{"gene":"PWWP2B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2021,"finding":"PWWP2B is a component of the NuRD (nucleosome remodeling and deacetylation) complex and interacts with and stabilizes HDAC1/2 at thermogenic gene promoters to suppress their expression; ablation of Pwwp2b promotes adipocyte thermogenesis in vivo.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, genetic knockout mouse model with thermogenic phenotype readout","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction data and ChIP at gene promoters in a single lab, with in vivo KO phenotype providing functional validation","pmids":["34180153"],"is_preprint":false},{"year":2022,"finding":"PWWP2B localizes to sites of DNA double-strand breaks through its interaction with UHRF1, interacts with MRE11, promotes DNA end-resection, and facilitates homologous recombination; depletion of PWWP2B impairs RAD51 foci formation and increases cellular sensitivity to ionizing radiation.","method":"Co-immunoprecipitation (interaction with UHRF1 and MRE11), immunofluorescence foci assays (RAD51, DSB markers), siRNA/shRNA depletion with IR sensitivity assays, HR reporter assay","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, foci formation, functional HR assay) in a single lab","pmids":["35582821"],"is_preprint":false}],"current_model":"PWWP2B is a nuclear chromatin-associated protein that (1) assembles into the NuRD complex where it stabilizes HDAC1/2 at thermogenic gene promoters to suppress thermogenesis, and (2) is recruited to DNA double-strand break sites via UHRF1 interaction, where it interacts with MRE11 to promote DNA end-resection and homologous recombination repair."},"narrative":{"mechanistic_narrative":"PWWP2B is a nuclear chromatin-associated protein with two characterized roles in gene regulation and genome maintenance [PMID:34180153, PMID:35582821]. As a component of the NuRD nucleosome remodeling and deacetylation complex, it interacts with and stabilizes HDAC1/2 at thermogenic gene promoters to repress their expression, and its genetic ablation promotes adipocyte thermogenesis in vivo [PMID:34180153]. Independently, PWWP2B is recruited to DNA double-strand break sites through interaction with UHRF1, where it associates with MRE11 to promote DNA end-resection and homologous recombination; its depletion impairs RAD51 foci formation and sensitizes cells to ionizing radiation [PMID:35582821]. Beyond these two activities, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Established PWWP2B as a transcriptional repressor by placing it within the NuRD complex and linking it to a physiological output, answering whether this chromatin protein has a defined regulatory function.","evidence":"Co-IP and ChIP at thermogenic promoters with a Pwwp2b knockout mouse showing enhanced adipocyte thermogenesis","pmids":["34180153"],"confidence":"Medium","gaps":["Single-lab interaction and ChIP data without orthogonal confirmation","How PWWP2B targets HDAC1/2 specifically to thermogenic loci versus other NuRD targets is undefined","Whether PWWP2B chromatin engagement is reader-domain mediated is not addressed"]},{"year":2022,"claim":"Defined a second, distinct role for PWWP2B in DNA repair, showing it is recruited to break sites and functions in homologous recombination, which connects this chromatin factor to genome stability.","evidence":"Co-IP (UHRF1, MRE11), IR-induced foci imaging, HR reporter assay, and IR-sensitivity assays after siRNA/shRNA depletion","pmids":["35582821"],"confidence":"Medium","gaps":["Single-lab dataset without independent replication","Whether the NuRD/repressive role and the DSB-repair role are mechanistically connected is unknown","How UHRF1 recruits PWWP2B and whether PWWP2B acts directly on MRE11 activity is not resolved"]},{"year":null,"claim":"Whether PWWP2B's transcriptional repression and DNA repair activities reflect one molecular function or two separable contexts, and what its PWWP domain reads on chromatin, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of chromatin or partner engagement","No unifying mechanism linking thermogenic repression and HR repair"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0]}],"complexes":["NuRD"],"partners":["HDAC1","HDAC2","UHRF1","MRE11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NUJ5","full_name":"PWWP domain-containing protein 2B","aliases":[],"length_aa":590,"mass_kda":64.0,"function":"Chromatin-binding protein that acts as an adapter between distinct nucleosome components (H3K36me3 or H2A.Z) and chromatin-modifying complexes, contributing to the regulation of the levels of histone acetylation at actively transcribed genes (PubMed:30228260). Competes with CHD4 and MBD3 for interaction with MTA1 to form a NuRD subcomplex, preventing the formation of full NuRD complex (containing CHD4 and MBD3), leading to recruitment of HDACs to gene promoters resulting in turn in the deacetylation of nearby H3K27 and H2A.Z (PubMed:30228260). Plays a role in facilitating transcriptional elongation through regulation of histone acetylation (By similarity). Negatively regulates brown adipocyte thermogenesis by interacting with and stabilizing HDAC1 at the UCP1 gene promoter, thereby promoting histone deacetylation at the promoter leading to the repression of UCP1 expression (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6NUJ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PWWP2B","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/PWWP2B","total_profiled":1310},"omim":[{"mim_id":"621586","title":"PWWP DOMAIN-CONTAINING PROTEIN 2B; PWWP2B","url":"https://www.omim.org/entry/621586"},{"mim_id":"617823","title":"PWWP DOMAIN-CONTAINING PROTEIN 2A; PWWP2A","url":"https://www.omim.org/entry/617823"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PWWP2B"},"hgnc":{"alias_symbol":["bA432J24.1","FLJ46823"],"prev_symbol":["PWWP2"]},"alphafold":{"accession":"Q6NUJ5","domains":[{"cath_id":"-","chopping":"10-38","consensus_level":"medium","plddt":87.991,"start":10,"end":38},{"cath_id":"2.30.30.140","chopping":"474-589","consensus_level":"high","plddt":90.3897,"start":474,"end":589}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUJ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUJ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NUJ5-F1-predicted_aligned_error_v6.png","plddt_mean":60.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PWWP2B","jax_strain_url":"https://www.jax.org/strain/search?query=PWWP2B"},"sequence":{"accession":"Q6NUJ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NUJ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NUJ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NUJ5"}},"corpus_meta":[{"pmid":"34271259","id":"PMC_34271259","title":"Histone and DNA binding ability studies of the NSD subfamily of PWWP domains.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34271259","citation_count":19,"is_preprint":false},{"pmid":"34180153","id":"PMC_34180153","title":"PWWP2B Fine-Tunes Adipose Thermogenesis by Stabilizing HDACs in a NuRD Subcomplex.","date":"2021","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/34180153","citation_count":15,"is_preprint":false},{"pmid":"35582821","id":"PMC_35582821","title":"PWWP2B promotes DNA end resection and homologous recombination.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35582821","citation_count":4,"is_preprint":false},{"pmid":"38516186","id":"PMC_38516186","title":"Structural insights into the C-terminus of the histone-lysine N-methyltransferase NSD3 by small-angle X-ray scattering.","date":"2024","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/38516186","citation_count":2,"is_preprint":false},{"pmid":"40118455","id":"PMC_40118455","title":"The sotos syndrome gene Nsd1 safeguards developmental gene enhancers poised for transcription by maintaining the precise deposition of histone methylation.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40118455","citation_count":2,"is_preprint":false},{"pmid":"40913772","id":"PMC_40913772","title":"Paraspeckle protein NONO regulates active chromatin by allosterically stimulating NSD1.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40913772","citation_count":1,"is_preprint":false},{"pmid":"39809369","id":"PMC_39809369","title":"PWWP2A/B: Prominent players in the proteomic landscape.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39809369","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5393,"output_tokens":596,"usd":0.012559,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6939,"output_tokens":1347,"usd":0.034185,"stage2_stop_reason":"end_turn"},"total_usd":0.046744,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"PWWP2B is a component of the NuRD (nucleosome remodeling and deacetylation) complex and interacts with and stabilizes HDAC1/2 at thermogenic gene promoters to suppress their expression; ablation of Pwwp2b promotes adipocyte thermogenesis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, genetic knockout mouse model with thermogenic phenotype readout\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction data and ChIP at gene promoters in a single lab, with in vivo KO phenotype providing functional validation\",\n      \"pmids\": [\"34180153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PWWP2B localizes to sites of DNA double-strand breaks through its interaction with UHRF1, interacts with MRE11, promotes DNA end-resection, and facilitates homologous recombination; depletion of PWWP2B impairs RAD51 foci formation and increases cellular sensitivity to ionizing radiation.\",\n      \"method\": \"Co-immunoprecipitation (interaction with UHRF1 and MRE11), immunofluorescence foci assays (RAD51, DSB markers), siRNA/shRNA depletion with IR sensitivity assays, HR reporter assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, foci formation, functional HR assay) in a single lab\",\n      \"pmids\": [\"35582821\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PWWP2B is a nuclear chromatin-associated protein that (1) assembles into the NuRD complex where it stabilizes HDAC1/2 at thermogenic gene promoters to suppress thermogenesis, and (2) is recruited to DNA double-strand break sites via UHRF1 interaction, where it interacts with MRE11 to promote DNA end-resection and homologous recombination repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PWWP2B is a nuclear chromatin-associated protein with two characterized roles in gene regulation and genome maintenance [#0, #1]. As a component of the NuRD nucleosome remodeling and deacetylation complex, it interacts with and stabilizes HDAC1/2 at thermogenic gene promoters to repress their expression, and its genetic ablation promotes adipocyte thermogenesis in vivo [#0]. Independently, PWWP2B is recruited to DNA double-strand break sites through interaction with UHRF1, where it associates with MRE11 to promote DNA end-resection and homologous recombination; its depletion impairs RAD51 foci formation and sensitizes cells to ionizing radiation [#1]. Beyond these two activities, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PWWP2B as a transcriptional repressor by placing it within the NuRD complex and linking it to a physiological output, answering whether this chromatin protein has a defined regulatory function.\",\n      \"evidence\": \"Co-IP and ChIP at thermogenic promoters with a Pwwp2b knockout mouse showing enhanced adipocyte thermogenesis\",\n      \"pmids\": [\"34180153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab interaction and ChIP data without orthogonal confirmation\",\n        \"How PWWP2B targets HDAC1/2 specifically to thermogenic loci versus other NuRD targets is undefined\",\n        \"Whether PWWP2B chromatin engagement is reader-domain mediated is not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a second, distinct role for PWWP2B in DNA repair, showing it is recruited to break sites and functions in homologous recombination, which connects this chromatin factor to genome stability.\",\n      \"evidence\": \"Co-IP (UHRF1, MRE11), IR-induced foci imaging, HR reporter assay, and IR-sensitivity assays after siRNA/shRNA depletion\",\n      \"pmids\": [\"35582821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab dataset without independent replication\",\n        \"Whether the NuRD/repressive role and the DSB-repair role are mechanistically connected is unknown\",\n        \"How UHRF1 recruits PWWP2B and whether PWWP2B acts directly on MRE11 activity is not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PWWP2B's transcriptional repression and DNA repair activities reflect one molecular function or two separable contexts, and what its PWWP domain reads on chromatin, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of chromatin or partner engagement\",\n        \"No unifying mechanism linking thermogenic repression and HR repair\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"NuRD\"],\n    \"partners\": [\"HDAC1\", \"HDAC2\", \"UHRF1\", \"MRE11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}