{"gene":"VPS72","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2005,"finding":"Swc2 (yeast ortholog of VPS72/YL1) binds directly to histone H2A.Z and is essential for its transfer during ATP-dependent nucleosomal histone exchange by the SWR1 complex. Swc6 and Arp6 are required for Swc2 association and nucleosome binding, while the C-terminal alpha-helix of H2A.Z is crucial for SWR1 recognition.","method":"Co-immunoprecipitation, in vitro binding assays, domain dissection, mutant analysis in yeast","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and functional assays in vitro and in vivo, replicated across multiple subunit mutants with defined phenotypic readouts","pmids":["16299513"],"is_preprint":false},{"year":2005,"finding":"Mammalian YL1 (VPS72) is a shared subunit of two distinct chromatin-modifying complexes: the TRRAP/TIP60 histone acetyltransferase (HAT) complex and the SRCAP chromatin-remodeling complex (a mammalian equivalent of the yeast SWR1 complex).","method":"Mass spectrometry of affinity-purified complexes, co-immunoprecipitation from HeLa cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spectrometry of purified complexes plus reciprocal co-IP, single lab but multiple orthogonal methods","pmids":["15647280"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the H2A.Z-binding domain of Drosophila YL1 (dYL1-Z) in complex with H2A.Z-H2B dimer at 1.9-Å resolution revealed a whip-like structure that wraps over H2A.Z-H2B. Preferential recognition of H2A.Z is conferred by three residues in loop 2, the hyperacidic patch, and the extended αC helix of H2A.Z. The YL1-Z domain is essential for H2A.Z deposition in vivo and SRCAP-catalyzed histone replacement in vitro.","method":"X-ray crystallography at 1.9-Å resolution, in vitro histone exchange assay, in vivo H2A.Z ChIP in yeast","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation in vitro and in vivo, orthogonal methods in a single rigorous study","pmids":["26974124"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the human YL1-H2A.Z-H2B complex at 2.7-Å resolution showed that YL1 acts as a specific H2A.Z-deposition chaperone. YL1 binding triggers extension of the H2A.Z αC helix (similar to the eviction chaperone ANP32E), but the interaction is more extensive and includes both the extended acidic patch and the entire DNA-binding surface of H2A.Z-H2B. Substitution of only four residues of H2A is sufficient to create an H2A.Z-like interface specifically recognized by YL1.","method":"X-ray crystallography at 2.7-Å resolution, mutagenesis, in vitro binding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis and functional validation, multiple orthogonal methods","pmids":["26974126"],"is_preprint":false},{"year":2020,"finding":"VPS72/YL1 is required for nuclear reassembly after mitosis. siRNA-mediated knockdown of VPS72 extends telophase in HeLa cells (live-cell imaging). In cell-free nuclear assembly assays, depletion of VPS72 or H2A.Z results in malformed and nonfunctional nuclei. Importantly, VPS72 functions outside of the SRCAP and EP400 remodeling complexes to deposit H2A.Z for nuclear reformation.","method":"siRNA knockdown, live-cell imaging, cell-free nuclear assembly assay, immunodepletion","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cellular knockdown with live imaging plus cell-free reconstitution assay with multiple orthogonal readouts in one study","pmids":["32708675"],"is_preprint":false},{"year":2021,"finding":"The N-terminal 1-135 residues of Swc2 (Swc2-Z) facilitate disassembly of nucleosomes containing H2A but not H2A.Z, enabling unidirectional exchange. This selectivity depends on inherent instability of the H2A nucleosome conferred by three H2A α2-helical residues (Gly47, Pro49, Ile63). The Swc2-ZN subdomain (residues 1-37) directly anchors to the H2A nucleosome and is required for SWR1-catalyzed H2A.Z replacement in vitro and H2A.Z deposition in vivo.","method":"Single-molecule force spectroscopy, mutagenesis, in vitro SWR1 histone exchange assay, in vivo ChIP in yeast","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule biophysics combined with mutagenesis and both in vitro and in vivo functional assays in one study","pmids":["34038732"],"is_preprint":false},{"year":2023,"finding":"VPS72 interacts with MYC and ACTL6A and promotes formation of the ACTL6A/MYC complex in HCC cells. ACTL6A regulates VPS72 protein stability by weakening the interaction between the E3 ubiquitin ligase TRIM21 and VPS72. The VPS72-ACTL6A interaction enhances MYC binding affinity to target gene promoters and promotes their transcription.","method":"Co-immunoprecipitation, shRNA knockdown, overexpression, in vivo xenograft, ChIP assays, AAV8-mediated shRNA delivery","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vitro and in vivo functional assays, single lab","pmids":["36631007"],"is_preprint":false},{"year":2022,"finding":"VPS72 physically binds KAT5 (TIP60/KAT5 acetyltransferase) in hepatocellular carcinoma cells. KAT5 overexpression rescues the suppression of proliferation, invasion, and migration caused by VPS72 knockdown, and VPS72 silencing downregulates p-PI3K and p-AKT expression in a KAT5-dependent manner.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, western blotting for PI3K/AKT phosphorylation","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus epistasis rescue experiment, single lab with multiple cellular readouts","pmids":["35383533"],"is_preprint":false},{"year":2020,"finding":"In Drosophila, YL-1 (VPS72 ortholog) is a component of a nuclear acetyltransferase complex and interacts with Atg8a (LC3 ortholog). Atg8a is acetylated in nutrient-rich conditions, and this acetylation is linked to YL-1 association, suggesting YL-1 participates in regulating autophagy gene expression through Atg8a acetylation status.","method":"Co-immunoprecipitation, mass spectrometry, genetic knockdown in Drosophila, autophagy assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and genetic depletion in Drosophila with functional readout, single lab","pmids":["32460019"],"is_preprint":false},{"year":1995,"finding":"Forced expression of YL-1 (VPS72) protein in Kirsten sarcoma virus-transformed NIH3T3 cells markedly suppressed anchorage-independent growth (colony formation in soft agar), identifying it as a transformation suppressor. Rare soft-agar colonies that escaped expressed reduced or no exogenous YL-1, sometimes with loss/rearrangement of the introduced cDNA. YL-1 did not affect adherent-culture transformed phenotypes or tumorigenicity in nude mice.","method":"Stable cDNA overexpression, soft agar colony formation assay, antisense control experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with rigorous controls including antisense, but single lab and single assay type","pmids":["7664828"],"is_preprint":false},{"year":2001,"finding":"YL-1 (VPS72) undergoes intergenic splicing into TMOD4 and also produces alternative transcripts via intraexonic splicing using non-canonical splice sites. YL-1 encodes six exons with the last exon 291 bp from a 5' UTR exon of TMOD4.","method":"5' RACE, RT-PCR, genomic sequence analysis","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcript-level characterization without functional protein mechanistic follow-up","pmids":["11716785"],"is_preprint":false}],"current_model":"VPS72/YL1 is a conserved histone H2A.Z-binding chaperone subunit of the SRCAP (SWR1) chromatin-remodeling complex and the TRRAP/TIP60 (EP400) HAT complex; its whip-like H2A.Z-binding domain (structurally defined at near-atomic resolution) directly contacts the extended αC helix and acidic patch of H2A.Z-H2B to facilitate ATP-dependent exchange of nucleosomal H2A for H2A.Z, a process also requiring its ability to recognize the inherent instability of H2A nucleosomes; beyond chromatin remodeling, VPS72 functions independently of SRCAP/EP400 to deposit H2A.Z during post-mitotic nuclear reassembly, interacts with MYC/ACTL6A to promote oncogenic transcription in HCC (regulated partly through TRIM21-mediated ubiquitination), and binds KAT5/TIP60 to modulate PI3K/AKT signaling."},"narrative":{"mechanistic_narrative":"VPS72 (YL1) is a conserved histone chaperone that confers H2A.Z specificity to ATP-dependent chromatin remodeling, functioning as a shared subunit of the SRCAP remodeling complex and the TRRAP/TIP60 histone acetyltransferase complex [PMID:15647280, PMID:26974124]. Through a whip-like H2A.Z-binding domain, VPS72 directly wraps over the H2A.Z-H2B dimer, recognizing the extended αC helix, the hyperacidic patch, and the DNA-binding surface that distinguish H2A.Z from canonical H2A; substitution of as few as four H2A residues is sufficient to create a VPS72-recognized interface [PMID:26974124, PMID:26974126]. The chaperone enforces unidirectional exchange by exploiting the inherent instability of H2A-containing nucleosomes, with an N-terminal subdomain anchoring the H2A nucleosome to license SWR1/SRCAP-catalyzed replacement of nucleosomal H2A with H2A.Z [PMID:34038732]. This activity was first defined in yeast, where the ortholog Swc2 binds H2A.Z directly and is essential for its transfer during nucleosomal histone exchange [PMID:16299513]. Beyond canonical remodeling, VPS72 acts independently of SRCAP and EP400 to deposit H2A.Z during post-mitotic nuclear reassembly, and its depletion produces malformed, nonfunctional nuclei [PMID:32708675]. In hepatocellular carcinoma, VPS72 interacts with MYC and ACTL6A to enhance MYC promoter binding and oncogenic transcription, with its stability governed by ACTL6A antagonism of TRIM21-mediated ubiquitination, and it binds KAT5/TIP60 to modulate PI3K/AKT signaling [PMID:36631007, PMID:35383533].","teleology":[{"year":2005,"claim":"Established that the VPS72 ortholog is a direct H2A.Z-binding factor essential for histone exchange, defining the molecular basis for variant-specific nucleosome remodeling.","evidence":"Co-immunoprecipitation, in vitro binding, and subunit-mutant analysis of Swc2 in yeast SWR1","pmids":["16299513"],"confidence":"High","gaps":["Structural basis of H2A.Z discrimination not yet resolved","Requirement for Swc6/Arp6 in association left mechanism of recruitment unclear"]},{"year":2005,"claim":"Defined VPS72 as a shared subunit bridging two distinct mammalian chromatin machines, placing it at the intersection of remodeling and acetylation.","evidence":"Mass spectrometry of affinity-purified complexes and reciprocal co-IP from HeLa cells","pmids":["15647280"],"confidence":"High","gaps":["Functional division of labor between the two complexes not addressed","No structural detail of how VPS72 docks into either complex"]},{"year":2016,"claim":"Resolved at near-atomic resolution how VPS72 achieves H2A.Z selectivity, showing a whip-like domain that reads out H2A.Z-specific surfaces and is essential for deposition.","evidence":"X-ray crystallography of Drosophila and human YL1-H2A.Z-H2B complexes with in vitro exchange and in vivo ChIP validation","pmids":["26974124","26974126"],"confidence":"High","gaps":["Structure of full-length VPS72 within the SRCAP holocomplex unresolved","Coupling of chaperone binding to ATP-dependent catalysis not visualized"]},{"year":2021,"claim":"Explained the directionality of exchange, showing VPS72 exploits intrinsic H2A nucleosome instability to drive unidirectional H2A-to-H2A.Z replacement.","evidence":"Single-molecule force spectroscopy, mutagenesis, and in vitro/in vivo SWR1 exchange assays in yeast","pmids":["34038732"],"confidence":"High","gaps":["Generality of the three H2A α2 residues across species not established","Kinetics of the anchoring-to-eviction transition unresolved"]},{"year":2020,"claim":"Revealed a chromatin-remodeling-independent role, demonstrating VPS72 deposits H2A.Z for proper nuclear reformation after mitosis outside the SRCAP/EP400 complexes.","evidence":"siRNA knockdown with live-cell imaging plus cell-free nuclear assembly assay with immunodepletion in HeLa","pmids":["32708675"],"confidence":"High","gaps":["Identity of the alternative complex (if any) delivering H2A.Z during reassembly unknown","Mechanism linking H2A.Z deposition to functional nuclear envelope formation not defined"]},{"year":2020,"claim":"Connected the ortholog to autophagy regulation via an acetyltransferase complex acting on the LC3 ortholog Atg8a.","evidence":"Co-IP, mass spectrometry, and genetic knockdown with autophagy assays in Drosophila","pmids":["32460019"],"confidence":"Medium","gaps":["Direct enzymatic role of VPS72 in Atg8a acetylation not established","Conservation of this autophagy link in mammals untested"]},{"year":2022,"claim":"Linked VPS72 to oncogenic signaling, showing it binds KAT5/TIP60 to sustain PI3K/AKT activation in hepatocellular carcinoma.","evidence":"Co-IP, siRNA knockdown, and KAT5 overexpression rescue with phospho-PI3K/AKT readouts in HCC cells","pmids":["35383533"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation of the VPS72-KAT5 interaction","Mechanism connecting KAT5 binding to PI3K/AKT phosphorylation undefined"]},{"year":2023,"claim":"Defined an oncogenic transcriptional axis in which VPS72 cooperates with MYC and ACTL6A, with stability controlled by TRIM21 ubiquitination.","evidence":"Reciprocal Co-IP, shRNA knockdown, ChIP, and in vivo xenograft assays in HCC","pmids":["36631007"],"confidence":"Medium","gaps":["Whether this axis depends on VPS72 chromatin-chaperone activity unclear","Direct TRIM21 ubiquitination sites on VPS72 not mapped"]},{"year":null,"claim":"How VPS72's biochemically defined H2A.Z chaperone activity mechanistically underlies its disparate cellular roles in nuclear reassembly, autophagy, and oncogenic transcription remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking H2A.Z deposition to MYC-driven transcription","Tissue-specific contributions of the SRCAP versus TIP60 complexes not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2,3,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6]}],"complexes":["SRCAP complex","TRRAP/TIP60 (EP400) HAT complex","SWR1 complex"],"partners":["H2A.Z","MYC","ACTL6A","TRIM21","KAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15906","full_name":"Vacuolar protein sorting-associated protein 72 homolog","aliases":["Protein YL-1","Transcription factor-like 1"],"length_aa":364,"mass_kda":40.6,"function":"Deposition-and-exchange histone chaperone specific for H2AZ1, specifically chaperones H2AZ1 and deposits it into nucleosomes. As component of the SRCAP complex, mediates the ATP-dependent exchange of histone H2AZ1/H2B dimers for nucleosomal H2A/H2B, leading to transcriptional regulation of selected genes by chromatin remodeling","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15906/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS72","classification":"Common Essential","n_dependent_lines":847,"n_total_lines":1208,"dependency_fraction":0.7011589403973509},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":10.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS72","total_profiled":1310},"omim":[{"mim_id":"618617","title":"ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 1; ZNHIT1","url":"https://www.omim.org/entry/618617"},{"mim_id":"600607","title":"VACUOLAR PROTEIN SORTING 72 HOMOLOG; VPS72","url":"https://www.omim.org/entry/600607"},{"mim_id":"142763","title":"H2A.Z VARIANT HISTONE 1; H2AZ1","url":"https://www.omim.org/entry/142763"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS72"},"hgnc":{"alias_symbol":["YL-1","YL1","Swc2"],"prev_symbol":["TCFL1"]},"alphafold":{"accession":"Q15906","domains":[{"cath_id":"-","chopping":"289-330","consensus_level":"medium","plddt":94.1995,"start":289,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15906","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15906-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15906-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS72","jax_strain_url":"https://www.jax.org/strain/search?query=VPS72"},"sequence":{"accession":"Q15906","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15906.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15906/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15906"}},"corpus_meta":[{"pmid":"16299513","id":"PMC_16299513","title":"Swc2 is a widely 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2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors.","date":"2011","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22154349","citation_count":12,"is_preprint":false},{"pmid":"36375354","id":"PMC_36375354","title":"Coumarin-4-yl-1,2,3-triazol-4-yl-methyl-thiazolidine-2,4-diones: Synthesis, glucose uptake activity and cytotoxic evaluation.","date":"2022","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36375354","citation_count":11,"is_preprint":false},{"pmid":"35584513","id":"PMC_35584513","title":"Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor.","date":"2022","source":"Journal of medicinal 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derivatives.","date":"2014","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/24674646","citation_count":11,"is_preprint":false},{"pmid":"10858326","id":"PMC_10858326","title":"Mutagenicity of the 1-nitropyrene-DNA adduct N-(deoxyguanosin-8-yl)-1-aminopyrene in Escherichia coli located in a nonrepetitive CGC sequence.","date":"2000","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/10858326","citation_count":11,"is_preprint":false},{"pmid":"33785838","id":"PMC_33785838","title":"Discovery of novel antituberculosis agents among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives targeting aminoacyl-tRNA synthetases.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33785838","citation_count":10,"is_preprint":false},{"pmid":"38129413","id":"PMC_38129413","title":"Discovery of 1-(5-bromopyrazin-2-yl)-1-[3-(trifluoromethyl)benzyl]urea as a promising anticancer drug via 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Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain.","date":"2017","source":"Anesthesia and analgesia","url":"https://pubmed.ncbi.nlm.nih.gov/28002166","citation_count":10,"is_preprint":false},{"pmid":"15561798","id":"PMC_15561798","title":"Induction of nitric oxide production by the cytostatic macrolide apicularen A [2,4-heptadienamide, N-[(1E)-3-[(3S,5R,7R,9S)-3,4,5,6,7,8,9,10-octahydro-7,14 dihydroxy-1-oxo-5,9-epoxy-1H-2-benzoxacyclododecin-3-yl]-1 propenyl]-, (2Z,4Z)-(9CI)] and possible role of nitric oxide in apicularen A-induced apoptosis in RAW 264.7 cells.","date":"2004","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/15561798","citation_count":10,"is_preprint":false},{"pmid":"34683333","id":"PMC_34683333","title":"Phenazine-1-carboxylic Acid Produced by Pseudomonas chlororaphis YL-1 Is Effective against Acidovorax 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approach and the receptor profile of the 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide and analogue derivatives.","date":"2016","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27240274","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56157,"output_tokens":3038,"usd":0.107021,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10342,"output_tokens":3007,"usd":0.063442,"stage2_stop_reason":"end_turn"},"total_usd":0.170463,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Swc2 (yeast ortholog of VPS72/YL1) binds directly to histone H2A.Z and is essential for its transfer during ATP-dependent nucleosomal histone exchange by the SWR1 complex. Swc6 and Arp6 are required for Swc2 association and nucleosome binding, while the C-terminal alpha-helix of H2A.Z is crucial for SWR1 recognition.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, domain dissection, mutant analysis in yeast\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and functional assays in vitro and in vivo, replicated across multiple subunit mutants with defined phenotypic readouts\",\n      \"pmids\": [\"16299513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mammalian YL1 (VPS72) is a shared subunit of two distinct chromatin-modifying complexes: the TRRAP/TIP60 histone acetyltransferase (HAT) complex and the SRCAP chromatin-remodeling complex (a mammalian equivalent of the yeast SWR1 complex).\",\n      \"method\": \"Mass spectrometry of affinity-purified complexes, co-immunoprecipitation from HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spectrometry of purified complexes plus reciprocal co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15647280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the H2A.Z-binding domain of Drosophila YL1 (dYL1-Z) in complex with H2A.Z-H2B dimer at 1.9-Å resolution revealed a whip-like structure that wraps over H2A.Z-H2B. Preferential recognition of H2A.Z is conferred by three residues in loop 2, the hyperacidic patch, and the extended αC helix of H2A.Z. The YL1-Z domain is essential for H2A.Z deposition in vivo and SRCAP-catalyzed histone replacement in vitro.\",\n      \"method\": \"X-ray crystallography at 1.9-Å resolution, in vitro histone exchange assay, in vivo H2A.Z ChIP in yeast\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation in vitro and in vivo, orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"26974124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the human YL1-H2A.Z-H2B complex at 2.7-Å resolution showed that YL1 acts as a specific H2A.Z-deposition chaperone. YL1 binding triggers extension of the H2A.Z αC helix (similar to the eviction chaperone ANP32E), but the interaction is more extensive and includes both the extended acidic patch and the entire DNA-binding surface of H2A.Z-H2B. Substitution of only four residues of H2A is sufficient to create an H2A.Z-like interface specifically recognized by YL1.\",\n      \"method\": \"X-ray crystallography at 2.7-Å resolution, mutagenesis, in vitro binding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis and functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"26974126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VPS72/YL1 is required for nuclear reassembly after mitosis. siRNA-mediated knockdown of VPS72 extends telophase in HeLa cells (live-cell imaging). In cell-free nuclear assembly assays, depletion of VPS72 or H2A.Z results in malformed and nonfunctional nuclei. Importantly, VPS72 functions outside of the SRCAP and EP400 remodeling complexes to deposit H2A.Z for nuclear reformation.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, cell-free nuclear assembly assay, immunodepletion\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cellular knockdown with live imaging plus cell-free reconstitution assay with multiple orthogonal readouts in one study\",\n      \"pmids\": [\"32708675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal 1-135 residues of Swc2 (Swc2-Z) facilitate disassembly of nucleosomes containing H2A but not H2A.Z, enabling unidirectional exchange. This selectivity depends on inherent instability of the H2A nucleosome conferred by three H2A α2-helical residues (Gly47, Pro49, Ile63). The Swc2-ZN subdomain (residues 1-37) directly anchors to the H2A nucleosome and is required for SWR1-catalyzed H2A.Z replacement in vitro and H2A.Z deposition in vivo.\",\n      \"method\": \"Single-molecule force spectroscopy, mutagenesis, in vitro SWR1 histone exchange assay, in vivo ChIP in yeast\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule biophysics combined with mutagenesis and both in vitro and in vivo functional assays in one study\",\n      \"pmids\": [\"34038732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VPS72 interacts with MYC and ACTL6A and promotes formation of the ACTL6A/MYC complex in HCC cells. ACTL6A regulates VPS72 protein stability by weakening the interaction between the E3 ubiquitin ligase TRIM21 and VPS72. The VPS72-ACTL6A interaction enhances MYC binding affinity to target gene promoters and promotes their transcription.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, overexpression, in vivo xenograft, ChIP assays, AAV8-mediated shRNA delivery\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"36631007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS72 physically binds KAT5 (TIP60/KAT5 acetyltransferase) in hepatocellular carcinoma cells. KAT5 overexpression rescues the suppression of proliferation, invasion, and migration caused by VPS72 knockdown, and VPS72 silencing downregulates p-PI3K and p-AKT expression in a KAT5-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression rescue, western blotting for PI3K/AKT phosphorylation\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus epistasis rescue experiment, single lab with multiple cellular readouts\",\n      \"pmids\": [\"35383533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila, YL-1 (VPS72 ortholog) is a component of a nuclear acetyltransferase complex and interacts with Atg8a (LC3 ortholog). Atg8a is acetylated in nutrient-rich conditions, and this acetylation is linked to YL-1 association, suggesting YL-1 participates in regulating autophagy gene expression through Atg8a acetylation status.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, genetic knockdown in Drosophila, autophagy assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and genetic depletion in Drosophila with functional readout, single lab\",\n      \"pmids\": [\"32460019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Forced expression of YL-1 (VPS72) protein in Kirsten sarcoma virus-transformed NIH3T3 cells markedly suppressed anchorage-independent growth (colony formation in soft agar), identifying it as a transformation suppressor. Rare soft-agar colonies that escaped expressed reduced or no exogenous YL-1, sometimes with loss/rearrangement of the introduced cDNA. YL-1 did not affect adherent-culture transformed phenotypes or tumorigenicity in nude mice.\",\n      \"method\": \"Stable cDNA overexpression, soft agar colony formation assay, antisense control experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with rigorous controls including antisense, but single lab and single assay type\",\n      \"pmids\": [\"7664828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"YL-1 (VPS72) undergoes intergenic splicing into TMOD4 and also produces alternative transcripts via intraexonic splicing using non-canonical splice sites. YL-1 encodes six exons with the last exon 291 bp from a 5' UTR exon of TMOD4.\",\n      \"method\": \"5' RACE, RT-PCR, genomic sequence analysis\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcript-level characterization without functional protein mechanistic follow-up\",\n      \"pmids\": [\"11716785\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS72/YL1 is a conserved histone H2A.Z-binding chaperone subunit of the SRCAP (SWR1) chromatin-remodeling complex and the TRRAP/TIP60 (EP400) HAT complex; its whip-like H2A.Z-binding domain (structurally defined at near-atomic resolution) directly contacts the extended αC helix and acidic patch of H2A.Z-H2B to facilitate ATP-dependent exchange of nucleosomal H2A for H2A.Z, a process also requiring its ability to recognize the inherent instability of H2A nucleosomes; beyond chromatin remodeling, VPS72 functions independently of SRCAP/EP400 to deposit H2A.Z during post-mitotic nuclear reassembly, interacts with MYC/ACTL6A to promote oncogenic transcription in HCC (regulated partly through TRIM21-mediated ubiquitination), and binds KAT5/TIP60 to modulate PI3K/AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS72 (YL1) is a conserved histone chaperone that confers H2A.Z specificity to ATP-dependent chromatin remodeling, functioning as a shared subunit of the SRCAP remodeling complex and the TRRAP/TIP60 histone acetyltransferase complex [#1, #2]. Through a whip-like H2A.Z-binding domain, VPS72 directly wraps over the H2A.Z-H2B dimer, recognizing the extended αC helix, the hyperacidic patch, and the DNA-binding surface that distinguish H2A.Z from canonical H2A; substitution of as few as four H2A residues is sufficient to create a VPS72-recognized interface [#2, #3]. The chaperone enforces unidirectional exchange by exploiting the inherent instability of H2A-containing nucleosomes, with an N-terminal subdomain anchoring the H2A nucleosome to license SWR1/SRCAP-catalyzed replacement of nucleosomal H2A with H2A.Z [#5]. This activity was first defined in yeast, where the ortholog Swc2 binds H2A.Z directly and is essential for its transfer during nucleosomal histone exchange [#0]. Beyond canonical remodeling, VPS72 acts independently of SRCAP and EP400 to deposit H2A.Z during post-mitotic nuclear reassembly, and its depletion produces malformed, nonfunctional nuclei [#4]. In hepatocellular carcinoma, VPS72 interacts with MYC and ACTL6A to enhance MYC promoter binding and oncogenic transcription, with its stability governed by ACTL6A antagonism of TRIM21-mediated ubiquitination, and it binds KAT5/TIP60 to modulate PI3K/AKT signaling [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that the VPS72 ortholog is a direct H2A.Z-binding factor essential for histone exchange, defining the molecular basis for variant-specific nucleosome remodeling.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro binding, and subunit-mutant analysis of Swc2 in yeast SWR1\",\n      \"pmids\": [\"16299513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of H2A.Z discrimination not yet resolved\", \"Requirement for Swc6/Arp6 in association left mechanism of recruitment unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined VPS72 as a shared subunit bridging two distinct mammalian chromatin machines, placing it at the intersection of remodeling and acetylation.\",\n      \"evidence\": \"Mass spectrometry of affinity-purified complexes and reciprocal co-IP from HeLa cells\",\n      \"pmids\": [\"15647280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional division of labor between the two complexes not addressed\", \"No structural detail of how VPS72 docks into either complex\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved at near-atomic resolution how VPS72 achieves H2A.Z selectivity, showing a whip-like domain that reads out H2A.Z-specific surfaces and is essential for deposition.\",\n      \"evidence\": \"X-ray crystallography of Drosophila and human YL1-H2A.Z-H2B complexes with in vitro exchange and in vivo ChIP validation\",\n      \"pmids\": [\"26974124\", \"26974126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length VPS72 within the SRCAP holocomplex unresolved\", \"Coupling of chaperone binding to ATP-dependent catalysis not visualized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Explained the directionality of exchange, showing VPS72 exploits intrinsic H2A nucleosome instability to drive unidirectional H2A-to-H2A.Z replacement.\",\n      \"evidence\": \"Single-molecule force spectroscopy, mutagenesis, and in vitro/in vivo SWR1 exchange assays in yeast\",\n      \"pmids\": [\"34038732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the three H2A α2 residues across species not established\", \"Kinetics of the anchoring-to-eviction transition unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a chromatin-remodeling-independent role, demonstrating VPS72 deposits H2A.Z for proper nuclear reformation after mitosis outside the SRCAP/EP400 complexes.\",\n      \"evidence\": \"siRNA knockdown with live-cell imaging plus cell-free nuclear assembly assay with immunodepletion in HeLa\",\n      \"pmids\": [\"32708675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the alternative complex (if any) delivering H2A.Z during reassembly unknown\", \"Mechanism linking H2A.Z deposition to functional nuclear envelope formation not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected the ortholog to autophagy regulation via an acetyltransferase complex acting on the LC3 ortholog Atg8a.\",\n      \"evidence\": \"Co-IP, mass spectrometry, and genetic knockdown with autophagy assays in Drosophila\",\n      \"pmids\": [\"32460019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic role of VPS72 in Atg8a acetylation not established\", \"Conservation of this autophagy link in mammals untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked VPS72 to oncogenic signaling, showing it binds KAT5/TIP60 to sustain PI3K/AKT activation in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, and KAT5 overexpression rescue with phospho-PI3K/AKT readouts in HCC cells\",\n      \"pmids\": [\"35383533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation of the VPS72-KAT5 interaction\", \"Mechanism connecting KAT5 binding to PI3K/AKT phosphorylation undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an oncogenic transcriptional axis in which VPS72 cooperates with MYC and ACTL6A, with stability controlled by TRIM21 ubiquitination.\",\n      \"evidence\": \"Reciprocal Co-IP, shRNA knockdown, ChIP, and in vivo xenograft assays in HCC\",\n      \"pmids\": [\"36631007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this axis depends on VPS72 chromatin-chaperone activity unclear\", \"Direct TRIM21 ubiquitination sites on VPS72 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS72's biochemically defined H2A.Z chaperone activity mechanistically underlies its disparate cellular roles in nuclear reassembly, autophagy, and oncogenic transcription remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking H2A.Z deposition to MYC-driven transcription\", \"Tissue-specific contributions of the SRCAP versus TIP60 complexes not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"SRCAP complex\", \"TRRAP/TIP60 (EP400) HAT complex\", \"SWR1 complex\"],\n    \"partners\": [\"H2A.Z\", \"MYC\", \"ACTL6A\", \"TRIM21\", \"KAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}