id: Q96BH1
gene_symbol: RNF25
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: RNF25 (RING finger protein 25, originally identified as AO7) is a cytoplasmic RING-H2 E3 ubiquitin-protein ligase that, with an N-terminal RWD domain for E2 recognition, functions in ribosome-associated quality control. It is a core component of the RNF14-RNF25 translation quality control pathway that operates when ribosomes stall and collide during translation. RNF25 catalyzes ubiquitination of the ribosomal protein RPS27A/eS31 in response to ribosome collisions, providing a signal that activates the partner ligase RNF14, and it ubiquitinates additional ribosomal proteins and stalled release factor ETF1/eRF1, marking translation factors on stalled ribosomes for degradation. RNF25 also assembles atypical K6-linked ubiquitin chains that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution. It works with the E2 enzyme UBE2D2 (UbcH5B). Independently of the stalled-ribosome response, RNF25 was originally characterized as a regulator that supports NF-kappaB (RELA/p65)-mediated transcription and can target substrates such as NKD2 for degradation.
existing_annotations:
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes in the RNF14-RNF25 quality control pathway. IBA inference is corroborated by direct experimental evidence.
    action: ACCEPT
    reason: Core process; RNF25 ubiquitinates ribosomal proteins and translation factors on stalled ribosomes as part of ribosome-associated quality control.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: RNF25 ubiquitinates translation factors and ribosomal proteins on stalled ribosomes, targeting them for degradation. Core biological process.
    action: ACCEPT
    reason: Directly supported; RNF25 promotes ubiquitin-dependent degradation of stalled translation factors (e.g. eEF1A, eRF1).
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: RNF25 is a RING E3 ubiquitin ligase. This is its core molecular function.
    action: ACCEPT
    reason: Defining molecular function, supported by phylogenetic inference and direct biochemistry.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: A nuclear pool of RNF25 is reported (from its AO7/NF-kB role), but its principal quality-control function is cytoplasmic/ribosome-associated.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is documented but peripheral to the core cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, consistent with RNF25's ribosome-associated quality-control function.
    action: ACCEPT
    reason: Correct compartment for the core RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic transfer of ubiquitin ligase activity, consistent with direct evidence.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18757723
  qualifier: enables
  review:
    summary: High-throughput interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a physical interaction but the generic term adds nothing to RNF25's E3 ligase function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19549727
  qualifier: enables
  review:
    summary: E2 ubiquitin-conjugating enzyme interaction network capturing RNF25-E2 (UbcH5/UBE2D) binding. Relevant to catalysis but recorded as bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: The E2 interaction underlies RNF25's ligase activity, but the generic protein binding term is uninformative; the catalytic role is captured by the ligase-activity term.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Interacts with UBE2D2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19690564
  qualifier: enables
  review:
    summary: E2-RING E3 interaction framework capturing RNF25-E2 binding. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Reflects E2 engagement underlying catalysis; generic term is non-core.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Interacts with UBE2D2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactome screen capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome (e.g. NKD2, a substrate; KCTD21). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Records interactions including a substrate (NKD2), but the generic term is uninformative.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'Q969F2: NKD2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome screen. Bare protein binding with high-throughput partners unrelated to the core function.
    action: KEEP_AS_NON_CORE
    reason: Isolated high-throughput interactions; generic term uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex affinity-purification interactome capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-maps interactome capturing RNF25 interactions. Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Generic term; uninformative for core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ubiquitin-protein transferase activity, equivalent to RNF25's E3 ligase function.
    action: ACCEPT
    reason: Correct molecular function (the EC 2.3.2.27 ligase reaction).
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: RNF25 ubiquitinates substrate proteins; protein ubiquitination is the process it catalyzes.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer of cytoplasmic localization, consistent with direct evidence.
    action: ACCEPT
    reason: Correct compartment for the core function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: is_active_in
  review:
    summary: RNF25 acts at the cytosolic ribosome, ubiquitinating ribosomal proteins on stalled/collided ribosomes.
    action: ACCEPT
    reason: Directly supported site of action for the RQC function.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RNF14-RNF25 pathway, ubiquitinating RPS27A and translation factors on stalled ribosomes.
    action: ACCEPT
    reason: Directly demonstrated core molecular function in the GCN1-engaging E3 network.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:36638793
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes, ubiquitinating RPS27A to activate RNF14 and promote degradation of stalled translation factors.
    action: ACCEPT
    reason: Directly demonstrated involvement in the stalled-ribosome quality-control response.
    supported_by:
    - reference_id: PMID:36638793
      supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 E3 ligase activity in marking RNA-protein crosslinks with ubiquitin.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0160127
    label: protein-RNA covalent cross-linking repair
  evidence_type: IDA
  original_reference_id: PMID:37951215
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) assembles K6-linked ubiquitin chains that flag RNA-protein crosslinks for translation-coupled resolution.
    action: ACCEPT
    reason: Directly demonstrated role in resolving covalent RNA-protein crosslinks.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ligase activity in drug-induced eRF1 degradation that promotes readthrough.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37651229
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) acts on stalled/collided ribosomes following eRF1 trapping to clear stalled translation factors.
    action: ACCEPT
    reason: Directly demonstrated involvement in resolving stalled ribosomes.
    supported_by:
    - reference_id: PMID:37651229
      supporting_text: E3 ubiquitin ligases RNF14 and RNF25
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:37951216
  qualifier: involved_in
  review:
    summary: RNF25 (with RNF14) acts in translation-coupled resolution of RNA-protein crosslinks at collided ribosomes.
    action: ACCEPT
    reason: Directly demonstrated involvement in stalled-ribosome resolution.
    supported_by:
    - reference_id: PMID:37951216
      supporting_text: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:26475854
  qualifier: enables
  review:
    summary: Structural/biochemical study of the AO7 (RNF25) RING-E2 (UbcH5B) interaction demonstrating its ubiquitin ligase activity.
    action: ACCEPT
    reason: Directly demonstrated RING E3 ligase activity with its E2 partner.
    supported_by:
    - reference_id: PMID:26475854
      supporting_text: Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25-dependent ubiquitination targets factors on stalled ribosomes for degradation.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0022626
    label: cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: is_active_in
  review:
    summary: RNF25 acts at the cytosolic ribosome in ribosome-associated quality control.
    action: ACCEPT
    reason: Directly supported site of action.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: enables
  review:
    summary: Direct demonstration of RNF25 ubiquitin ligase activity in the RQC context.
    action: ACCEPT
    reason: Directly demonstrated core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25 acts on stalled/collided ribosomes in ribosome-associated quality control.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions
- term:
    id: GO:0085020
    label: protein K6-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:27863242
  qualifier: involved_in
  review:
    summary: RNF25 assembles atypical K6-linked ubiquitin chains, a distinctive feature of its RQC signaling.
    action: ACCEPT
    reason: Directly demonstrated; K6-linked ubiquitination marks RNA-protein crosslinks and stalled-ribosome substrates.
    supported_by:
    - reference_id: PMID:37951215
      supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer of ubiquitin-protein transferase activity, consistent with direct evidence.
    action: ACCEPT
    reason: Correct core molecular function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that plays a key role in the RNF14-RNF25 translation quality control pathway
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:12748188
  qualifier: located_in
  review:
    summary: Direct nuclear localization reported in the original AO7/NF-kB study.
    action: KEEP_AS_NON_CORE
    reason: Genuine nuclear pool linked to the NF-kB role; peripheral to the core cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: may also stimulate transcription mediated by NF-kappa-B via its interaction with RELA/p65
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:12748188
  qualifier: located_in
  review:
    summary: Direct cytosolic localization, consistent with the core ribosome-associated function.
    action: ACCEPT
    reason: Correct localization for the cytoplasmic RQC function.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: RNF25 catalyzes protein ubiquitination.
    action: ACCEPT
    reason: Correct core process.
    supported_by:
    - reference_id: file:human/RNF25/RNF25-uniprot.txt
      supporting_text: promotes ubiquitination and degradation of translation factors on stalled ribosomes
- term:
    id: GO:0051059
    label: NF-kappaB binding
  evidence_type: IPI
  original_reference_id: PMID:12748188
  qualifier: enables
  review:
    summary: RNF25 (AO7) binds RELA/p65 and supports NF-kappaB-mediated transcription, a function distinct from its ribosome-associated quality-control role.
    action: KEEP_AS_NON_CORE
    reason: Documented physical interaction underlying the NF-kB moonlighting role; retained as non-core relative to the E3-ligase RQC function.
    supported_by:
    - reference_id: PMID:12748188
      supporting_text: RING finger protein AO7 supports NF-kappaB-mediated transcription
references:
- id: GO_REF:0000024
  title: Manual transfer of annotations from one model organism to another based on sequence orthology
  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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12748188
  title: RING finger protein AO7 supports NF-kappaB-mediated transcription by interacting with the transactivation domain of the p65 subunit.
  findings:
  - statement: AO7 (RNF25) interacts with RELA/p65 and supports NF-kappaB-mediated transcription; localizes to nucleus and cytosol.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; original characterization of AO7/RNF25 as a RING E3 interacting with the E2 UbcH5B/UBE2D2 (supports ubiquitin ligase identity), though the NF-kappaB transcription role is now considered secondary to the ribosome-quality-control function.
- id: PMID:18757723
  title: "EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation."
  findings: []
- id: PMID:19549727
  title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network.
  findings: []
- id: PMID:19690564
  title: A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system.
  findings: []
- id: PMID:26475854
  title: Insights into Ubiquitination from the Unique Clamp-like Binding of the RING E3 AO7 to the E2 UbcH5B.
  findings:
  - statement: Structural and biochemical characterization of the RING E3 AO7 (RNF25) binding to the E2 UbcH5B (UBE2D2), establishing its ubiquitin ligase activity.
    reference_section_type: RESULTS
- id: PMID:27863242
  title: Decoding Mammalian Ribosome-mRNA States by Translational GTPase Complexes.
  findings:
  - statement: RNF25 acts at the cytosolic ribosome and forms K6-linked ubiquitin chains in ribosome-associated quality control.
    reference_section_type: RESULTS
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:36638793
  title: An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
  findings:
  - statement: RNF14 and RNF25 are required for eEF1A degradation on stalled ribosomes; RNF25 ubiquitinates RPS27A/eS31 as an essential signaling input that activates RNF14.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; Results establish the RNF14-RNF25 pathway in which RNF25 ubiquitinates RPS27A/eS31 on collided ribosomes to activate RNF14 and drive degradation of stalled translation factors - RNF25's core E3 ligase function (GO:0061630).
- id: PMID:37651229
  title: Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.
  findings:
  - statement: Readthrough drugs trap eRF1, causing ribosome stalls/collisions and eRF1 degradation by the E3 ubiquitin ligases RNF14 and RNF25.
    reference_section_type: RESULTS
- id: PMID:37951215
  title: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution.
  findings:
  - statement: RNF25 assembles K6-linked ubiquitin chains that mark formaldehyde-induced RNA-protein crosslinks for resolution.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches PubMed; supports RNF25's assembly of atypical K6-linked ubiquitin chains (with RNF14) flagging formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution.
- id: PMID:37951216
  title: RNF14-dependent atypical ubiquitylation promotes translation-coupled resolution of RNA-protein crosslinks.
  findings:
  - statement: RNF14-dependent atypical ubiquitylation (with RNF25) promotes translation-coupled resolution of RNA-protein crosslinks at collided ribosomes.
    reference_section_type: RESULTS
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
core_functions:
- description: RING-type E3 ubiquitin ligase that, in the RNF14-RNF25 translation quality control pathway, ubiquitinates the ribosomal protein RPS27A/eS31 on collided ribosomes (activating RNF14) and ubiquitinates other ribosomal proteins and stalled ETF1/eRF1, targeting translation factors on stalled ribosomes for degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: file:human/RNF25/RNF25-uniprot.txt
    supporting_text: Catalyzes ubiquitination of RPS27A in response to ribosome collisions, promoting activation of RNF14
  - reference_id: PMID:36638793
    supporting_text: RNF25-dependent ubiquitination of the ribosomal protein
- description: Assembles atypical K6-linked ubiquitin chains (with RNF14) that flag formaldehyde-induced RNA-protein crosslinks for translation-coupled resolution.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0022626
    label: cytosolic ribosome
  supported_by:
  - reference_id: PMID:37951215
    supporting_text: K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks
proposed_new_terms: []
suggested_questions:
- question: What determines the substrate hierarchy in RNF25-mediated ubiquitination (RPS27A vs eRF1 vs other ribosomal proteins) and how does RPS27A ubiquitination activate RNF14?
- question: How is RNF25's RQC E3-ligase role partitioned from its older AO7/NF-kappaB transcriptional role, and are these mediated by distinct pools or stimuli?
suggested_experiments:
- description: Site-specific ubiquitin-proteomics (diGly) in RNF25-knockout versus wild-type cells under collision-inducing stress to define the endogenous RNF25 substrate set and ubiquitin-chain linkage types.
- description: Reconstituted ubiquitination assays with RNF25, RNF14, UBE2D2 and collided ribosomes to dissect the order of RPS27A ubiquitination and RNF14 activation.