id: Q5F1R6
gene_symbol: DNAJC21
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC21 (DnaJ homolog subfamily C member 21; also DNAJA5) is a J-domain co-chaperone of the HSP70 system that functions in ribosome biogenesis, specifically in the maturation of the large (60S) ribosomal subunit. It contains an N-terminal J-domain and two C2H2 zinc fingers within an otherwise disordered C-terminal region. DNAJC21 localizes to the cytoplasm, the nucleus and especially the nucleolus, associates with precursor 45S rRNA, and works with the HSP70 chaperone HSPA8 and the cofactors PA2G4 (a 60S nuclear-export factor) and ZNF622 to drive late nucleolar rRNA biogenesis and cytoplasmic maturation/recycling of the 60S subunit. It is the human counterpart of the yeast 60S-maturation factor Jjj1/Zuo1-like J-protein. Biallelic loss-of-function variants cause a cancer-prone bone marrow failure syndrome (BMFS3, Shwachman-Diamond-like), establishing DNAJC21 as a ribosomopathy gene.
alternative_products:
- name: '1'
  id: Q5F1R6-1
- name: '2'
  id: Q5F1R6-2
  sequence_note: VSP_024005
- name: '3'
  id: Q5F1R6-3
  sequence_note: VSP_024004
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: DNAJC21 acts in the cytoplasm (as well as nucleus/nucleolus). Cytoplasmic localization is experimentally confirmed and consistent with its role in late cytoplasmic 60S maturation.
    action: ACCEPT
    reason: Direct experimental evidence (PMID:27346687) places DNAJC21 in the cytoplasm, corroborating this phylogenetic inference; it acts there in cytoplasmic 60S subunit maturation.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0003676
    label: nucleic acid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic nucleic-acid binding inferred from the C2H2 zinc-finger/Matrin-type domain. DNAJC21 does bind RNA (precursor 45S rRNA), so the specific RNA-binding term is more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'nucleic acid binding' is uninformative and inferred only from domain architecture; the experimentally supported RNA binding (GO:0003723) captures the real activity more precisely.
    supported_by:
    - reference_id: PMID:27346687
      supporting_text: We have shown that DNAJC21 associates with precursor 45S rRNA.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization, supported experimentally. Consistent with DNAJC21's nucleolar role in rRNA biogenesis.
    action: ACCEPT
    reason: Nuclear localization is directly demonstrated (PMID:27346687); the IEA from UniProt subcellular location agrees with stronger experimental evidence.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27346687}. Nucleus'
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nucleolar localization, the primary nuclear site of DNAJC21. This is its key compartment for rRNA biogenesis and 60S maturation.
    action: ACCEPT
    reason: DNAJC21 localizes primarily to the nucleolus (experimentally supported), the site of late nucleolar rRNA biogenesis it participates in.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'Within the nucleus, localizes primarily to the nucleolus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization (UniProt subcellular location IEA), redundant with the IBA and EXP cytoplasm annotations.
    action: ACCEPT
    reason: Correct localization; agrees with the experimentally supported cytoplasm annotations.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: DNAJC21 contains two C2H2-type zinc fingers, so zinc-ion binding is a reasonable structural molecular function inferred from sequence.
    action: KEEP_AS_NON_CORE
    reason: The C2H2 zinc fingers support zinc-ion binding; this is a structural feature rather than the gene's core co-chaperone/ribosome-biogenesis function.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: ZN_FING         314..338
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17500595
  qualifier: enables
  review:
    summary: IPI interaction with huntingtin (HTT, P42858) from an interactome screen. The bare 'protein binding' term is uninformative; HTT is not part of DNAJC21's ribosome-biogenesis function.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput interactome with a partner (HTT) unrelated to DNAJC21's co-chaperone/60S-maturation function; uninformative and not core.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'Q5F1R6; P42858: HTT'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  qualifier: enables
  review:
    summary: IPI interaction with MTERF1 (Q99551) from an interactome screen. The bare 'protein binding' term is uninformative and the partner is unrelated to ribosome biogenesis.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from a high-throughput interactome with a partner (MTERF1) unrelated to DNAJC21's known function; uninformative and not core.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'Q5F1R6; Q99551: MTERF1'
- term:
    id: GO:0005730
    label: nucleolus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for nucleolar localization, the primary nuclear site of DNAJC21 and consistent with its rRNA-biogenesis role.
    action: ACCEPT
    reason: IDA-supported nucleolar localization, the key compartment for DNAJC21's 60S-maturation function.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'Within the nucleus, localizes primarily to the nucleolus'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with the cytoplasmic pool that acts in late 60S maturation.
    action: ACCEPT
    reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:27346687
  qualifier: located_in
  review:
    summary: Experimental evidence (Tummala et al.) for nuclear localization of DNAJC21, where it acts in nucleolar rRNA biogenesis.
    action: ACCEPT
    reason: Direct experimental nuclear localization from the defining functional study; consistent with its nucleolar rRNA-biogenesis role.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27346687}. Nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:27346687
  qualifier: located_in
  review:
    summary: Experimental evidence (Tummala et al.) for cytoplasmic localization of DNAJC21, where it participates in late cytoplasmic 60S maturation/recycling.
    action: ACCEPT
    reason: Direct experimental cytoplasmic localization from the defining functional study; consistent with its role in cytoplasmic maturation of the 60S subunit.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: High-throughput RNA-interactome capture identified DNAJC21 as an RNA-binding protein. This is corroborated by the demonstrated association with precursor 45S rRNA, a core part of its ribosome-biogenesis function.
    action: ACCEPT
    reason: RNA binding is experimentally supported both by HDA RNA-interactome capture and by the targeted demonstration that DNAJC21 binds precursor 45S rRNA; it is a genuine molecular function central to its role in 60S maturation.
    supported_by:
    - reference_id: PMID:27346687
      supporting_text: We have shown that DNAJC21 associates with precursor 45S rRNA.
- term:
    id: GO:0005840
    label: ribosome
  evidence_type: NAS
  original_reference_id: PMID:16952052
  qualifier: located_in
  review:
    summary: DNAJC21 associates with the ribosome / nascent ribosomal subunits during biogenesis. Plausible given its 60S-maturation role, though 'ribosome' as a static location is less precise than its rRNA/60S-maturation activity.
    action: KEEP_AS_NON_CORE
    reason: Association with the ribosome is consistent with the 60S-maturation role, but the static cellular-component term is non-core relative to the rRNA-binding and biogenesis functions.
    supported_by:
    - reference_id: PMID:27346687
      supporting_text: 'plays a highly conserved role in the maturation of the 60S ribosomal subunit'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:16952052
  qualifier: involved_in
  review:
    summary: As an HSP70 co-chaperone (J-protein), DNAJC21 is annotated to protein folding. Its characterized biological role, however, is in ribosome biogenesis rather than general protein folding.
    action: KEEP_AS_NON_CORE
    reason: DNAJC21 is a J-domain co-chaperone that assists HSP70 rather than autonomously folding clients; protein folding is a downstream/generic process and the specific role is 60S subunit maturation.
    supported_by:
    - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
      supporting_text: May act as a co-chaperone for HSP70.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:16952052
  title: 'The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones.'
  findings: []
- id: PMID:17500595
  title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
  findings: []
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human transcription factor networks.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; a systematic mRNA-interactome-capture atlas (not DNAJC21-specific) that identified DNAJC21 as an RNA-binding protein, corroborating its RNA-binding molecular function consistent with the 45S rRNA-association role."
  findings:
  - statement: mRNA/RNA-interactome capture identified DNAJC21 as an RNA-binding protein.
    reference_section_type: RESULTS
- id: PMID:27346687
  title: DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication title matches the YAML title; the text establishes that DNAJC21 associates with rRNA and has a conserved role in 60S ribosomal subunit maturation, acting via cofactors HSPA8, PA2G4 and ZNF622, with mutations causing a cancer-prone bone marrow failure syndrome. Primary reference for the core functions (chaperone binding / 60S maturation / RNA binding); cited in core_functions.supported_by."
  findings:
  - statement: DNAJC21 associates with precursor 45S rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit; it acts with HSPA8, PA2G4 and ZNF622, and biallelic mutations cause a cancer-prone bone marrow failure syndrome.
    reference_section_type: RESULTS
  - statement: Disease mutations impair DNAJC21 interactions with the cofactors PA2G4, HSPA8 and ZNF622 involved in 60S maturation; DNAJC21 deficiency causes cytoplasmic accumulation of the 60S subunit and aberrant ribosome profiles.
    reference_section_type: RESULTS
- id: file:human/DNAJC21/DNAJC21-uniprot.txt
  title: UniProt entry Q5F1R6 (DJC21_HUMAN), DnaJ homolog subfamily C member 21
  findings:
  - statement: J-domain co-chaperone for HSP70; role in rRNA biogenesis and 60S subunit maturation; binds precursor 45S rRNA; interacts with HSPA8, PA2G4 and ZNF622; cytoplasm/nucleus/nucleolus; cause of bone marrow failure syndrome 3.
    reference_section_type: OTHER
core_functions:
- description: J-domain co-chaperone of the HSP70 chaperone HSPA8 that, together with the cofactors PA2G4 and ZNF622, drives nucleolar rRNA biogenesis and maturation of the large (60S) ribosomal subunit.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  locations:
  - id: GO:0005730
    label: nucleolus
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:27346687
    supporting_text: 'plays a highly conserved role in the maturation of the 60S ribosomal subunit'
  - reference_id: file:human/DNAJC21/DNAJC21-uniprot.txt
    supporting_text: Interacts with HSPA8, PA2G4 and ZNF622.
- description: RNA-binding activity that engages precursor 45S rRNA during ribosome biogenesis, contributing to processing/maturation of the 60S subunit.
  molecular_function:
    id: GO:0003723
    label: RNA binding
  locations:
  - id: GO:0005730
    label: nucleolus
  supported_by:
  - reference_id: PMID:27346687
    supporting_text: We have shown that DNAJC21 associates with precursor 45S rRNA.
proposed_new_terms: []
suggested_questions:
- question: Does DNAJC21 stimulate the ATPase activity of HSPA8 in the context of 60S maturation, and is its J-domain activity required for ribosome biogenesis?
- question: What is the precise step of 60S maturation (nucleolar processing vs. cytoplasmic recycling of PA2G4) that is most sensitive to DNAJC21 loss in BMFS3 patient cells?
suggested_experiments:
- description: Reconstitute DNAJC21-HSPA8 J-domain activity in vitro (ATPase stimulation assays) using wild-type and BMFS3 (P32A) variant proteins to test whether co-chaperone activity is required for 60S maturation.
- description: Polysome/ribosome profiling and pre-rRNA processing analysis (Northern blot of 45S/32S/28S intermediates) in DNAJC21-depleted versus rescued cells to map the maturation step affected.
- description: Proximity labeling (BioID/APEX) of DNAJC21 in nucleolus versus cytoplasm to define compartment-specific 60S-maturation interaction partners.