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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Direct experimental evidence (PMID:27346687) places DNAJC21 in the cytoplasm, corroborating this phylogenetic inference; it acts there in cytoplasmic 60S subunit maturation. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:27346687 We have shown that DNAJC21 associates with precursor 45S rRNA. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization, supported experimentally. Consistent with DNAJC21's nucleolar role in rRNA biogenesis. Reason: Nuclear localization is directly demonstrated (PMID:27346687); the IEA from UniProt subcellular location agrees with stronger experimental evidence. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27346687}. Nucleus |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | ACCEPT | Summary: Nucleolar localization, the primary nuclear site of DNAJC21. This is its key compartment for rRNA biogenesis and 60S maturation. Reason: DNAJC21 localizes primarily to the nucleolus (experimentally supported), the site of late nucleolar rRNA biogenesis it participates in. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt Within the nucleus, localizes primarily to the nucleolus |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization (UniProt subcellular location IEA), redundant with the IBA and EXP cytoplasm annotations. Reason: Correct localization; agrees with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: DNAJC21 contains two C2H2-type zinc fingers, so zinc-ion binding is a reasonable structural molecular function inferred from sequence. 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. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt ZN_FING 314..338 |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt Q5F1R6; P42858: HTT |
| GO:0005515 protein binding | IPI PMID:20195357 A comprehensive resource of interacting protein regions for ... | KEEP AS NON CORE | 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. Reason: Bare protein binding from a high-throughput interactome with a partner (MTERF1) unrelated to DNAJC21's known function; uninformative and not core. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt Q5F1R6; Q99551: MTERF1 |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for nucleolar localization, the primary nuclear site of DNAJC21 and consistent with its rRNA-biogenesis role. Reason: IDA-supported nucleolar localization, the key compartment for DNAJC21's 60S-maturation function. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt Within the nucleus, localizes primarily to the nucleolus |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with the cytoplasmic pool that acts in late 60S maturation. Reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005634 nucleus | EXP PMID:27346687 DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Sy... | ACCEPT | Summary: Experimental evidence (Tummala et al.) for nuclear localization of DNAJC21, where it acts in nucleolar rRNA biogenesis. Reason: Direct experimental nuclear localization from the defining functional study; consistent with its nucleolar rRNA-biogenesis role. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27346687}. Nucleus |
| GO:0005737 cytoplasm | EXP PMID:27346687 DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Sy... | ACCEPT | Summary: Experimental evidence (Tummala et al.) for cytoplasmic localization of DNAJC21, where it participates in late cytoplasmic 60S maturation/recycling. Reason: Direct experimental cytoplasmic localization from the defining functional study; consistent with its role in cytoplasmic maturation of the 60S subunit. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | ACCEPT | 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. 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. Supporting Evidence: PMID:27346687 We have shown that DNAJC21 associates with precursor 45S rRNA. |
| GO:0005840 ribosome | NAS PMID:16952052 The diversity of the DnaJ/Hsp40 family, the crucial partners... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:27346687 plays a highly conserved role in the maturation of the 60S ribosomal subunit |
| GO:0006457 protein folding | NAS PMID:16952052 The diversity of the DnaJ/Hsp40 family, the crucial partners... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/DNAJC21/DNAJC21-uniprot.txt May act as a co-chaperone for HSP70. |
Loading supporting content…
Download this section (compressed HTML)Q: Does DNAJC21 stimulate the ATPase activity of HSPA8 in the context of 60S maturation, and is its J-domain activity required for ribosome biogenesis?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: Proximity labeling (BioID/APEX) of DNAJC21 in nucleolus versus cytoplasm to define compartment-specific 60S-maturation interaction partners.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)