{"gene":"DNAJC9","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2021,"finding":"DNAJC9 functions as a histone chaperone that binds histone H3-H4 substrates and recruits HSP70-type enzymes via its J domain to fold histone H3-H4. Its structure in a co-chaperone complex with MCM2 was elucidated, revealing how this dual histone and heat shock co-chaperone binds histone substrates. DNAJC9 operates upstream in the histone supply chain, during replication- and transcription-coupled nucleosome assembly, and resolves spurious histone interactions.","method":"Structure-guided and functional proteomics, cryo-EM/structural determination of DNAJC9–H3-H4–MCM2 complex, Co-IP, mass spectrometry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination combined with functional proteomics and multiple orthogonal methods (Co-IP, MS, mutagenesis-guided analysis) in a single rigorous study","pmids":["33857403"],"is_preprint":false},{"year":2021,"finding":"DNAJC9 is identified as an essential heat shock co-chaperone that links ATP-dependent molecular chaperones (HSP70) to the histone supply and deposition pathways, functioning as a bona fide histone chaperone.","method":"Commentary/review of Hammond et al. 2021 experimental findings","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — corroborates primary discovery paper (PMID 33857403); this paper itself is a commentary, not original data","pmids":["34143966"],"is_preprint":false},{"year":2024,"finding":"DNAJC9 depletion causes mislocalization of CENP-A throughout the genome and chromosomal instability (CIN). Global interactome analysis showed DNAJC9 depletion promotes interaction of CENP-A with MCM2, and CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, identifying MCM2 as a driver of ectopic CENP-A deposition when H3-H4 supply chains are disrupted. Histone H3.3 depletion phenocopies DNAJC9 loss.","method":"Genome-wide RNAi screen, global interactome analysis, epistasis (double depletion of DNAJC9 and MCM2), live-cell imaging for CIN phenotypes","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen plus interactome plus genetic epistasis with multiple orthogonal methods establishing pathway position","pmids":["38600242"],"is_preprint":false},{"year":2025,"finding":"In fission yeast, Djc9 (DNAJC9 ortholog) binds helix α3 of histone H3 in a manner that precludes simultaneous binding by Asf1, and competes with Asf1 for H3-H4 dimer binding in vitro. Loss of Djc9 renders Asf1 non-essential for growth. In the absence of Asf1, unrestrained Djc9-mediated downregulation of H3 and H4 hinders cell growth. In the presence of Asf1, Djc9 promotes degradation of superfluous or dysfunctional histones and confers resistance to hydroxyurea and dominant-negative histone mutants.","method":"AlphaFold-based structural prediction validated by in vitro competition binding assays, genetic epistasis (double mutants), H3-α3 point mutations, growth assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of competition, structural prediction with mutagenesis validation, genetic epistasis across multiple conditions","pmids":["39878217"],"is_preprint":false},{"year":2025,"finding":"DNAJC9 binds to HBV covalently closed circular DNA (cccDNA) in a histone-independent and sequence-independent manner, interacts with histone H3.3 (shown by Co-IP and cccDNA ChIP), and promotes cccDNA transcription by increasing H3.3, H3K4me3, and H3K27ac density on cccDNA, thereby activating HBV promoters and enhancers. HBV replication promotes nuclear relocalization of DNAJC9.","method":"DNA pull-down, cccDNA ChIP, Co-IP, dual luciferase reporter assay, immunofluorescence, siRNA knockdown and overexpression in HBV infection/replication cell models","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pull-down, ChIP, Co-IP, reporter assay, imaging) in a single lab study","pmids":["40407066"],"is_preprint":false},{"year":2026,"finding":"DNAJC9 promotes cervical cancer cell proliferation by facilitating p300–H3 interaction to sustain H3K27ac at the GLI1 enhancer, thereby driving GLI1 transcription. GLI1 rescue reverses proliferation defects caused by DNAJC9 downregulation. DNAJC9 knockdown induces G1/S arrest and suppresses tumorigenicity.","method":"siRNA knockdown, GLI1 rescue experiments, chromatin immunoprecipitation (H3K27ac at GLI1 enhancer), co-immunoprecipitation (p300–H3 interaction), cell proliferation and tumor assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP with rescue experiment, single lab, multiple orthogonal methods","pmids":["42185231"],"is_preprint":false},{"year":2026,"finding":"DNAJC9 and MCM2 are identified as central players in chromatin repair following UV-induced DNA damage. DNAJC9 provides new H3-H4 histones to CAF-1 and HIRA chaperones for deposition into chromatin and stimulates recovery of old H3-H4 histones. MCM2 cooperates with DNAJC9 to coordinate old and new histone dynamics during UV damage repair.","method":"Novel quantitative, time-resolved proteomic strategy characterizing dynamic changes in chromatin landscape during UV damage repair in human cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative unbiased proteomics with temporal resolution, single lab, mechanistic pathway placement","pmids":["41605964"],"is_preprint":false},{"year":2001,"finding":"JDD1 (rat ortholog of DNAJC9) encodes a ~30 kDa protein with a J domain characteristic of the DnaJ family but lacking the G/F region and zinc finger (cysteine-rich) region. Its mRNA is expressed in the germinal (ventricular and subventricular) zones of the rat brain during embryonic development and persists after birth, as well as in liver, lung, kidney cortex, and other embryonic tissues.","method":"cDNA cloning, immunoblot analysis, in situ hybridization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct protein characterization (immunoblot) and localization (in situ hybridization), single lab, single study","pmids":["11444854"],"is_preprint":false},{"year":2025,"finding":"DNAJC9 directly interacts with ALV-J integrase p32 (validated by Co-IP and laser confocal microscopy) and enhances ALV-J replication, indicating a proviral role as a host cofactor for retroviral integration.","method":"Co-immunoprecipitation combined with mass spectrometry, Western blot, laser confocal microscopy, functional replication assays","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP validation, avian virus system (non-mammalian virus context), single lab","pmids":["41386616"],"is_preprint":false}],"current_model":"DNAJC9 is a dual-function heat shock co-chaperone and histone chaperone that binds histone H3-H4 via the α3 helix of H3 (competing with Asf1), recruits HSP70 through its J domain to fold histone substrates, and integrates ATP-dependent protein folding into the histone supply pathway to support replication- and transcription-coupled nucleosome assembly, resolve aberrant histone intermediates, restrict CENP-A mislocalization by maintaining H3-H4 supply chain fidelity (with MCM2 acting downstream to drive ectopic CENP-A deposition when DNAJC9 is lost), facilitate UV damage chromatin repair by supplying new H3-H4 to CAF-1/HIRA and recovering old histones, and in the nucleus promote active gene transcription by modulating histone H3.3 and H3K27ac deposition at gene regulatory elements."},"narrative":{"mechanistic_narrative":"DNAJC9 is a dual-function heat shock co-chaperone and histone chaperone that integrates ATP-dependent protein folding into the histone H3-H4 supply chain to support nucleosome assembly [PMID:33857403]. It binds H3-H4 substrates and recruits HSP70-type chaperones through its J domain to fold histones, operating upstream in the histone supply chain during replication- and transcription-coupled nucleosome assembly and resolving spurious histone interactions, with a structurally defined co-chaperone complex involving MCM2 [PMID:33857403]. DNAJC9 engages histone H3 via helix α3, a binding mode that precludes simultaneous Asf1 binding, so that the two compete for H3-H4 dimers; in this configuration DNAJC9 also drives degradation of superfluous or dysfunctional histones and confers resistance to replication stress and toxic histone mutants [PMID:39878217]. Maintaining H3-H4 supply-chain fidelity restricts CENP-A mislocalization: loss of DNAJC9 promotes ectopic genome-wide CENP-A deposition and chromosomal instability through MCM2, which acts as the downstream driver of this aberrant deposition [PMID:38600242]. In genome maintenance, DNAJC9 supplies new H3-H4 to the CAF-1 and HIRA deposition pathways and stimulates recovery of old histones during chromatin repair after UV damage, cooperating with MCM2 to coordinate old and new histone dynamics [PMID:41605964]. Through its control over histone deposition, DNAJC9 also promotes active transcription by modulating H3.3 and H3K27ac at regulatory elements, including sustaining p300–H3 contact to drive GLI1 enhancer activity in cervical cancer cells [PMID:42185231] and activating HBV cccDNA transcription [PMID:40407066].","teleology":[{"year":2001,"claim":"Before any functional role was known, the gene was defined as a DnaJ-family member by its molecular architecture, establishing it as a J-domain co-chaperone lacking the G/F and zinc-finger regions.","evidence":"cDNA cloning, immunoblot, and in situ hybridization of the rat ortholog JDD1 in embryonic brain and other tissues","pmids":["11444854"],"confidence":"Medium","gaps":["No substrate or biochemical activity identified","Function inferred only from domain composition, not assayed","Localization is at mRNA level in rat, not protein-level subcellular assignment"]},{"year":2021,"claim":"The central question of what DNAJC9 chaperones was answered by showing it is a histone chaperone that recruits HSP70 via its J domain to fold H3-H4, defining it as the link between ATP-dependent chaperones and the histone supply chain.","evidence":"Cryo-EM/structural determination of the DNAJC9–H3-H4–MCM2 complex with Co-IP, mass spectrometry, and functional proteomics, corroborated by an accompanying commentary","pmids":["33857403","34143966"],"confidence":"High","gaps":["Did not establish how DNAJC9 hands off histones to downstream deposition machinery","Physiological consequences of disrupting the J-domain/HSP70 interaction not tested in vivo","Relationship to Asf1 and other handoff chaperones not resolved"]},{"year":2024,"claim":"The genome-stability consequence of DNAJC9 loss was placed mechanistically by showing that disrupting the H3-H4 supply chain causes MCM2-dependent ectopic CENP-A deposition and chromosomal instability.","evidence":"Genome-wide RNAi screen, global interactome analysis, genetic epistasis (DNAJC9/MCM2 double depletion), and live-cell imaging in human cells","pmids":["38600242"],"confidence":"High","gaps":["Mechanism by which MCM2 redirects CENP-A to ectopic sites not fully defined","Whether CENP-A mislocalization is direct or secondary to general supply-chain failure unclear","Does not distinguish replication- versus transcription-coupled contributions"]},{"year":2025,"claim":"The structural and functional relationship to Asf1 was resolved by showing DNAJC9 binds H3 helix α3 in a manner mutually exclusive with Asf1 and promotes degradation of excess or dysfunctional histones.","evidence":"AlphaFold-based structural prediction validated by in vitro competition binding, H3-α3 point mutations, and genetic epistasis under replication stress in fission yeast","pmids":["39878217"],"confidence":"High","gaps":["The degradation machinery DNAJC9 routes histones to is not identified","Conservation of the Asf1 competition in human cells not directly tested here","How the balance between folding and degradation is regulated is unknown"]},{"year":2025,"claim":"DNAJC9 was extended beyond cellular chromatin into viral chromatin, showing it binds HBV cccDNA independently of histone or sequence and activates its transcription by raising H3.3, H3K4me3, and H3K27ac density.","evidence":"DNA pull-down, cccDNA ChIP, Co-IP, dual luciferase reporter, and immunofluorescence in HBV infection/replication cell models","pmids":["40407066"],"confidence":"Medium","gaps":["Mechanism of histone-independent cccDNA binding not structurally defined","Whether this reflects a normal cellular function co-opted by HBV is unclear","Single-lab study without independent replication"]},{"year":2026,"claim":"DNAJC9's role in chromatin repair was defined by showing it supplies new H3-H4 to CAF-1/HIRA and aids recovery of old histones during UV damage repair, cooperating with MCM2.","evidence":"Quantitative time-resolved proteomic profiling of chromatin dynamics during UV damage repair in human cells","pmids":["41605964"],"confidence":"Medium","gaps":["Direct physical contacts with CAF-1 and HIRA not biochemically dissected here","Distinction between new-histone supply and old-histone recovery roles not mechanistically separated","Single-lab proteomic study"]},{"year":2026,"claim":"A transcriptional/oncogenic output was established by showing DNAJC9 sustains H3K27ac at the GLI1 enhancer via p300–H3 contact to drive proliferation, demonstrating chromatin-supply control feeds into gene regulation.","evidence":"siRNA knockdown, GLI1 rescue, H3K27ac ChIP, p300–H3 Co-IP, and proliferation/tumor assays in cervical cancer cells","pmids":["42185231"],"confidence":"Medium","gaps":["Whether the GLI1 effect is direct or downstream of global H3.3/H3K27ac changes unclear","Generalizability beyond cervical cancer not tested","Mechanism by which DNAJC9 facilitates p300–H3 interaction not defined"]},{"year":null,"claim":"How DNAJC9 mechanistically partitions H3-H4 between folding, deposition (CAF-1/HIRA), degradation, and competition with Asf1, and how this is regulated across replication, transcription, and damage contexts, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how histone fate is selected","Regulatory inputs controlling DNAJC9 activity unknown","Human counterpart of yeast Asf1 competition not directly demonstrated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,3]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":[],"partners":["MCM2","HSPA8","ASF1","H3.3","CAF-1","HIRA","EP300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXX5","full_name":"DnaJ homolog subfamily C member 9","aliases":["DnaJ protein SB73"],"length_aa":260,"mass_kda":29.9,"function":"Acts as a dual histone chaperone and heat shock co-chaperone (PubMed:33857403). As a histone chaperone, forms a co-chaperone complex with MCM2 and histone H3-H4 heterodimers; and may thereby assist MCM2 in histone H3-H4 heterodimer recognition and facilitate the assembly of histones into nucleosomes (PubMed:33857403). May also act as a histone co-chaperone together with TONSL (PubMed:33857403). May recruit histone chaperones ASF1A, NASP and SPT2 to histone H3-H4 heterodimers (PubMed:33857403). Also plays a role as co-chaperone of the HSP70 family of molecular chaperone proteins, such as HSPA1A, HSPA1B and HSPA8 (PubMed:17182002, PubMed:33857403). As a co-chaperone, may play a role in the recruitment of HSP70-type molecular chaperone machinery to histone H3-H4 substrates, thereby maintaining the histone structural integrity (PubMed:33857403). Exhibits activity to assemble histones onto DNA in vitro (PubMed:33857403)","subcellular_location":"Nucleus; Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8WXX5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAJC9","classification":"Common Essential","n_dependent_lines":1093,"n_total_lines":1208,"dependency_fraction":0.9048013245033113},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000213551","cell_line_id":"CID000038","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"HSPH1","stoichiometry":0.2},{"gene":"IPO4","stoichiometry":0.2},{"gene":"NUP214","stoichiometry":0.2},{"gene":"HSPA4","stoichiometry":0.2},{"gene":"HSPA8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000038","total_profiled":1310},"omim":[{"mim_id":"611206","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 9; DNAJC9","url":"https://www.omim.org/entry/611206"},{"mim_id":"607721","title":"NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1; NSLH1","url":"https://www.omim.org/entry/607721"},{"mim_id":"602775","title":"SHOC2 LEUCINE-RICH REPEAT SCAFFOLD PROTEIN; SHOC2","url":"https://www.omim.org/entry/602775"},{"mim_id":"122400","title":"EPITHELIAL RECURRENT EROSION DYSTROPHY; ERED","url":"https://www.omim.org/entry/122400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":86.6}],"url":"https://www.proteinatlas.org/search/DNAJC9"},"hgnc":{"alias_symbol":["JDD1","SB73"],"prev_symbol":[]},"alphafold":{"accession":"Q8WXX5","domains":[{"cath_id":"1.10.287.110","chopping":"2-103","consensus_level":"high","plddt":87.6007,"start":2,"end":103},{"cath_id":"-","chopping":"110-181","consensus_level":"high","plddt":94.3443,"start":110,"end":181}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXX5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXX5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXX5-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAJC9","jax_strain_url":"https://www.jax.org/strain/search?query=DNAJC9"},"sequence":{"accession":"Q8WXX5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXX5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXX5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXX5"}},"corpus_meta":[{"pmid":"33225964","id":"PMC_33225964","title":"Characterization of the dual functional effects of heat shock proteins (HSPs) in cancer hallmarks to aid development of HSP inhibitors.","date":"2020","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33225964","citation_count":57,"is_preprint":false},{"pmid":"33857403","id":"PMC_33857403","title":"DNAJC9 integrates heat shock molecular chaperones into the histone chaperone network.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33857403","citation_count":49,"is_preprint":false},{"pmid":"26786512","id":"PMC_26786512","title":"A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions.","date":"2016","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/26786512","citation_count":31,"is_preprint":false},{"pmid":"21531385","id":"PMC_21531385","title":"ANXA7, PPP3CB, DNAJC9, and ZMYND17 genes at chromosome 10q22 associated with the subgroup of schizophrenia with deficits in attention and executive function.","date":"2011","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/21531385","citation_count":25,"is_preprint":false},{"pmid":"38600242","id":"PMC_38600242","title":"DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/38600242","citation_count":17,"is_preprint":false},{"pmid":"30809433","id":"PMC_30809433","title":"Long non-coding RNAs as pan-cancer master gene regulators of associated protein-coding genes: a systems biology approach.","date":"2019","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/30809433","citation_count":12,"is_preprint":false},{"pmid":"35906682","id":"PMC_35906682","title":"Proteotranscriptomics of ocular adnexal B-cell lymphoma reveals an oncogenic role of alternative splicing and identifies a diagnostic marker.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35906682","citation_count":10,"is_preprint":false},{"pmid":"27581768","id":"PMC_27581768","title":"Identification of p53-target genes in Danio rerio.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27581768","citation_count":9,"is_preprint":false},{"pmid":"30746964","id":"PMC_30746964","title":"Upregulation of DNA Metabolism-Related Genes Contributes to Radioresistance of Glioblastoma.","date":"2019","source":"Human gene therapy. Clinical development","url":"https://pubmed.ncbi.nlm.nih.gov/30746964","citation_count":8,"is_preprint":false},{"pmid":"11444854","id":"PMC_11444854","title":"JDD1, a novel member of the DnaJ family, is expressed in the germinal zone of the rat brain.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11444854","citation_count":4,"is_preprint":false},{"pmid":"2136564","id":"PMC_2136564","title":"Comparison of the antiviral activity and toxicity of a protein magnesium ammonium phospholinoleate anhydride polymer with other antiviral drugs.","date":"1990","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/2136564","citation_count":4,"is_preprint":false},{"pmid":"37422538","id":"PMC_37422538","title":"DNAJC9 expression in basal-like and luminal A breast cancer subtypes predicts worse survival.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37422538","citation_count":2,"is_preprint":false},{"pmid":"37158535","id":"PMC_37158535","title":"The Role of Endoplasmic Reticulum Stress in Gastroesophageal Reflux Disease Symptoms and Treatment.","date":"2023","source":"The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/37158535","citation_count":2,"is_preprint":false},{"pmid":"40407066","id":"PMC_40407066","title":"DNAJC9 Binds to and Enhances the Transcription of Hepatitis B Virus cccDNA by Recruiting Histone H3.3.","date":"2025","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/40407066","citation_count":1,"is_preprint":false},{"pmid":"39878217","id":"PMC_39878217","title":"The ortholog of human DNAJC9 promotes histone H3-H4 degradation and is counteracted by Asf1 in fission yeast.","date":"2025","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/39878217","citation_count":1,"is_preprint":false},{"pmid":"42185231","id":"PMC_42185231","title":"DNAJC9 promotes cervical cancer cell proliferation by regulating GLI1 expression.","date":"2026","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/42185231","citation_count":0,"is_preprint":false},{"pmid":"41778435","id":"PMC_41778435","title":"Potential Therapeutic Targets for Neuroblastoma Screened through Mendelian Randomization Analysis.","date":"2025","source":"Archives of Iranian medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41778435","citation_count":0,"is_preprint":false},{"pmid":"41605964","id":"PMC_41605964","title":"Proteomic profiling of UV damage repair patches uncovers histone chaperones with central functions in chromatin repair.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41605964","citation_count":0,"is_preprint":false},{"pmid":"41915616","id":"PMC_41915616","title":"Gut Microbiome, Immune Cells, and Heart Failure: A Multi-Omics Mendelian Randomization Study.","date":"2026","source":"Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/41915616","citation_count":0,"is_preprint":false},{"pmid":"38698217","id":"PMC_38698217","title":"Tipping the balance in histone supply puts genome stability at stake.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/38698217","citation_count":0,"is_preprint":false},{"pmid":"34143966","id":"PMC_34143966","title":"An energetic meet-and-greet: Molecular chaperones in the histone supply and deposition pathways.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/34143966","citation_count":0,"is_preprint":false},{"pmid":"41386616","id":"PMC_41386616","title":"Unveiling the host arsenal: Interactome profiling of ALV-J p32 integrase reveals novel antiviral targets.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41386616","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13226,"output_tokens":2568,"usd":0.039099,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9683,"output_tokens":3390,"usd":0.066583,"stage2_stop_reason":"end_turn"},"total_usd":0.105682,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"DNAJC9 functions as a histone chaperone that binds histone H3-H4 substrates and recruits HSP70-type enzymes via its J domain to fold histone H3-H4. Its structure in a co-chaperone complex with MCM2 was elucidated, revealing how this dual histone and heat shock co-chaperone binds histone substrates. DNAJC9 operates upstream in the histone supply chain, during replication- and transcription-coupled nucleosome assembly, and resolves spurious histone interactions.\",\n      \"method\": \"Structure-guided and functional proteomics, cryo-EM/structural determination of DNAJC9–H3-H4–MCM2 complex, Co-IP, mass spectrometry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination combined with functional proteomics and multiple orthogonal methods (Co-IP, MS, mutagenesis-guided analysis) in a single rigorous study\",\n      \"pmids\": [\"33857403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNAJC9 is identified as an essential heat shock co-chaperone that links ATP-dependent molecular chaperones (HSP70) to the histone supply and deposition pathways, functioning as a bona fide histone chaperone.\",\n      \"method\": \"Commentary/review of Hammond et al. 2021 experimental findings\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — corroborates primary discovery paper (PMID 33857403); this paper itself is a commentary, not original data\",\n      \"pmids\": [\"34143966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAJC9 depletion causes mislocalization of CENP-A throughout the genome and chromosomal instability (CIN). Global interactome analysis showed DNAJC9 depletion promotes interaction of CENP-A with MCM2, and CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, identifying MCM2 as a driver of ectopic CENP-A deposition when H3-H4 supply chains are disrupted. Histone H3.3 depletion phenocopies DNAJC9 loss.\",\n      \"method\": \"Genome-wide RNAi screen, global interactome analysis, epistasis (double depletion of DNAJC9 and MCM2), live-cell imaging for CIN phenotypes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen plus interactome plus genetic epistasis with multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"38600242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In fission yeast, Djc9 (DNAJC9 ortholog) binds helix α3 of histone H3 in a manner that precludes simultaneous binding by Asf1, and competes with Asf1 for H3-H4 dimer binding in vitro. Loss of Djc9 renders Asf1 non-essential for growth. In the absence of Asf1, unrestrained Djc9-mediated downregulation of H3 and H4 hinders cell growth. In the presence of Asf1, Djc9 promotes degradation of superfluous or dysfunctional histones and confers resistance to hydroxyurea and dominant-negative histone mutants.\",\n      \"method\": \"AlphaFold-based structural prediction validated by in vitro competition binding assays, genetic epistasis (double mutants), H3-α3 point mutations, growth assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of competition, structural prediction with mutagenesis validation, genetic epistasis across multiple conditions\",\n      \"pmids\": [\"39878217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC9 binds to HBV covalently closed circular DNA (cccDNA) in a histone-independent and sequence-independent manner, interacts with histone H3.3 (shown by Co-IP and cccDNA ChIP), and promotes cccDNA transcription by increasing H3.3, H3K4me3, and H3K27ac density on cccDNA, thereby activating HBV promoters and enhancers. HBV replication promotes nuclear relocalization of DNAJC9.\",\n      \"method\": \"DNA pull-down, cccDNA ChIP, Co-IP, dual luciferase reporter assay, immunofluorescence, siRNA knockdown and overexpression in HBV infection/replication cell models\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pull-down, ChIP, Co-IP, reporter assay, imaging) in a single lab study\",\n      \"pmids\": [\"40407066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAJC9 promotes cervical cancer cell proliferation by facilitating p300–H3 interaction to sustain H3K27ac at the GLI1 enhancer, thereby driving GLI1 transcription. GLI1 rescue reverses proliferation defects caused by DNAJC9 downregulation. DNAJC9 knockdown induces G1/S arrest and suppresses tumorigenicity.\",\n      \"method\": \"siRNA knockdown, GLI1 rescue experiments, chromatin immunoprecipitation (H3K27ac at GLI1 enhancer), co-immunoprecipitation (p300–H3 interaction), cell proliferation and tumor assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP with rescue experiment, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42185231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAJC9 and MCM2 are identified as central players in chromatin repair following UV-induced DNA damage. DNAJC9 provides new H3-H4 histones to CAF-1 and HIRA chaperones for deposition into chromatin and stimulates recovery of old H3-H4 histones. MCM2 cooperates with DNAJC9 to coordinate old and new histone dynamics during UV damage repair.\",\n      \"method\": \"Novel quantitative, time-resolved proteomic strategy characterizing dynamic changes in chromatin landscape during UV damage repair in human cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative unbiased proteomics with temporal resolution, single lab, mechanistic pathway placement\",\n      \"pmids\": [\"41605964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"JDD1 (rat ortholog of DNAJC9) encodes a ~30 kDa protein with a J domain characteristic of the DnaJ family but lacking the G/F region and zinc finger (cysteine-rich) region. Its mRNA is expressed in the germinal (ventricular and subventricular) zones of the rat brain during embryonic development and persists after birth, as well as in liver, lung, kidney cortex, and other embryonic tissues.\",\n      \"method\": \"cDNA cloning, immunoblot analysis, in situ hybridization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct protein characterization (immunoblot) and localization (in situ hybridization), single lab, single study\",\n      \"pmids\": [\"11444854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAJC9 directly interacts with ALV-J integrase p32 (validated by Co-IP and laser confocal microscopy) and enhances ALV-J replication, indicating a proviral role as a host cofactor for retroviral integration.\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, Western blot, laser confocal microscopy, functional replication assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP validation, avian virus system (non-mammalian virus context), single lab\",\n      \"pmids\": [\"41386616\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAJC9 is a dual-function heat shock co-chaperone and histone chaperone that binds histone H3-H4 via the α3 helix of H3 (competing with Asf1), recruits HSP70 through its J domain to fold histone substrates, and integrates ATP-dependent protein folding into the histone supply pathway to support replication- and transcription-coupled nucleosome assembly, resolve aberrant histone intermediates, restrict CENP-A mislocalization by maintaining H3-H4 supply chain fidelity (with MCM2 acting downstream to drive ectopic CENP-A deposition when DNAJC9 is lost), facilitate UV damage chromatin repair by supplying new H3-H4 to CAF-1/HIRA and recovering old histones, and in the nucleus promote active gene transcription by modulating histone H3.3 and H3K27ac deposition at gene regulatory elements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAJC9 is a dual-function heat shock co-chaperone and histone chaperone that integrates ATP-dependent protein folding into the histone H3-H4 supply chain to support nucleosome assembly [#0]. It binds H3-H4 substrates and recruits HSP70-type chaperones through its J domain to fold histones, operating upstream in the histone supply chain during replication- and transcription-coupled nucleosome assembly and resolving spurious histone interactions, with a structurally defined co-chaperone complex involving MCM2 [#0]. DNAJC9 engages histone H3 via helix \\u03b13, a binding mode that precludes simultaneous Asf1 binding, so that the two compete for H3-H4 dimers; in this configuration DNAJC9 also drives degradation of superfluous or dysfunctional histones and confers resistance to replication stress and toxic histone mutants [#3]. Maintaining H3-H4 supply-chain fidelity restricts CENP-A mislocalization: loss of DNAJC9 promotes ectopic genome-wide CENP-A deposition and chromosomal instability through MCM2, which acts as the downstream driver of this aberrant deposition [#2]. In genome maintenance, DNAJC9 supplies new H3-H4 to the CAF-1 and HIRA deposition pathways and stimulates recovery of old histones during chromatin repair after UV damage, cooperating with MCM2 to coordinate old and new histone dynamics [#6]. Through its control over histone deposition, DNAJC9 also promotes active transcription by modulating H3.3 and H3K27ac at regulatory elements, including sustaining p300\\u2013H3 contact to drive GLI1 enhancer activity in cervical cancer cells [#5] and activating HBV cccDNA transcription [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Before any functional role was known, the gene was defined as a DnaJ-family member by its molecular architecture, establishing it as a J-domain co-chaperone lacking the G/F and zinc-finger regions.\",\n      \"evidence\": \"cDNA cloning, immunoblot, and in situ hybridization of the rat ortholog JDD1 in embryonic brain and other tissues\",\n      \"pmids\": [\"11444854\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No substrate or biochemical activity identified\", \"Function inferred only from domain composition, not assayed\", \"Localization is at mRNA level in rat, not protein-level subcellular assignment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The central question of what DNAJC9 chaperones was answered by showing it is a histone chaperone that recruits HSP70 via its J domain to fold H3-H4, defining it as the link between ATP-dependent chaperones and the histone supply chain.\",\n      \"evidence\": \"Cryo-EM/structural determination of the DNAJC9\\u2013H3-H4\\u2013MCM2 complex with Co-IP, mass spectrometry, and functional proteomics, corroborated by an accompanying commentary\",\n      \"pmids\": [\"33857403\", \"34143966\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not establish how DNAJC9 hands off histones to downstream deposition machinery\", \"Physiological consequences of disrupting the J-domain/HSP70 interaction not tested in vivo\", \"Relationship to Asf1 and other handoff chaperones not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The genome-stability consequence of DNAJC9 loss was placed mechanistically by showing that disrupting the H3-H4 supply chain causes MCM2-dependent ectopic CENP-A deposition and chromosomal instability.\",\n      \"evidence\": \"Genome-wide RNAi screen, global interactome analysis, genetic epistasis (DNAJC9/MCM2 double depletion), and live-cell imaging in human cells\",\n      \"pmids\": [\"38600242\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which MCM2 redirects CENP-A to ectopic sites not fully defined\", \"Whether CENP-A mislocalization is direct or secondary to general supply-chain failure unclear\", \"Does not distinguish replication- versus transcription-coupled contributions\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The structural and functional relationship to Asf1 was resolved by showing DNAJC9 binds H3 helix \\u03b13 in a manner mutually exclusive with Asf1 and promotes degradation of excess or dysfunctional histones.\",\n      \"evidence\": \"AlphaFold-based structural prediction validated by in vitro competition binding, H3-\\u03b13 point mutations, and genetic epistasis under replication stress in fission yeast\",\n      \"pmids\": [\"39878217\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The degradation machinery DNAJC9 routes histones to is not identified\", \"Conservation of the Asf1 competition in human cells not directly tested here\", \"How the balance between folding and degradation is regulated is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"DNAJC9 was extended beyond cellular chromatin into viral chromatin, showing it binds HBV cccDNA independently of histone or sequence and activates its transcription by raising H3.3, H3K4me3, and H3K27ac density.\",\n      \"evidence\": \"DNA pull-down, cccDNA ChIP, Co-IP, dual luciferase reporter, and immunofluorescence in HBV infection/replication cell models\",\n      \"pmids\": [\"40407066\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of histone-independent cccDNA binding not structurally defined\", \"Whether this reflects a normal cellular function co-opted by HBV is unclear\", \"Single-lab study without independent replication\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"DNAJC9's role in chromatin repair was defined by showing it supplies new H3-H4 to CAF-1/HIRA and aids recovery of old histones during UV damage repair, cooperating with MCM2.\",\n      \"evidence\": \"Quantitative time-resolved proteomic profiling of chromatin dynamics during UV damage repair in human cells\",\n      \"pmids\": [\"41605964\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct physical contacts with CAF-1 and HIRA not biochemically dissected here\", \"Distinction between new-histone supply and old-histone recovery roles not mechanistically separated\", \"Single-lab proteomic study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A transcriptional/oncogenic output was established by showing DNAJC9 sustains H3K27ac at the GLI1 enhancer via p300\\u2013H3 contact to drive proliferation, demonstrating chromatin-supply control feeds into gene regulation.\",\n      \"evidence\": \"siRNA knockdown, GLI1 rescue, H3K27ac ChIP, p300\\u2013H3 Co-IP, and proliferation/tumor assays in cervical cancer cells\",\n      \"pmids\": [\"42185231\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether the GLI1 effect is direct or downstream of global H3.3/H3K27ac changes unclear\", \"Generalizability beyond cervical cancer not tested\", \"Mechanism by which DNAJC9 facilitates p300\\u2013H3 interaction not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNAJC9 mechanistically partitions H3-H4 between folding, deposition (CAF-1/HIRA), degradation, and competition with Asf1, and how this is regulated across replication, transcription, and damage contexts, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unified model of how histone fate is selected\", \"Regulatory inputs controlling DNAJC9 activity unknown\", \"Human counterpart of yeast Asf1 competition not directly demonstrated in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCM2\", \"HSPA8\", \"ASF1\", \"H3.3\", \"CAF-1\", \"HIRA\", \"EP300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}