation, disrupts maternal mRNA storage and degradation, dysregulates de novo protein synthesis, and impairs embryonic/zygotic genome activation [PMID:18599511, PMID:27929740]. PADI6 also controls the cytoplasmic localization and stability of the epigenetic factors UHRF1 and DNMT1, so that its loss causes reduced DNMT1/UHRF1 levels, decreased H3K9me3, and genome-wide hypomethylation at imprinted loci, establishing PADI6 as a regulator of genomic imprinting maintenance through preimplantation development [PMID:38453481, PMID:41998711]. During oocyte maturation PADI6 is hyperphosphorylated and binds 14-3-3 (YWHA) proteins in a phosphorylation-dependent manner [PMID:18463355]. Loss-of-function mutations in PADI6 cause early embryonic arrest with failed genome activation [PMID:27545678].","teleology":[{"year":2008,"claim":"Established that PADI6 is structurally required to build cytoplasmic lattices and to store ribosomal machinery, linking its loss to failed protein synthesis and genome activation — defining its core scaffolding role.","evidence":"Padi6 knockout mouse, sucrose gradient sedimentation, ribosome fractionation and metabolic labeling of protein synthesis in oocytes/embryos","pmids":["18599511"],"confidence":"High","gaps":["Did not resolve the molecular basis of how PADI6 builds lattices","No structural mechanism for ribosome sequestration"]},{"year":2008,"claim":"Showed that PADI6 is post-translationally regulated during maturation, becoming a phosphorylation-dependent 14-3-3 binding partner, implying its activity is gated by the meiotic kinase environment.","evidence":"GST-YWHA pulldown and tandem affinity purification/LC-MS with phosphorylation analysis during oocyte maturation","pmids":["18463355"],"confidence":"Medium","gaps":["Functional consequence of YWHA binding unresolved","Phosphorylation sites and responsible kinase not identified"]},{"year":2016,"claim":"Extended the scaffolding role to RNA storage, showing PADI6 anchors the mRNA-MSY2 ribonucleoprotein complex into the insoluble CPL fraction, providing a mechanism for maternal mRNA sequestration.","evidence":"Padi6 KO mouse, Triton X-100 fractionation, RNase A treatment, immunofluorescence and western blotting","pmids":["27929740"],"confidence":"Medium","gaps":["Direct vs. indirect PADI6-MSY2 association not distinguished","Single-lab biochemical fractionation"]},{"year":2016,"claim":"Translated the mouse model into human disease, demonstrating that human PADI6 loss-of-function reduces phosphorylated RNA Pol II and impairs zygotic genome activation gene expression in patient embryos.","evidence":"Immunostaining and gene expression analysis in oocytes/embryos from patients carrying PADI6 nonsense/frameshift mutations","pmids":["27545678"],"confidence":"Medium","gaps":["Limited patient sample size","Mechanistic link between PADI6 and Pol II phosphorylation undefined"]},{"year":2024,"claim":"Revealed a distinct epigenetic arm: PADI6 controls cytoplasmic localization and levels of UHRF1 and DNMT1, with developmental arrest separable from DNA methylation defects, indicating multiple independent cytoplasmic functions.","evidence":"Knockin mouse, single-cell multiomics (scRNA-seq + scBS-seq), immunofluorescence and 5-azacytidine rescue","pmids":["38453481"],"confidence":"High","gaps":["How PADI6 governs UHRF1/DNMT1 stability mechanistically unresolved","Identity of the cytoplasmic function required for development beyond methylation unknown"]},{"year":2025,"claim":"Single-cell proteomics defined a CPL-enriched proteome connecting lattices to endolysosomal vesicular assembly, positioning CPLs as hubs integrating translation, respiration, and protein degradation.","evidence":"Single-cell transcriptomics and proteomics fractionation with Padi6 null and hypomorphic mouse models (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Functional significance of CPL-ELVA interconnection not experimentally tested"]},{"year":2026,"claim":"Provided the defining mechanistic and structural model: a cryo-EM-resolved PADI6-UHRF1-UBE2D ternary complex (MPU) in which PADI6 sequesters the E2 to suppress ubiquitin transfer, with most clinical variants disrupting complex assembly.","evidence":"Cryo-EM structure determination, co-immunoprecipitation, biochemical reconstitution and mapping of clinical missense variants","pmids":["41772195"],"confidence":"High","gaps":["Specific substrates protected from ubiquitination not enumerated","How MPU function integrates with ribosome/mRNA storage roles unclear"]},{"year":2026,"claim":"Showed the epigenetic consequence persists through late preimplantation: PADI6 depletion destabilizes UHRF1/DNMT1, lowers H3K9me3, and causes genome-wide and imprinted-locus hypomethylation with implantation failure.","evidence":"Single-blastocyst RNA-seq/BS-seq, immunostaining and Padi6 mutant mouse model","pmids":["41998711"],"confidence":"High","gaps":["Mechanism by which a cytoplasmic scaffold stabilizes nuclear epigenetic factors not resolved","Trophoblast sparing vs. ICM sensitivity unexplained"]},{"year":null,"claim":"How PADI6's distinct activities — ubiquitin-cascade suppression via MPU, ribosomal/mRNA sequestration, and UHRF1/DNMT1 stabilization — are mechanistically unified within a single CPL scaffold, and whether they share or diverge in molecular determinants, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single study integrates the ubiquitin, translation, and epigenetic functions","Catalytic activity absent yet structural determinants of each function only partially mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2,4,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,4,6]}],"complexes":["MPU (PADI6-UHRF1-UBE2D)","cytoplasmic lattices (CPLs)","subcortical maternal complex (SCMC)"],"partners":["UHRF1","UBE2D","MSY2","YWHA","DNMT1","NLRP7","YAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6TGC4","full_name":"Inactive protein-arginine deiminase type-6","aliases":["Peptidyl arginine deiminase-like protein","Peptidylarginine deiminase VI","hPADVI","Protein-arginine deiminase type VI","Protein-arginine deiminase type-6"],"length_aa":694,"mass_kda":77.7,"function":"Structural constituent of cytoplasmic lattices, which plays a key role in early embryonic development (PubMed:37922900). Cytoplasmic lattices consist in fibrous structures found in the cytoplasm of oocytes and preimplantation embryos (PubMed:37922900). They are required to store maternal proteins critical for embryonic development, such as ribosomal proteins and proteins that control epigenetic reprogramming of the preimplantation embryo, and prevent their degradation or activation (PubMed:37922900). In contrast to other members of the family, does not show protein-arginine deiminase activity due to its inability to bind Ca(2+) (PubMed:38656308, PubMed:39286527)","subcellular_location":"Cytoplasm; Cytoplasmic vesicle, secretory vesicle, Cortical granule; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6TGC4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PADI6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PADI6","total_profiled":1310},"omim":[{"mim_id":"617234","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 16; OZEMA16","url":"https://www.omim.org/entry/617234"},{"mim_id":"615774","title":"OOCYTE/ZYGOTE/EMBRYO MATURATION ARREST 1; OZEMA1","url":"https://www.omim.org/entry/615774"},{"mim_id":"610363","title":"PEPTIDYLARGININE DEIMINASE, TYPE VI; PADI6","url":"https://www.omim.org/entry/610363"},{"mim_id":"609661","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 7; NLRP7","url":"https://www.omim.org/entry/609661"},{"mim_id":"605462","title":"BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 1; BCC1","url":"https://www.omim.org/entry/605462"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"ovary","ntpm":5.5}],"url":"https://www.proteinatlas.org/search/PADI6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6TGC4","domains":[{"cath_id":"3.75.10.10","chopping":"307-692","consensus_level":"medium","plddt":86.8076,"start":307,"end":692},{"cath_id":"2.60.40.1860","chopping":"15-123","consensus_level":"high","plddt":86.9013,"start":15,"end":123},{"cath_id":"2.60.40.1700","chopping":"130-303","consensus_level":"high","plddt":85.2143,"start":130,"end":303}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6TGC4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6TGC4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6TGC4-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PADI6","jax_strain_url":"https://www.jax.org/strain/search?query=PADI6"},"sequence":{"accession":"Q6TGC4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6TGC4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6TGC4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6TGC4"}},"corpus_meta":[{"pmid":"27545678","id":"PMC_27545678","title":"Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27545678","citation_count":180,"is_preprint":false},{"pmid":"18599511","id":"PMC_18599511","title":"Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18599511","citation_count":165,"is_preprint":false},{"pmid":"15087120","id":"PMC_15087120","title":"Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15087120","citation_count":157,"is_preprint":false},{"pmid":"29693651","id":"PMC_29693651","title":"Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles.","date":"2018","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/29693651","citation_count":79,"is_preprint":false},{"pmid":"32928291","id":"PMC_32928291","title":"Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance.","date":"2020","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/32928291","citation_count":50,"is_preprint":false},{"pmid":"31664658","id":"PMC_31664658","title":"New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage.","date":"2019","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31664658","citation_count":39,"is_preprint":false},{"pmid":"33221824","id":"PMC_33221824","title":"Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family.","date":"2020","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/33221824","citation_count":35,"is_preprint":false},{"pmid":"27929740","id":"PMC_27929740","title":"Role for PADI6 in securing the mRNA-MSY2 complex to the oocyte cytoplasmic lattices.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27929740","citation_count":30,"is_preprint":false},{"pmid":"34036456","id":"PMC_34036456","title":"Two novel mutations in PADI6 and TLE6 genes cause female infertility due to arrest in embryonic development.","date":"2021","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34036456","citation_count":29,"is_preprint":false},{"pmid":"38453481","id":"PMC_38453481","title":"A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos.","date":"2024","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/38453481","citation_count":24,"is_preprint":false},{"pmid":"35433708","id":"PMC_35433708","title":"Novel Homozygous PADI6 Variants in Infertile Females with Early Embryonic Arrest.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35433708","citation_count":19,"is_preprint":false},{"pmid":"37778376","id":"PMC_37778376","title":"PADI6: What we know about the elusive fifth member of the peptidyl arginine deiminase family.","date":"2023","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37778376","citation_count":18,"is_preprint":false},{"pmid":"18463355","id":"PMC_18463355","title":"Phosphorylation-dependent interaction of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHA) with PADI6 following oocyte maturation in mice.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18463355","citation_count":16,"is_preprint":false},{"pmid":"36088419","id":"PMC_36088419","title":"A novel homozygous mutation in the PADI6 gene causes early embryo arrest.","date":"2022","source":"Reproductive health","url":"https://pubmed.ncbi.nlm.nih.gov/36088419","citation_count":14,"is_preprint":false},{"pmid":"34573423","id":"PMC_34573423","title":"Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized 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PADI6.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26403316","citation_count":4,"is_preprint":false},{"pmid":"41772195","id":"PMC_41772195","title":"The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis.","date":"2026","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41772195","citation_count":2,"is_preprint":false},{"pmid":"40830544","id":"PMC_40830544","title":"A novel PADI6 splice-site variant induces non-canonical GC-AG splicing and embryonic arrest in humans.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40830544","citation_count":2,"is_preprint":false},{"pmid":"38562607","id":"PMC_38562607","title":"Padi6 expression patterns in buffalo oocytes and preimplantation embryos.","date":"2024","source":"Animal reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/38562607","citation_count":0,"is_preprint":false},{"pmid":"41998711","id":"PMC_41998711","title":"Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos.","date":"2026","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/41998711","citation_count":0,"is_preprint":false},{"pmid":"41451497","id":"PMC_41451497","title":"[Pathogenicity analysis of a novel PADI6 gene variant associated with female infertility].","date":"2025","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41451497","citation_count":0,"is_preprint":false},{"pmid":"41884623","id":"PMC_41884623","title":"Case Report: Biallelic PADI6 frameshift variants contribute to preimplantation embryonic lethality.","date":"2026","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41884623","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.21.639491","title":"Dissecting PADI6 function defines oocyte cytoplasmic lattices as regulatory hubs for fundamental cellular processes","date":"2025-02-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.639491","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.03.25337209","title":"Mapping Chemical-Gene Interactions for Developmental Lethality and Pregnancy Loss","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.25337209","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15700,"output_tokens":3313,"usd":0.048398,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10797,"output_tokens":3274,"usd":0.067918,"stage2_stop_reason":"end_turn"},"total_usd":0.116316,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2026,\n      \"finding\": \"PADI6 forms a conserved ternary complex (MPU: maternal PADI6-UHRF1-UBE2D) that regulates protein ubiquitination during oocyte maturation and early embryogenesis. Cryo-EM structure of MPU was determined. PADI6, assisted by UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to substrate proteins, thereby suppressing the ubiquitination cascade. 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly.\",\n      \"method\": \"Cryo-electron microscopy structure determination, Co-immunoprecipitation, biochemical reconstitution, mutational analysis of clinical variants\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure resolved, reconstituted complex, mechanistic biochemistry (ubiquitin transfer suppression), and clinical variant mapping all in a single rigorous study\",\n      \"pmids\": [\"41772195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PADI6 is required for cytoplasmic lattice (CPL) formation in oocytes; in Padi6-/- oocytes, CPLs cannot be visualized. Ribosomal small subunit protein S6 sedimentation properties are dramatically altered in Padi6-/- oocytes, indicating that ribosomal components are stored in CPLs via PADI6. Padi6-/- two-cell embryos show reduced abundance and mislocalization of ribosomal components, dysregulated de novo protein synthesis, and defective embryonic genome activation (EGA).\",\n      \"method\": \"Padi6 knockout mouse model, sucrose gradient sedimentation, immunofluorescence, ribosome fractionation, metabolic labeling of protein synthesis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal biochemical readouts (sedimentation, protein synthesis, EGA), replicated across related studies\",\n      \"pmids\": [\"18599511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PADI6 is required to anchor the mRNA-MSY2 complex to oocyte cytoplasmic lattices (CPLs). In Padi6 KO oocytes, rRNAs are dramatically decreased, mRNA abundance and localization are disrupted, and the association of the major RNA-binding protein MSY2 with the insoluble (CPL) fraction is markedly decreased. RNase A treatment impairs PADI6 and MSY2 localization in oocytes, suggesting mRNAs in complex with MSY2 and PADI6 are bound within CPLs.\",\n      \"method\": \"Padi6 knockout mouse model, Triton X-100 fractionation, RNase A treatment, immunofluorescence, western blotting\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple biochemical fractionation and localization methods in single lab\",\n      \"pmids\": [\"27929740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PADI6 undergoes a dramatic increase in phosphorylation during oocyte maturation, and this phosphorylation-dependent modification leads to interaction of PADI6 with YWHA (14-3-3) proteins in the mature egg. GST-YWHA pulldown and tandem affinity purification/LC-MS confirmed the YWHA-PADI6 binding interaction.\",\n      \"method\": \"GST pulldown, transgenic tandem affinity purification with LC-MS, phosphorylation analysis during oocyte maturation\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and mass spectrometry confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"18463355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A Padi6 missense variant causes defective oocyte maturation including incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, and up-regulation of maternal decay genes. PADI6 controls cytoplasmic localization of epigenetic factors UHRF1 and DNMT1: UHRF1 levels are reduced in mutant oocytes and DNMT1/UHRF1 localization is abnormal in oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue developmental arrest, indicating cytoplasmic functions of PADI6 are separately required.\",\n      \"method\": \"Mouse knockin model, single-cell multiomic analysis (scRNA-seq + scBS-seq), western blotting, immunofluorescence, 5-azacytidine rescue experiment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knockin mouse model with single-cell multiomics, protein localization, and pharmacological rescue, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"38453481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Maternal PADI6 depletion (Padi6P620A mutant oocytes) causes dramatic reduction of UHRF1 and DNMT1 protein levels, decreased H3K9me3, and whole-genome hypomethylation including imprinted loci and repetitive elements at the blastocyst stage. PADI6-deficient embryos show deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. These data establish PADI6 as a key regulator of epigenetic factor stability required for genomic imprinting maintenance in late preimplantation embryos.\",\n      \"method\": \"Combined single-blastocyst RNA-seq/BS-seq, immunostaining, Padi6 mutant mouse model\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with single-blastocyst multiomics and immunostaining validation, multiple orthogonal methods demonstrating imprinting and epigenetic factor mechanistic link\",\n      \"pmids\": [\"41998711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function PADI6 mutations in humans cause reduced phosphorylated RNA polymerase II and decreased expression of seven genes involved in zygotic genome activation in affected embryos, consistent with a role for PADI6 in zygotic genome activation.\",\n      \"method\": \"Immunostaining of affected patient oocytes and embryos, gene expression analysis in embryos from patients with PADI6 nonsense/frameshift mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunostaining in human patient embryos with confirmed PADI6 mutations, single lab, limited sample size\",\n      \"pmids\": [\"27545678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PADI6 co-localizes with and physically interacts with YAP1 in human trophoblast cells (cytotrophoblast). PADI6 positively regulates YAP1 expression. Overexpression of PADI6 promotes cell cycle progression, migration, invasion, proliferation, and apoptosis in trophoblast cells; knockdown has opposite effects. PADI6 regulates trophoblast cell behavior through the Hippo/YAP1 pathway.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, siRNA knockdown, overexpression, wound healing, Transwell migration/invasion assays, EdU staining, flow cytometry, western blot\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP confirmed interaction, functional KD/OE with multiple cellular readouts, single lab\",\n      \"pmids\": [\"34326657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sp1 transcription factor binds directly to the -56/-47 region of the porcine PADI6 promoter and is required for basal PADI6 transcription. Overexpression of Sp1 increases PADI6 promoter activity and gene expression; siRNA-mediated Sp1 knockdown reduces both. Mithramycin A (Sp1 inhibitor) reduces PADI6 transcriptional activity in a dose-dependent manner.\",\n      \"method\": \"5'-RACE to map transcription start site, promoter deletion constructs, EMSA, Sp1 overexpression/siRNA knockdown, Mithramycin A treatment, luciferase reporter assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — EMSA and mutagenesis of promoter, functional rescue/knockdown, single lab, porcine model\",\n      \"pmids\": [\"26403316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PADI6 null mutation inhibits embryonic genome activation and causes defective maternal mRNA degradation and disruption of protein storage on cytoplasmic lattices. Single-cell proteomics fractionation defined a CPL-enriched proteome that includes essential components of the endolysosomal vesicular assembly (ELVA), suggesting previously unknown functional interconnections between CPLs and ELVA. PADI6 performs a critical scaffolding function implicating CPLs as regulatory hubs for translation, respiration, and protein degradation in oocytes and early embryos.\",\n      \"method\": \"Single-cell transcriptomics, single-cell proteomics fractionation, Padi6 null and hypomorphic mouse models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal single-cell methods, two genetic mouse models, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos, establishing PADI6 as a member of the subcortical maternal complex (SCMC) alongside NLRP7 in humans.\",\n      \"method\": \"Immunofluorescence co-localization in human oocytes and preimplantation embryos\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunofluorescence co-localization, no biochemical interaction confirmation, single lab\",\n      \"pmids\": [\"29693651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PADI6 has no reported catalytic (peptidylarginine deiminase) activity despite belonging to the PAD enzyme family; it is less conserved than other PADIs and its molecular mechanisms of function remain unknown according to the review of available literature.\",\n      \"method\": \"Review and synthesis of published literature\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — review conclusion based on absence of reported activity across multiple studies; negative finding\",\n      \"pmids\": [\"37778376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PADI6 is a core scaffolding component of oocyte cytoplasmic lattices (CPLs) that forms a ternary MPU complex with UHRF1 and UBE2D (E2 ubiquitin-conjugating enzyme) to suppress ubiquitination cascades during oocyte maturation; it also sequesters ribosomal subunits and mRNA-MSY2 complexes in CPLs for translational control, controls cytoplasmic localization of epigenetic factors UHRF1 and DNMT1 to maintain genomic imprinting, supports zygotic genome activation, and interacts with YWHA (14-3-3) proteins in a phosphorylation-dependent manner—with loss of function causing early embryonic arrest at the two-cell stage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PADI6 is a maternal-effect scaffolding protein essential for the formation and function of oocyte cytoplasmic lattices (CPLs), the storage hubs that organize translation, protein degradation, and epigenetic factor stability during oocyte maturation and early embryogenesis [#1, #9]. Despite belonging to the peptidylarginine deiminase family, PADI6 has no reported catalytic deiminase activity, and its function is structural rather than enzymatic [#11]. PADI6 nucleates a conserved ternary complex (MPU) in which it, assisted by UHRF1, sequesters the E2 ubiquitin-conjugating enzyme UBE2D to block ubiquitin transfer to substrates and thereby suppress the ubiquitination cascade; most clinically identified PADI6 missense variants disrupt assembly of this complex [#1]. Beyond ubiquitin control, PADI6 anchors ribosomal subunits and the mRNA-MSY2 complex within CPLs, and its loss alters ribosomal sedimentation, disrupts maternal mRNA storage and degradation, dysregulates de novo protein synthesis, and impairs embryonic/zygotic genome activation [#1, #2]. PADI6 also controls the cytoplasmic localization and stability of the epigenetic factors UHRF1 and DNMT1, so that its loss causes reduced DNMT1/UHRF1 levels, decreased H3K9me3, and genome-wide hypomethylation at imprinted loci, establishing PADI6 as a regulator of genomic imprinting maintenance through preimplantation development [#4, #5]. During oocyte maturation PADI6 is hyperphosphorylated and binds 14-3-3 (YWHA) proteins in a phosphorylation-dependent manner [#3]. Loss-of-function mutations in PADI6 cause early embryonic arrest with failed genome activation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PADI6 is structurally required to build cytoplasmic lattices and to store ribosomal machinery, linking its loss to failed protein synthesis and genome activation — defining its core scaffolding role.\",\n      \"evidence\": \"Padi6 knockout mouse, sucrose gradient sedimentation, ribosome fractionation and metabolic labeling of protein synthesis in oocytes/embryos\",\n      \"pmids\": [\"18599511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular basis of how PADI6 builds lattices\", \"No structural mechanism for ribosome sequestration\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that PADI6 is post-translationally regulated during maturation, becoming a phosphorylation-dependent 14-3-3 binding partner, implying its activity is gated by the meiotic kinase environment.\",\n      \"evidence\": \"GST-YWHA pulldown and tandem affinity purification/LC-MS with phosphorylation analysis during oocyte maturation\",\n      \"pmids\": [\"18463355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of YWHA binding unresolved\", \"Phosphorylation sites and responsible kinase not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the scaffolding role to RNA storage, showing PADI6 anchors the mRNA-MSY2 ribonucleoprotein complex into the insoluble CPL fraction, providing a mechanism for maternal mRNA sequestration.\",\n      \"evidence\": \"Padi6 KO mouse, Triton X-100 fractionation, RNase A treatment, immunofluorescence and western blotting\",\n      \"pmids\": [\"27929740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect PADI6-MSY2 association not distinguished\", \"Single-lab biochemical fractionation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Translated the mouse model into human disease, demonstrating that human PADI6 loss-of-function reduces phosphorylated RNA Pol II and impairs zygotic genome activation gene expression in patient embryos.\",\n      \"evidence\": \"Immunostaining and gene expression analysis in oocytes/embryos from patients carrying PADI6 nonsense/frameshift mutations\",\n      \"pmids\": [\"27545678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited patient sample size\", \"Mechanistic link between PADI6 and Pol II phosphorylation undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a distinct epigenetic arm: PADI6 controls cytoplasmic localization and levels of UHRF1 and DNMT1, with developmental arrest separable from DNA methylation defects, indicating multiple independent cytoplasmic functions.\",\n      \"evidence\": \"Knockin mouse, single-cell multiomics (scRNA-seq + scBS-seq), immunofluorescence and 5-azacytidine rescue\",\n      \"pmids\": [\"38453481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PADI6 governs UHRF1/DNMT1 stability mechanistically unresolved\", \"Identity of the cytoplasmic function required for development beyond methylation unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Single-cell proteomics defined a CPL-enriched proteome connecting lattices to endolysosomal vesicular assembly, positioning CPLs as hubs integrating translation, respiration, and protein degradation.\",\n      \"evidence\": \"Single-cell transcriptomics and proteomics fractionation with Padi6 null and hypomorphic mouse models (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Functional significance of CPL-ELVA interconnection not experimentally tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the defining mechanistic and structural model: a cryo-EM-resolved PADI6-UHRF1-UBE2D ternary complex (MPU) in which PADI6 sequesters the E2 to suppress ubiquitin transfer, with most clinical variants disrupting complex assembly.\",\n      \"evidence\": \"Cryo-EM structure determination, co-immunoprecipitation, biochemical reconstitution and mapping of clinical missense variants\",\n      \"pmids\": [\"41772195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific substrates protected from ubiquitination not enumerated\", \"How MPU function integrates with ribosome/mRNA storage roles unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed the epigenetic consequence persists through late preimplantation: PADI6 depletion destabilizes UHRF1/DNMT1, lowers H3K9me3, and causes genome-wide and imprinted-locus hypomethylation with implantation failure.\",\n      \"evidence\": \"Single-blastocyst RNA-seq/BS-seq, immunostaining and Padi6 mutant mouse model\",\n      \"pmids\": [\"41998711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a cytoplasmic scaffold stabilizes nuclear epigenetic factors not resolved\", \"Trophoblast sparing vs. ICM sensitivity unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PADI6's distinct activities — ubiquitin-cascade suppression via MPU, ribosomal/mRNA sequestration, and UHRF1/DNMT1 stabilization — are mechanistically unified within a single CPL scaffold, and whether they share or diverge in molecular determinants, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single study integrates the ubiquitin, translation, and epigenetic functions\", \"Catalytic activity absent yet structural determinants of each function only partially mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"complexes\": [\n      \"MPU (PADI6-UHRF1-UBE2D)\",\n      \"cytoplasmic lattices (CPLs)\",\n      \"subcortical maternal complex (SCMC)\"\n    ],\n    \"partners\": [\n      \"UHRF1\",\n      \"UBE2D\",\n      \"MSY2\",\n      \"YWHA\",\n      \"DNMT1\",\n      \"NLRP7\",\n      \"YAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}