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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006355 regulation of DNA-templated transcription | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:12077347 essential role in AP-1, SRF, and NF-kappaB transactivation |
| GO:0043130 ubiquitin binding | IBA GO_REF:0000033 | MODIFY | Summary: ASCC2 is a ubiquitin-binding CUE-domain protein, but the supported specificity is K63-linked polyubiquitin rather than generic ubiquitin binding. 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 replacements: K63-linked polyubiquitin modification-dependent protein binding Supporting Evidence: PMID:29144457 bound K63- but not K48-linked ubiquitin chains PMID:36302773 ASCC2 specifically interacts with K63-linked polyubiquitin chains |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization is supported by UniProt curation and by ASCC2/ASCC complex recruitment to nuclear foci during alkylation damage. Reason: The nucleus is a correct cellular location for the DNA alkylation repair branch of ASCC2 function. Supporting Evidence: PMID:29144457 the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci |
| GO:0016607 nuclear speck | IEA GO_REF:0000044 | ACCEPT | Summary: ASCC2/ASCC components localize to nuclear speckle-associated foci and spliceosome-rich nuclear regions in alkylation damage studies. Reason: Nuclear speckle localization is supported for the nuclear ASCC repair context, where ASCC foci overlap spliceosome components and elongating RNA polymerase II. Supporting Evidence: PMID:29144457 ASCC2 also associated with many spliceosome components and basal transcription factors |
| GO:0043130 ubiquitin binding | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-derived ubiquitin-binding annotation is directionally correct but too broad for ASCC2. 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 replacements: K63-linked polyubiquitin modification-dependent protein binding Supporting Evidence: PMID:29144457 bound K63- but not K48-linked ubiquitin chains PMID:36302773 ASCC2 specifically interacts with K63-linked polyubiquitin chains |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: BioPlex AP-MS reports ASCC2 co-associations, but generic protein binding does not describe ASCC2 molecular function. 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. Supporting Evidence: PMID:28514442 uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks |
| GO:0005515 protein binding | IPI PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | MARK AS OVER ANNOTATED | Summary: ASCC2 interaction with ASCC3 is biologically meaningful for ASCC/RQT complexes, but GO:0005515 is too generic to retain as function. 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. Supporting Evidence: file:human/ASCC2/ASCC2-uniprot.txt Interacts directly with ASCC3 PMID:29997253 most of these foci lack ASCC2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI binary interactome evidence reports protein interactions involving ASCC2, but the GO term is low-information. 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. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex 3.0 interaction evidence is useful as network context but not as a specific GO molecular function for ASCC2. 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. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948291 | ACCEPT | Summary: Reactome places ASCC2 in cytosolic RQT binding of K63-polyubiquitinated stalled ribosomes. Reason: Cytosol is an appropriate location for the RQT/ribosome quality-control role, distinct from ASCC2 nuclear DNA repair activity. Supporting Evidence: Reactome:R-HSA-9948291 The ASCC2 subunit (Narita et al. 2022) of the Activating Signal Co-integrator 1 complex |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948300 | ACCEPT | Summary: Reactome places ASCC2 in cytosolic RQT-mediated splitting of stalled K63-polyubiquitinated ribosomes. Reason: Cytosol is correct for the ribosome rescue/proteostasis branch of ASCC2 function. Supporting Evidence: Reactome:R-HSA-9948300 The ribosome quality control trigger (RQT) complex (ASCC2:TRIP4:ASCC3 |
| GO:0005634 nucleus | IDA PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | ACCEPT | Summary: The ASCC repair complex is recruited to nuclear foci during alkylation damage. Reason: Nuclear localization is directly supported by alkylation-damage repair studies and is core to the DNA repair branch of ASCC2 function. Supporting Evidence: PMID:29144457 ASCC complex subunit ASCC2 also formed foci specifically after treatment with MMS |
| GO:0006260 DNA replication | NAS PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | REMOVE | Summary: ASCC2 is involved in DNA alkylation repair, but the specific evidence does not support annotating ASCC2 to DNA replication. 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. Supporting Evidence: PMID:29997253 signaling pathway induced upon alkylation damage |
| GO:0006307 DNA alkylation repair | NAS PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | ACCEPT | Summary: ASCC2 participates in the ubiquitin-dependent ALKBH3-ASCC pathway for DNA alkylation repair. 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. Supporting Evidence: PMID:29144457 the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci PMID:29144457 Loss of this subunit impedes alkylation adduct repair kinetics PMID:29997253 alkylation damage sensitivity in a manner epistatic with ASCC3 |
| GO:0032790 ribosome disassembly | NAS PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: ASCC2 is part of the mammalian hRQT complex that promotes dissociation of stalled/collided ribosomes. Reason: The cited ComplexPortal annotation is supported by direct hRQT literature showing ASCC3-ASCC2-TRIP4 complex function in RQC-triggered ribosome subunit dissociation. Supporting Evidence: PMID:32099016 The hRQT complex is composed of ASCC3, ASCC2, and TRIP4 PMID:36302773 The human RQT (hRQT) complex composed only of ASCC3, ASCC2 and TRIP4 dissociates collided ribosomes PMID:32579943 disassembles the leading ribosome in an ATP-dependent reaction PMID:36302773 requires the K63-linked polyubiquitination of uS10 |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | NAS PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: ASCC2 contributes to ribosome-associated quality control that targets aberrant nascent protein products after ribosome stalling/collision. 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. Supporting Evidence: PMID:32099016 Ribosome stalling induces quality control mechanisms for mRNA PMID:36302773 The RQC pathway monitors translation and ensures the efficient elimination of aberrant nascent protein products |
| GO:1990391 DNA repair complex | IPI PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | ACCEPT | Summary: ASCC2 is part of ASCC DNA repair complexes that recruit ALKBH3/ASCC3 to alkylation-damage sites. Reason: The cellular component term is appropriate for the nuclear ASCC repair role. Supporting Evidence: PMID:29144457 ASCC2 serves as an adaptor PMID:29997253 critical regulator of the ALKBH3-ASCC alkylation damage signaling pathway |
| GO:0005634 nucleus | EXP PMID:29144457 A ubiquitin-dependent signalling axis specific for ALKBH-med... | ACCEPT | Summary: ASCC2 forms nuclear foci in response to alkylation damage. Reason: Direct experimental evidence supports nuclear localization for ASCC2 in the alkylation-damage response. Supporting Evidence: PMID:29144457 ASCC complex subunit ASCC2 also formed foci specifically after treatment with MMS |
| GO:0016607 nuclear speck | EXP PMID:29144457 A ubiquitin-dependent signalling axis specific for ALKBH-med... | ACCEPT | Summary: ASCC2 localizes to nuclear speckle/spliceosome-associated foci in the ASCC alkylation-damage pathway. Reason: The term fits the ASCC2 nuclear repair context, especially its association with spliceosome components and nuclear foci. Supporting Evidence: PMID:29144457 ASCC components co-localized with BRR2 and PRP8 upon alkylation damage |
| GO:0016607 nuclear speck | EXP PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c... | ACCEPT | 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. Reason: Although PMID:29997253 focuses on ASCC1, it supports ASCC complex regulation in nuclear speckles during alkylation damage, consistent with ASCC2 nuclear speckle localization. Supporting Evidence: PMID:29997253 ASCC1 is present at nuclear speckle foci prior to damage |
| GO:0022626 cytosolic ribosome | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ASCC2 acts at cytosolic ribosomes as part of hRQT-mediated collision resolution. Reason: The is_active_in qualifier is appropriate: ASCC2 is not a structural ribosomal subunit, but it acts on K63-polyubiquitinated collided ribosomes. Supporting Evidence: PMID:36302773 hRQT-driven splitting of ribosomes collided on endogenous XBP1u and poly(A) staller mRNAs |
| GO:0032790 ribosome disassembly | IDA PMID:32579943 The ASC-1 Complex Disassembles Collided Ribosomes. | ACCEPT | Summary: ASCC/ASC-1 complex activity disassembles collided ribosomes in mammalian RQC. Reason: This is a core ASCC2 proteostasis process supported by reconstitution of ASCC-mediated disassembly of collided polysomes. Supporting Evidence: PMID:32579943 ASCC acts on ubiquitinated collided ribosomes to selectively disassemble the lead ribosome |
| GO:0032790 ribosome disassembly | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: hRQT containing ASCC2 dissociates collided ribosomes in a K63-polyubiquitin-dependent RQC initiation step. Reason: The later biochemical/structural work directly supports ASCC2-containing hRQT-mediated ribosome subunit dissociation. Supporting Evidence: PMID:36302773 dissociates collided ribosomes dependent on the ATPase activity of ASCC3 and the ubiquitin-binding capacity of ASCC2 |
| GO:0070530 K63-linked polyubiquitin modification-dependent protein binding | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ASCC2 binds K63-linked polyubiquitin marks on collided ribosomes through its ubiquitin-binding domain. 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. Supporting Evidence: PMID:36302773 ASCC2 specifically interacts with K63-linked polyubiquitin chains PMID:36302773 mutations in the ubiquitin-binding domain of ASCC2 disrupt the hRQT activity |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:32579943 The ASC-1 Complex Disassembles Collided Ribosomes. | ACCEPT | Summary: ASCC2-containing ASCC/RQT resolves stalled cytosolic ribosomes after collision-triggered ubiquitination. 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. Supporting Evidence: PMID:32579943 Ribosomes that stall internally within an mRNA (left) are recognized and resolved PMID:32579943 ASCC then acts on the lead ribosome to liberate a 60S-peptidyl-tRNA species |
| GO:0072344 rescue of stalled cytosolic ribosome | IDA PMID:36302773 A distinct mammalian disome collision interface harbors K63-... | ACCEPT | Summary: ASCC2-containing hRQT rescues stalled cytosolic ribosomes by splitting K63-polyubiquitinated collided ribosomes. Reason: This is the best existing GO process term for the PN ribosomal rescue projection and is already present in GOA. Supporting Evidence: PMID:36302773 functionally marks collided mammalian ribosomes by K63-linked polyubiquitination of uS10 PMID:36302773 hRQT complex-mediated subunit dissociation |
| GO:0072344 rescue of stalled cytosolic ribosome | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: ASCC2/hRQT facilitates RQC after stalled-ribosome ubiquitination. 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. Supporting Evidence: PMID:32099016 ASCC2 KD and TRIP4 KD partially disrupted the induction of RQC PMID:32099016 induces subunit dissociation to facilitate RQC |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IMP PMID:32099016 Identification of a novel trigger complex that facilitates r... | ACCEPT | Summary: ASCC2 contributes to RQC-linked disposal of aberrant nascent chains by enabling the ribosome-splitting step upstream of downstream degradation. 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. Supporting Evidence: PMID:32099016 followed by proteasomal degradation of the nascent peptide PMID:32579943 liberate a 60S-peptidyl-tRNA species that is targeted by RQC |
| GO:0180022 RQC-trigger complex | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | ACCEPT | 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. 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. Supporting Evidence: PMID:12077347 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50 PMID:32099016 The hRQT complex is composed of ASCC3, ASCC2, and TRIP4 |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | KEEP AS NON CORE | Summary: The ASC-1 complex including ASCC2/P100 supports transactivation by AP-1, SRF, and NF-kappaB. 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. Supporting Evidence: PMID:12077347 essential role in AP-1, SRF, and NF-kappaB transactivation |
| GO:0005634 nucleus | IDA PMID:12077347 Novel transcription coactivator complex containing activatin... | ACCEPT | Summary: The original ASC-1 complex study identified ASCC2/P100 in HeLa nuclei. Reason: Nucleus is a well-supported ASCC2 location and is also supported by later alkylation-damage repair studies. Supporting Evidence: PMID:12077347 P200, P100, and P50, in HeLa nuclei PMID:29144457 distinct nuclear foci specifically upon exposure of cells to alkylating agents |
| GO:0005634 nucleus | IDA PMID:26924529 Mutations in Subunits of the Activating Signal Cointegrator ... | ACCEPT | Summary: Independent disease/complex work supports ASCC complex nuclear biology, but ASCC2-specific nuclear localization is better supported by UniProt and alkylation-damage literature. 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. Supporting Evidence: PMID:26924529 Transcriptional signal cointegrators associate with transcription factors or nuclear receptors PMID:29144457 distinct nuclear foci specifically upon exposure of cells to alkylating agents |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-112123 | ACCEPT | Summary: Reactome places ALKBH3/ASCC repair reactions in the nucleoplasm. Reason: Nucleoplasm is compatible with ASCC2 participation in nuclear ASCC DNA alkylation repair events. Supporting Evidence: Reactome:R-HSA-112123 The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-112124 | ACCEPT | Summary: Reactome places ALKBH3-mediated oxidative demethylation of alkylated DNA in the nucleoplasm. Reason: This location is consistent with ASCC complex recruitment to nuclear alkylation-damage foci. Supporting Evidence: PMID:29144457 relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-112125 | ACCEPT | Summary: Reactome places ALKBH3-associated ASCC repair of ethylated DNA in the nucleoplasm. Reason: This is a reasonable compartment for ASCC2 nuclear DNA alkylation repair context. Supporting Evidence: PMID:29144457 DNA alkylation damage is particularly important |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5657617 | ACCEPT | Summary: Reactome places ASCC1:ASCC2:ASCC3-associated ALKBH3 binding to alkylated DNA in the nucleoplasm. Reason: The nucleoplasm term fits the nuclear ASCC repair complex pathway. Supporting Evidence: Reactome:R-HSA-5657617 ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5657637 | ACCEPT | Summary: Reactome places ASCC-associated ALKBH3 binding to 1-meA-containing alkylated DNA in the nucleoplasm. Reason: Nucleoplasm is a valid location for the ASCC DNA repair role, though the process should not be generalized to DNA replication. Supporting Evidence: PMID:29144457 These foci associate with alkylated nucleotides |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5657642 | ACCEPT | Summary: Reactome places ASCC-associated ALKBH3 binding to 1-etA-containing alkylated DNA in the nucleoplasm. Reason: Nucleoplasm is appropriate for the ASCC repair branch of ASCC2 function. Supporting Evidence: PMID:29144457 upstream ubiquitin signalling in the ASCC pathway |
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Download this section (compressed HTML)Q: 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?
Suggested experts: Hashimoto S, Juszkiewicz S, Narita M, Inada T
Q: Is ASCC2 CUE-domain ubiquitin binding mechanistically required for mammalian hRQT activity under endogenous cellular conditions, given differences between 2020 and 2022 studies?
Suggested experts: Juszkiewicz S, Narita M, Inada T
Experiment: 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.
Hypothesis: ASCC2 CUE-domain K63-polyubiquitin binding is conditionally required for hRQT function at endogenous stalled-ribosome substrates.
Type: cellular rescue and ribosome profiling
Experiment: 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.
Hypothesis: The broad PN projection to GO:0006515 is redundant for ASCC2 when specific RQC rescue terms are present.
Type: curation audit
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