id: Q9H1I8 gene_symbol: ASCC2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: ASCC2 is a CUE-domain ubiquitin-binding subunit of activating signal cointegrator complexes. In the nucleus, ASCC2 recognizes K63-linked polyubiquitin signals and helps recruit ASCC3 and ALKBH3 to alkylation-damage sites, supporting DNA dealkylation repair in nuclear foci associated with transcription and spliceosome components. In the cytosol, ASCC2 works with ASCC3 and TRIP4 as the human RQC-trigger complex to recognize K63-polyubiquitinated collided ribosomes and promote ribosome subunit dissociation, enabling rescue of stalled cytosolic ribosomes and downstream ribosome-associated quality control. ASCC2 was also described historically as the P100 subunit of an ASC-1 transcription coactivator complex, but its most mechanistically supported functions are K63-ubiquitin-dependent DNA repair and stalled-ribosome quality control. alternative_products: - name: '1' id: Q9H1I8-1 - name: '2' id: Q9H1I8-2 sequence_note: VSP_011009, VSP_011010, VSP_011011 - name: '3' id: Q9H1I8-3 sequence_note: VSP_045878, VSP_045879 existing_annotations: - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: ASCC2 was originally identified as the P100 subunit of an ASC-1 transcription coactivator complex. This supports a transcription-regulatory role, but current mechanistic evidence places ASCC2 core functions in K63-ubiquitin-dependent DNA alkylation repair and ribosome quality control. action: KEEP_AS_NON_CORE reason: Retain as a historical/non-core process annotation. The 2002 work supports ASC-1 complex effects on AP-1, SRF, and NF-kappaB transactivation, but ASCC2 is not a sequence-specific transcription factor and the more direct, better characterized roles are ASCC/RQT complex functions. additional_reference_ids: - PMID:29144457 - PMID:32099016 - PMID:32579943 - PMID:36302773 supported_by: - reference_id: PMID:12077347 supporting_text: essential role in AP-1, SRF, and NF-kappaB transactivation - term: id: GO:0043130 label: ubiquitin binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ASCC2 is a ubiquitin-binding CUE-domain protein, but the supported specificity is K63-linked polyubiquitin rather than generic ubiquitin binding. action: MODIFY reason: Replace the broad ubiquitin-binding term with the experimentally supported K63-linked polyubiquitin-dependent binding term. This specificity is central to alkylation-damage recruitment and to hRQT-mediated recognition of collided ribosomes. proposed_replacement_terms: - id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding additional_reference_ids: - PMID:29144457 - PMID:36302773 supported_by: - reference_id: PMID:29144457 supporting_text: bound K63- but not K48-linked ubiquitin chains - reference_id: PMID:36302773 supporting_text: ASCC2 specifically interacts with K63-linked polyubiquitin chains - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Nuclear localization is supported by UniProt curation and by ASCC2/ASCC complex recruitment to nuclear foci during alkylation damage. action: ACCEPT reason: The nucleus is a correct cellular location for the DNA alkylation repair branch of ASCC2 function. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29144457 supporting_text: the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci - term: id: GO:0016607 label: nuclear speck evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: ASCC2/ASCC components localize to nuclear speckle-associated foci and spliceosome-rich nuclear regions in alkylation damage studies. action: ACCEPT reason: Nuclear speckle localization is supported for the nuclear ASCC repair context, where ASCC foci overlap spliceosome components and elongating RNA polymerase II. additional_reference_ids: - PMID:29144457 - PMID:29997253 supported_by: - reference_id: PMID:29144457 supporting_text: ASCC2 also associated with many spliceosome components and basal transcription factors - term: id: GO:0043130 label: ubiquitin binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The InterPro-derived ubiquitin-binding annotation is directionally correct but too broad for ASCC2. action: MODIFY reason: ASCC2 binds K63-linked polyubiquitin through its CUE domain in both the DNA repair and hRQT literature; the narrower K63-linked polyubiquitin-dependent binding term should be used. proposed_replacement_terms: - id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding additional_reference_ids: - PMID:29144457 - PMID:36302773 supported_by: - reference_id: PMID:29144457 supporting_text: bound K63- but not K48-linked ubiquitin chains - reference_id: PMID:36302773 supporting_text: ASCC2 specifically interacts with K63-linked polyubiquitin chains - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: BioPlex AP-MS reports ASCC2 co-associations, but generic protein binding does not describe ASCC2 molecular function. action: REMOVE reason: This high-throughput interaction evidence should remain interaction data rather than a GO molecular-function annotation. ASCC2 molecular function is better captured by K63-linked polyubiquitin-dependent binding. additional_reference_ids: - PMID:29144457 - PMID:36302773 supported_by: - reference_id: PMID:28514442 supporting_text: uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29997253 qualifier: enables review: summary: ASCC2 interaction with ASCC3 is biologically meaningful for ASCC/RQT complexes, but GO:0005515 is too generic to retain as function. action: MARK_AS_OVER_ANNOTATED reason: The ASCC2-ASCC3 association should be represented through complex/process annotations such as DNA repair complex, RQC-trigger complex, DNA alkylation repair, and rescue of stalled cytosolic ribosome, not generic protein binding. additional_reference_ids: - PMID:29144457 - PMID:32099016 - PMID:36302773 supported_by: - reference_id: file:human/ASCC2/ASCC2-uniprot.txt supporting_text: Interacts directly with ASCC3 - reference_id: PMID:29997253 supporting_text: most of these foci lack ASCC2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI binary interactome evidence reports protein interactions involving ASCC2, but the GO term is low-information. action: REMOVE reason: A reference interactome map does not by itself define a specific ASCC2 molecular function. Retain mechanistic functions supported by ASCC and hRQT studies instead. supported_by: - reference_id: PMID:32296183 supporting_text: A reference map of the human binary protein interactome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex 3.0 interaction evidence is useful as network context but not as a specific GO molecular function for ASCC2. action: REMOVE reason: Generic protein binding is not informative and should not be retained for proteostasis curation; ASCC2-specific function is K63-polyubiquitin-dependent adaptor/subunit activity in ASCC/RQT complexes. additional_reference_ids: - PMID:36302773 supported_by: - reference_id: PMID:33961781 supporting_text: Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948291 qualifier: located_in review: summary: Reactome places ASCC2 in cytosolic RQT binding of K63-polyubiquitinated stalled ribosomes. action: ACCEPT reason: Cytosol is an appropriate location for the RQT/ribosome quality-control role, distinct from ASCC2 nuclear DNA repair activity. additional_reference_ids: - PMID:32099016 - PMID:32579943 - PMID:36302773 supported_by: - reference_id: Reactome:R-HSA-9948291 supporting_text: The ASCC2 subunit (Narita et al. 2022) of the Activating Signal Co-integrator 1 complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948300 qualifier: located_in review: summary: Reactome places ASCC2 in cytosolic RQT-mediated splitting of stalled K63-polyubiquitinated ribosomes. action: ACCEPT reason: Cytosol is correct for the ribosome rescue/proteostasis branch of ASCC2 function. additional_reference_ids: - PMID:32099016 - PMID:32579943 - PMID:36302773 supported_by: - reference_id: Reactome:R-HSA-9948300 supporting_text: The ribosome quality control trigger (RQT) complex (ASCC2:TRIP4:ASCC3 - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:29997253 qualifier: located_in review: summary: The ASCC repair complex is recruited to nuclear foci during alkylation damage. action: ACCEPT reason: Nuclear localization is directly supported by alkylation-damage repair studies and is core to the DNA repair branch of ASCC2 function. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29144457 supporting_text: ASCC complex subunit ASCC2 also formed foci specifically after treatment with MMS - term: id: GO:0006260 label: DNA replication evidence_type: NAS original_reference_id: PMID:29997253 qualifier: involved_in review: summary: ASCC2 is involved in DNA alkylation repair, but the specific evidence does not support annotating ASCC2 to DNA replication. action: REMOVE reason: The cited ASCC1/ASCC3 alkylation-damage abstract discusses DNA damage response and repair-complex recruitment, not DNA replication by ASCC2. This appears to be a pathway overreach from repair-context complex annotation. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29997253 supporting_text: signaling pathway induced upon alkylation damage - term: id: GO:0006307 label: DNA alkylation repair evidence_type: NAS original_reference_id: PMID:29997253 qualifier: involved_in review: summary: ASCC2 participates in the ubiquitin-dependent ALKBH3-ASCC pathway for DNA alkylation repair. action: ACCEPT reason: This is a core non-proteostasis ASCC2 process. ASCC2 CUE-domain recognition of K63-linked ubiquitin recruits ASCC3/ALKBH3 repair machinery and ASCC2 loss impairs repair kinetics and MMS resistance. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29144457 supporting_text: the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci - reference_id: PMID:29144457 supporting_text: Loss of this subunit impedes alkylation adduct repair kinetics - reference_id: PMID:29997253 supporting_text: alkylation damage sensitivity in a manner epistatic with ASCC3 - term: id: GO:0032790 label: ribosome disassembly evidence_type: NAS original_reference_id: PMID:32099016 qualifier: involved_in review: summary: ASCC2 is part of the mammalian hRQT complex that promotes dissociation of stalled/collided ribosomes. action: ACCEPT reason: The cited ComplexPortal annotation is supported by direct hRQT literature showing ASCC3-ASCC2-TRIP4 complex function in RQC-triggered ribosome subunit dissociation. additional_reference_ids: - PMID:32579943 - PMID:36302773 supported_by: - reference_id: PMID:32099016 supporting_text: The hRQT complex is composed of ASCC3, ASCC2, and TRIP4 - reference_id: PMID:36302773 supporting_text: The human RQT (hRQT) complex composed only of ASCC3, ASCC2 and TRIP4 dissociates collided ribosomes - reference_id: PMID:32579943 supporting_text: disassembles the leading ribosome in an ATP-dependent reaction - reference_id: PMID:36302773 supporting_text: requires the K63-linked polyubiquitination of uS10 - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:32099016 qualifier: involved_in review: summary: ASCC2 contributes to ribosome-associated quality control that targets aberrant nascent protein products after ribosome stalling/collision. action: ACCEPT reason: This proteostasis process is appropriate because ASCC2/hRQT acts upstream of downstream nascent-chain degradation by splitting ubiquitinated collided ribosomes and enabling RQC engagement. additional_reference_ids: - PMID:32579943 - PMID:36302773 supported_by: - reference_id: PMID:32099016 supporting_text: Ribosome stalling induces quality control mechanisms for mRNA - reference_id: PMID:36302773 supporting_text: The RQC pathway monitors translation and ensures the efficient elimination of aberrant nascent protein products - term: id: GO:1990391 label: DNA repair complex evidence_type: IPI original_reference_id: PMID:29997253 qualifier: part_of review: summary: ASCC2 is part of ASCC DNA repair complexes that recruit ALKBH3/ASCC3 to alkylation-damage sites. action: ACCEPT reason: The cellular component term is appropriate for the nuclear ASCC repair role. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29144457 supporting_text: ASCC2 serves as an adaptor - reference_id: PMID:29997253 supporting_text: critical regulator of the ALKBH3-ASCC alkylation damage signaling pathway - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:29144457 qualifier: located_in review: summary: ASCC2 forms nuclear foci in response to alkylation damage. action: ACCEPT reason: Direct experimental evidence supports nuclear localization for ASCC2 in the alkylation-damage response. supported_by: - reference_id: PMID:29144457 supporting_text: ASCC complex subunit ASCC2 also formed foci specifically after treatment with MMS - term: id: GO:0016607 label: nuclear speck evidence_type: EXP original_reference_id: PMID:29144457 qualifier: located_in review: summary: ASCC2 localizes to nuclear speckle/spliceosome-associated foci in the ASCC alkylation-damage pathway. action: ACCEPT reason: The term fits the ASCC2 nuclear repair context, especially its association with spliceosome components and nuclear foci. supported_by: - reference_id: PMID:29144457 supporting_text: ASCC components co-localized with BRR2 and PRP8 upon alkylation damage - term: id: GO:0016607 label: nuclear speck evidence_type: EXP original_reference_id: PMID:29997253 qualifier: located_in review: summary: ASCC1 is present at nuclear speckle foci and regulates ASCC recruitment during alkylation damage; this supports the ASCC complex nuclear speckle context that includes ASCC2. action: ACCEPT reason: Although PMID:29997253 focuses on ASCC1, it supports ASCC complex regulation in nuclear speckles during alkylation damage, consistent with ASCC2 nuclear speckle localization. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:29997253 supporting_text: ASCC1 is present at nuclear speckle foci prior to damage - term: id: GO:0022626 label: cytosolic ribosome evidence_type: IDA original_reference_id: PMID:36302773 qualifier: is_active_in review: summary: ASCC2 acts at cytosolic ribosomes as part of hRQT-mediated collision resolution. action: ACCEPT reason: 'The is_active_in qualifier is appropriate: ASCC2 is not a structural ribosomal subunit, but it acts on K63-polyubiquitinated collided ribosomes.' additional_reference_ids: - PMID:32099016 - PMID:32579943 supported_by: - reference_id: PMID:36302773 supporting_text: hRQT-driven splitting of ribosomes collided on endogenous XBP1u and poly(A) staller mRNAs - term: id: GO:0032790 label: ribosome disassembly evidence_type: IDA original_reference_id: PMID:32579943 qualifier: involved_in review: summary: ASCC/ASC-1 complex activity disassembles collided ribosomes in mammalian RQC. action: ACCEPT reason: This is a core ASCC2 proteostasis process supported by reconstitution of ASCC-mediated disassembly of collided polysomes. additional_reference_ids: - PMID:32099016 - PMID:36302773 supported_by: - reference_id: PMID:32579943 supporting_text: ASCC acts on ubiquitinated collided ribosomes to selectively disassemble the lead ribosome - term: id: GO:0032790 label: ribosome disassembly evidence_type: IDA original_reference_id: PMID:36302773 qualifier: involved_in review: summary: hRQT containing ASCC2 dissociates collided ribosomes in a K63-polyubiquitin-dependent RQC initiation step. action: ACCEPT reason: The later biochemical/structural work directly supports ASCC2-containing hRQT-mediated ribosome subunit dissociation. additional_reference_ids: - PMID:32099016 - PMID:32579943 supported_by: - reference_id: PMID:36302773 supporting_text: dissociates collided ribosomes dependent on the ATPase activity of ASCC3 and the ubiquitin-binding capacity of ASCC2 - term: id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding evidence_type: IDA original_reference_id: PMID:36302773 qualifier: enables review: summary: ASCC2 binds K63-linked polyubiquitin marks on collided ribosomes through its ubiquitin-binding domain. action: ACCEPT reason: This is the most informative molecular-function annotation for ASCC2. It captures both the K63 linkage specificity and the modification-dependent binding mechanism used in hRQT activity. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:36302773 supporting_text: ASCC2 specifically interacts with K63-linked polyubiquitin chains - reference_id: PMID:36302773 supporting_text: mutations in the ubiquitin-binding domain of ASCC2 disrupt the hRQT activity - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: IDA original_reference_id: PMID:32579943 qualifier: involved_in review: summary: ASCC2-containing ASCC/RQT resolves stalled cytosolic ribosomes after collision-triggered ubiquitination. action: ACCEPT reason: This direct experimental annotation is PN-relevant and should be retained. It is more specific and more conservative than adding broad GO:0006515 from the PN group-level projection. additional_reference_ids: - PMID:32099016 - PMID:36302773 supported_by: - reference_id: PMID:32579943 supporting_text: Ribosomes that stall internally within an mRNA (left) are recognized and resolved - reference_id: PMID:32579943 supporting_text: ASCC then acts on the lead ribosome to liberate a 60S-peptidyl-tRNA species - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: IDA original_reference_id: PMID:36302773 qualifier: involved_in review: summary: ASCC2-containing hRQT rescues stalled cytosolic ribosomes by splitting K63-polyubiquitinated collided ribosomes. action: ACCEPT reason: This is the best existing GO process term for the PN ribosomal rescue projection and is already present in GOA. additional_reference_ids: - PMID:32099016 - PMID:32579943 supported_by: - reference_id: PMID:36302773 supporting_text: functionally marks collided mammalian ribosomes by K63-linked polyubiquitination of uS10 - reference_id: PMID:36302773 supporting_text: hRQT complex-mediated subunit dissociation - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: IMP original_reference_id: PMID:32099016 qualifier: involved_in review: summary: ASCC2/hRQT facilitates RQC after stalled-ribosome ubiquitination. action: ACCEPT reason: The IMP annotation is supported by knockdown/rescue evidence in mammalian cells and aligns with direct biochemical studies. This specific process captures the PN ribosomal rescue assignment. additional_reference_ids: - PMID:32579943 - PMID:36302773 supported_by: - reference_id: PMID:32099016 supporting_text: ASCC2 KD and TRIP4 KD partially disrupted the induction of RQC - reference_id: PMID:32099016 supporting_text: induces subunit dissociation to facilitate RQC - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:32099016 qualifier: involved_in review: summary: ASCC2 contributes to RQC-linked disposal of aberrant nascent chains by enabling the ribosome-splitting step upstream of downstream degradation. action: ACCEPT reason: The process-level annotation is appropriate as involved_in, but ASCC2 should not be inferred to be a protease or degradation enzyme. Its role is to recognize/split ubiquitinated stalled ribosomes so downstream RQC can proceed. additional_reference_ids: - PMID:36302773 supported_by: - reference_id: PMID:32099016 supporting_text: followed by proteasomal degradation of the nascent peptide - reference_id: PMID:32579943 supporting_text: liberate a 60S-peptidyl-tRNA species that is targeted by RQC - term: id: GO:0180022 label: RQC-trigger complex evidence_type: IDA original_reference_id: PMID:12077347 qualifier: part_of review: summary: ASCC2 is a subunit of the human RQT/RQC-trigger complex, although the original 2002 reference describes the broader ASC-1 complex before the RQC role was known. action: ACCEPT reason: The term is correct based on newer RQC literature. The original reference supports ASCC2/P100 as an ASC-1 complex subunit, while later studies define the ASCC2-ASCC3-TRIP4 RQC-trigger complex. additional_reference_ids: - PMID:32099016 - PMID:32579943 - PMID:36302773 supported_by: - reference_id: PMID:12077347 supporting_text: exists as a steady-state complex associated with three polypeptides, P200, P100, and P50 - reference_id: PMID:32099016 supporting_text: The hRQT complex is composed of ASCC3, ASCC2, and TRIP4 - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:12077347 qualifier: involved_in review: summary: The ASC-1 complex including ASCC2/P100 supports transactivation by AP-1, SRF, and NF-kappaB. action: KEEP_AS_NON_CORE reason: Retain as a non-core annotation. It is supported by the original ASC-1 complex paper, but ASCC2-specific curation should emphasize the more mechanistic K63-ubiquitin-dependent DNA repair and RQC functions. additional_reference_ids: - PMID:29144457 - PMID:32099016 supported_by: - reference_id: PMID:12077347 supporting_text: essential role in AP-1, SRF, and NF-kappaB transactivation - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:12077347 qualifier: located_in review: summary: The original ASC-1 complex study identified ASCC2/P100 in HeLa nuclei. action: ACCEPT reason: Nucleus is a well-supported ASCC2 location and is also supported by later alkylation-damage repair studies. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:12077347 supporting_text: P200, P100, and P50, in HeLa nuclei - reference_id: PMID:29144457 supporting_text: distinct nuclear foci specifically upon exposure of cells to alkylating agents - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:26924529 qualifier: located_in review: summary: Independent disease/complex work supports ASCC complex nuclear biology, but ASCC2-specific nuclear localization is better supported by UniProt and alkylation-damage literature. action: ACCEPT reason: Nucleus remains correct for ASCC2. The original reference primarily concerns ASC-1 complex disease biology rather than a precise ASCC2 localization assay, so this is retained with stronger supporting context from other references. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: PMID:26924529 supporting_text: Transcriptional signal cointegrators associate with transcription factors or nuclear receptors - reference_id: PMID:29144457 supporting_text: distinct nuclear foci specifically upon exposure of cells to alkylating agents - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-112123 qualifier: located_in review: summary: Reactome places ALKBH3/ASCC repair reactions in the nucleoplasm. action: ACCEPT reason: Nucleoplasm is compatible with ASCC2 participation in nuclear ASCC DNA alkylation repair events. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: Reactome:R-HSA-112123 supporting_text: The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3 - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-112124 qualifier: located_in review: summary: Reactome places ALKBH3-mediated oxidative demethylation of alkylated DNA in the nucleoplasm. action: ACCEPT reason: This location is consistent with ASCC complex recruitment to nuclear alkylation-damage foci. supported_by: - reference_id: PMID:29144457 supporting_text: relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-112125 qualifier: located_in review: summary: Reactome places ALKBH3-associated ASCC repair of ethylated DNA in the nucleoplasm. action: ACCEPT reason: This is a reasonable compartment for ASCC2 nuclear DNA alkylation repair context. supported_by: - reference_id: PMID:29144457 supporting_text: DNA alkylation damage is particularly important - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5657617 qualifier: located_in review: summary: Reactome places ASCC1:ASCC2:ASCC3-associated ALKBH3 binding to alkylated DNA in the nucleoplasm. action: ACCEPT reason: The nucleoplasm term fits the nuclear ASCC repair complex pathway. additional_reference_ids: - PMID:29144457 supported_by: - reference_id: Reactome:R-HSA-5657617 supporting_text: ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5657637 qualifier: located_in review: summary: Reactome places ASCC-associated ALKBH3 binding to 1-meA-containing alkylated DNA in the nucleoplasm. action: ACCEPT reason: Nucleoplasm is a valid location for the ASCC DNA repair role, though the process should not be generalized to DNA replication. supported_by: - reference_id: PMID:29144457 supporting_text: These foci associate with alkylated nucleotides - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5657642 qualifier: located_in review: summary: Reactome places ASCC-associated ALKBH3 binding to 1-etA-containing alkylated DNA in the nucleoplasm. action: ACCEPT reason: Nucleoplasm is appropriate for the ASCC repair branch of ASCC2 function. supported_by: - reference_id: PMID:29144457 supporting_text: upstream ubiquitin signalling in the ASCC pathway 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, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: PMID:12077347 title: Novel transcription coactivator complex containing activating signal cointegrator 1. findings: [] - id: PMID:26924529 title: Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:29144457 title: A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. findings: [] - id: PMID:29997253 title: RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage. findings: [] - id: PMID:32099016 title: Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32579943 title: The ASC-1 Complex Disassembles Collided Ribosomes. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:36302773 title: A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation. findings: [] - id: PMID:33139697 title: The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. full_text_unavailable: true findings: - statement: The ASCC2 N-terminal region forms a compact unit clasped by the ASCC3 N-terminal arms in a high-affinity, evolutionarily conserved interface, and somatic cancer mutations mapping to this interface reduce ASCC2-ASCC3 affinity, suggesting a loss-of-scaffold-coupling disease principle rather than loss of ASCC3 helicase catalysis. - id: PMID:34971705 title: The ASCC2 CUE domain in the ALKBH3-ASCC DNA repair complex recognizes adjacent ubiquitins in K63-linked polyubiquitin. full_text_unavailable: true findings: - statement: The ASCC2 CUE domain selectively binds K63-linked diubiquitin by contacting both the distal and proximal ubiquitin, and N-terminal alpha1-helix residues are required for ASCC2 recruitment to alkylation-damage sites, providing a structural basis for K63-linkage-specific ubiquitin recognition. - id: PMID:37019967 title: Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex. full_text_unavailable: true findings: - statement: TRIP4 and the DNA/RNA dealkylase ALKBH3 bind ASCC3 mutually exclusively, directing the ASCC3 motor module either to ribosome quality control or to DNA alkylation repair, while ASCC2 functions as the shared K63-polyubiquitin reader across both assemblies. - id: PMID:38366554 title: Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC. full_text_unavailable: true findings: - statement: In vitro reconstitution shows ASCC can disassemble ubiquitinated monosomes, polysome queues, and 48S complexes without obligatory ribosome collision, provided sufficiently long K63-linked ubiquitin chains and at least ~30-35 nucleotides of 3' mRNA downstream of the P site are present. - id: PMID:39661518 title: 'Ubiquitin-dependent translation control mechanisms: Degradation and beyond.' full_text_unavailable: true findings: - statement: This review summarizes that K63-linked ubiquitination of uS10/eS10 recruits the ASC-1/RQT complex via ASCC2 ubiquitin binding to drive ribosome splitting, and notes context-dependence between strong in vitro requirement and partial in vivo dispensability of ASCC2 ubiquitin recognition. - id: PMID:36902118 title: DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways. full_text_unavailable: true findings: - statement: This review places the ubiquitin-binding ASCC subunit ASCC2 as the factor that recruits the ASCC machinery to transcription-linked alkylation lesions, enabling ASCC3-driven unwinding to generate single-stranded DNA for ALKBH3 access. - id: Reactome:R-HSA-112123 title: Oxidative demethylation of 1-meA damaged DNA By ALKBH3 findings: [] - id: Reactome:R-HSA-112124 title: Oxidative demethylation of 3-meC damaged DNA By ALKBH3 findings: [] - id: Reactome:R-HSA-112125 title: Oxidative dealkylation of 1-EtA damaged DNA by ABH3 findings: [] - id: Reactome:R-HSA-5657617 title: ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing 3-meC findings: [] - id: Reactome:R-HSA-5657637 title: ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing 1-meA findings: [] - id: Reactome:R-HSA-5657642 title: ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing 1-etA findings: [] - id: Reactome:R-HSA-9948291 title: RQT complex binds K63polyUb-80S ribosome:no-go mRNA:peptidyl-tRNA with nascent peptide findings: [] - id: Reactome:R-HSA-9948300 title: RQT complex:K63polyUb-80S ribosome dissociates yielding K63polyUb-40S subunit and 60S subunit:peptidyl-tRNA with nascent peptide findings: [] - id: file:human/ASCC2/ASCC2-uniprot.txt title: UniProtKB record for human ASCC2 findings: [] - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv title: Proteostasis PN projected annotations report findings: - statement: ASCC2 is projected to GO:0072344 as already present and to GO:0006515 as a candidate new-to-GOA group-level RQC annotation. supporting_text: "ASCC2\t\tTranslation|Cytosolic translation|Ribosome-associated QC|Ribosomal\ \ rescue" aliases: - ASC1P100 - RQT3 tags: - proteostasis_pn - ribosome_quality_control core_functions: - description: K63-linked polyubiquitin-dependent adaptor/subunit function in the nuclear ASCC DNA alkylation repair pathway. molecular_function: id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding directly_involved_in: - id: GO:0006307 label: DNA alkylation repair locations: - id: GO:0005634 label: nucleus - id: GO:0016607 label: nuclear speck in_complex: id: GO:1990391 label: DNA repair complex supported_by: - reference_id: PMID:29144457 supporting_text: Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE - reference_id: PMID:29144457 supporting_text: Loss of this subunit impedes alkylation adduct repair kinetics - description: K63-polyubiquitin-dependent hRQT/RQC-trigger complex role in resolving collided or stalled cytosolic ribosomes. molecular_function: id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding directly_involved_in: - id: GO:0072344 label: rescue of stalled cytosolic ribosome - id: GO:0032790 label: ribosome disassembly - id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process locations: - id: GO:0005829 label: cytosol - id: GO:0022626 label: cytosolic ribosome in_complex: id: GO:0180022 label: RQC-trigger complex supported_by: - reference_id: PMID:36302773 supporting_text: ASCC2 specifically interacts with K63-linked polyubiquitin chains - reference_id: PMID:36302773 supporting_text: The hRQT-mediated subunit dissociation requires the K63-linked polyubiquitination of uS10 - reference_id: PMID:32579943 supporting_text: ASCC then acts on the lead ribosome to liberate a 60S-peptidyl-tRNA species proposed_new_terms: [] suggested_questions: - question: For PN projection review, should ASCC2 be excluded from a new GO:0006515 protein quality-control annotation when GO:0072344 and GO:1990116 already capture its specific RQT/RQC role? experts: - Hashimoto S - Juszkiewicz S - Narita M - Inada T - question: Is ASCC2 CUE-domain ubiquitin binding mechanistically required for mammalian hRQT activity under endogenous cellular conditions, given differences between 2020 and 2022 studies? experts: - Juszkiewicz S - Narita M - Inada T suggested_experiments: - hypothesis: ASCC2 CUE-domain K63-polyubiquitin binding is conditionally required for hRQT function at endogenous stalled-ribosome substrates. description: Compare endogenous disome resolution, uS10 K63-polyubiquitin binding, and downstream RQC engagement in ASCC2 knockout cells rescued with wild-type versus CUE-domain mutant ASCC2 under XBP1u, poly(A), and stress-induced endogenous stalling conditions. experiment_type: cellular rescue and ribosome profiling - hypothesis: The broad PN projection to GO:0006515 is redundant for ASCC2 when specific RQC rescue terms are present. description: Audit ASCC2 together with ASCC3/TRIP4 and representative PELO/HBS1L genes against GO closure to determine whether GO:0072344 and GO:1990116 sufficiently represent the RQC proteostasis role without adding a broad protein quality-control annotation. experiment_type: curation audit