Existing Annotations Review

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

Core Functions

K63-linked polyubiquitin-dependent adaptor/subunit function in the nuclear ASCC DNA alkylation repair pathway.

Molecular Function:

K63-linked polyubiquitin modification-dependent protein binding

Directly Involved In:

DNA alkylation repair

Cellular Locations:

nucleus nuclear speck

In Complex:

DNA repair complex

Supporting Evidence:

PMID:29144457
Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE
PMID:29144457
Loss of this subunit impedes alkylation adduct repair kinetics

K63-polyubiquitin-dependent hRQT/RQC-trigger complex role in resolving collided or stalled cytosolic ribosomes.

Molecular Function:

K63-linked polyubiquitin modification-dependent protein binding

Directly Involved In:

rescue of stalled cytosolic ribosome ribosome disassembly ribosome-associated ubiquitin-dependent protein catabolic process

Cellular Locations:

cytosol cytosolic ribosome

In Complex:

RQC-trigger complex

Supporting Evidence:

PMID:36302773
ASCC2 specifically interacts with K63-linked polyubiquitin chains
PMID:36302773
The hRQT-mediated subunit dissociation requires the K63-linked polyubiquitination of uS10
PMID:32579943
ASCC then acts on the lead ribosome to liberate a 60S-peptidyl-tRNA species

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:12077347

Novel transcription coactivator complex containing activating signal cointegrator 1.

PMID:26924529

Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29144457

A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair.

PMID:29997253

RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage.

PMID:32099016

Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32579943

The ASC-1 Complex Disassembles Collided Ribosomes.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:36302773

A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation.

PMID:33139697

The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations.

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.

PMID:34971705

The ASCC2 CUE domain in the ALKBH3-ASCC DNA repair complex recognizes adjacent ubiquitins in K63-linked polyubiquitin.

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.

PMID:37019967

Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.

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.

PMID:38366554

Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC.

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.

PMID:39661518

Ubiquitin-dependent translation control mechanisms: Degradation and beyond.

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.

PMID:36902118

DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways.

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.

Reactome:R-HSA-112123

Oxidative demethylation of 1-meA damaged DNA By ALKBH3

Reactome:R-HSA-112124

Oxidative demethylation of 3-meC damaged DNA By ALKBH3

Reactome:R-HSA-112125

Oxidative dealkylation of 1-EtA damaged DNA by ABH3

Reactome:R-HSA-5657617

ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing 3-meC

Reactome:R-HSA-5657637

ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing 1-meA

Reactome:R-HSA-5657642

ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing 1-etA

Reactome:R-HSA-9948291

RQT complex binds K63polyUb-80S ribosome:no-go mRNA:peptidyl-tRNA with nascent peptide

Reactome:R-HSA-9948300

RQT complex:K63polyUb-80S ribosome dissociates yielding K63polyUb-40S subunit and 60S subunit:peptidyl-tRNA with nascent peptide

file:human/ASCC2/ASCC2-uniprot.txt

UniProtKB record for human ASCC2

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv

Proteostasis PN projected annotations report

ASCC2 is projected to GO:0072344 as already present and to GO:0006515 as a candidate new-to-GOA group-level RQC annotation.

"ASCC2 Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue"

Suggested Experiments

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

Deep Research

Falcon

(ASCC2-deep-research-falcon.md)

Research Report: Human **ASCC2** (UniProt **Q9H1I8**) Functional Annotation Falcon Edison Scientific Literature 52 citations 1 artifacts 2026-06-07T04:49:31.215719

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human ASCC2 (UniProt Q9H1I8) Functional Annotation

0. Target verification (critical disambiguation)

The requested target is human ASCC2 (UniProt Q9H1I8), annotated as Activating Signal Cointegrator 1 Complex Subunit 2 (also called ASC-1 complex subunit p100; gene symbol ASCC2, synonym RQT3) and characterized by a CUE ubiquitin-binding domain and participation in the ASCC/ASC-1 complex and the ribosome quality control trigger (hRQT/RQT) module. This identity (name, organism, and domain/function context) is consistently matched by peer‑reviewed primary literature on the ASCC complex in DNA alkylation repair and ribosome-associated quality control (RQC). (lombardi2022theascc2cue pages 1-2, jia2020theinteractionof pages 4-5, hashimoto2020identificationofa pages 1-2)

1. Key concepts and definitions (current understanding)

1.1 ASCC/ASC-1 complex and ASCC2’s role

ASCC (Activating Signal Co‑integrator Complex; sometimes discussed with the older “ASC-1” terminology) is a multi‑subunit assembly involved in multiple nucleic-acid–linked stress responses. ASCC2 functions as a ubiquitin-sensing adaptor within ASCC, coupling K63‑linked ubiquitin signaling to downstream actions of the ASCC motor subunit ASCC3 (a Ski2-like helicase) and, in DNA repair contexts, to the dioxygenase ALKBH3. (soll2018rnaligaselikedomain pages 1-2, fahrer2023dnaalkylationdamage pages 12-14)

A key organizing principle is that ASCC2 binds ASCC3 with very high affinity, enabling ASCC2’s ubiquitin recognition to be physically transmitted to an ASCC3-driven remodeling activity (DNA unwinding or ribosome splitting, depending on context). (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4)

1.2 CUE domain and linkage specificity (ubiquitin recognition)

ASCC2 contains a CUE domain (≈50 aa, a three‑helix bundle) that binds ubiquitin. Detailed structural/biophysical work shows ASCC2’s CUE domain has strong preference for K63‑linked diubiquitin (K63Ub2) over monoubiquitin, K48Ub2, or linear (M1) diubiquitin, and achieves linkage preference by contacting both distal and proximal ubiquitin moieties in K63Ub2. (lombardi2022theascc2cue pages 1-2, lombardi2022theascc2cue pages 2-4)

Mechanistically, conserved hydrophobic motifs (including L479 and L506) contribute to canonical ubiquitin binding, while an additional interaction surface in the N‑terminal part of helix α1 (including E467 and S470) strengthens K63Ub2 binding and is important for cellular recruitment to alkylation‑damage foci. (lombardi2022theascc2cue pages 4-7, lombardi2022theascc2cue pages 2-4)

1.3 hRQT/ASC-1 in ribosome-associated quality control (RQC)

In mammalian RQC, stalled ribosomes are marked by ZNF598‑dependent ubiquitination of small‑subunit ribosomal proteins (notably uS10/eS10). The ASC-1/ASCC machinery then promotes ribosome dissociation (splitting). In this context, ASCC2 acts as a key ubiquitin recognition component that helps recruit/activate the ASCC splitting machinery on ubiquitinated ribosomes. (ford2024ubiquitindependenttranslationcontrol pages 4-6, hashimoto2020identificationofa pages 5-7)

2. Molecular function, biological processes, and pathways

2.1 DNA alkylation damage response: ubiquitin-directed recruitment of ALKBH3–ASCC

Pathway concept

Alkylating agents create cytotoxic N‑alkyl lesions such as N1‑methyladenine (N1‑MeA) and N3‑methylcytosine (N3‑MeC) that can be repaired by AlkB family dioxygenases. ALKBH3 acts preferentially on single‑stranded nucleic acid substrates, creating a mechanistic requirement for an unwind/ssDNA‑generating activity. The ASCC helicase ASCC3 supplies this activity, while ASCC2 provides ubiquitin-based targeting. (fahrer2023dnaalkylationdamage pages 12-14, jia2020theinteractionof pages 1-2)

ASCC2’s specific role

Primary studies support a model in which RNF113A-dependent K63-linked ubiquitin signaling recruits ASCC2 (via its CUE domain) to alkylation-damage foci, and ASCC2 is required for robust recruitment of ASCC3 and ALKBH3 to these nuclear foci. Loss of ASCC2 increases sensitivity to alkylating agents, consistent with a functional requirement in damage tolerance/repair. (soll2018rnaligaselikedomain pages 1-2, brickner2019activationandregulation pages 139-144)

A 2023 review of alkylation damage repair explicitly places ASCC2 as the ubiquitin-binding ASCC subunit that mediates recruitment of the ASCC machinery to transcription-linked alkylation lesions and enables ASCC3-driven unwinding to generate ssDNA for ALKBH3 access. (fahrer2023dnaalkylationdamage pages 12-14)

Domain/function evidence (mechanistic)

The ASCC2 CUE domain recognizes adjacent ubiquitins in K63Ub2, providing a plausible biochemical basis for preferential recruitment to K63-polyubiquitinated damage-associated substrates. Mutations in the α1 helix interface (e.g., E467R/S470R) reduce recruitment of ASCC2 to alkylation-damage foci in cells, functionally linking K63Ub2 binding to nuclear targeting. (lombardi2022theascc2cue pages 4-7)

ASCC2–ASCC3 interface: transmitting the ubiquitin signal to a motor

ASCC2’s N-terminal region (residues 1–434) forms the principal ASCC3-binding module and is clasped by the ASCC3 N-terminal arms. Specific conserved ASCC3 residues (e.g., R5, R11) form salt bridges/hydrogen bonds with ASCC2 acidic residues, explaining the strong and evolutionarily conserved interaction. (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4)

2.2 Ribosome-associated quality control (RQC): ubiquitin-directed ribosome splitting

Core concept

In mammalian RQC, ZNF598 marks stalled ribosomal complexes by polyubiquitinating uS10/eS10 (often K63-linked). The ASCC machinery then splits ribosomes to enable downstream processing such as nascent-chain ubiquitination. (miscicka2024ribosomalcollisionis pages 1-1, ford2024ubiquitindependenttranslationcontrol pages 4-6)

ASCC2’s specific role

Hashimoto et al. identify a mammalian hRQT complex composed of ASCC3, ASCC2, and TRIP4 and provide functional evidence that ASCC2’s ubiquitin-binding activity is crucial for RQC induction (with partial phenotypes upon knockdown/mutation), consistent with ASCC2 acting as an ubiquitin-dependent recognition factor upstream of ASCC3 motor action. (hashimoto2020identificationofa pages 1-2, hashimoto2020identificationofa pages 3-5)

A 2024 expert review summarizes a key mechanistic consensus: ubiquitin on uS10/eS10 recruits ASC-1/RQT via ASCC2 ubiquitin binding, and ubiquitin-binding–deficient ASCC2 fails to support splitting in vitro, even if in vivo results differ across systems (partial dispensability in some cellular assays). (ford2024ubiquitindependenttranslationcontrol pages 4-6, ford2024ubiquitindependenttranslationcontrol pages 2-4)

Recent mechanistic advance (2024): collision independence and quantitative constraints

Miścicka et al. (2024) provide an in vitro reconstitution perspective showing that ribosome collision is not strictly required for ZNF598-mediated ubiquitination or for ASCC-mediated disassembly. Instead, ASCC can split a broad range of complexes—including stalled polysomal queues, monosomes, and even ubiquitinated 48S initiation complexes—provided two core conditions are met:

The ribosomal complex has a ≥30–35 nt 3′ mRNA region downstream of the P site (a quantitative constraint consistent with an mRNA-pulling mechanism). (miscicka2024ribosomalcollisionis pages 1-1, miscicka2024ribosomalcollisionis pages 12-13)
The ribosome bears sufficiently long ubiquitin chains, typically produced by ZNF598 on uS10/eS10 (with western annotations including species like Ub3–5~uS10 and Ub1–5~eS10). (miscicka2024ribosomalcollisionis pages 11-11, miscicka2024ribosomalcollisionis pages 1-1)

Additionally, ZNF598-generated ubiquitination is quantitatively characterized in stalled polysomes: with WT/K63-only ubiquitin, ZNF598 produces near-complete polyubiquitination of eS10 and about ~90% polyubiquitination of uS10, whereas K63R ubiquitin yields only 1–4 ubiquitin attachments, and splitting efficiency correspondingly decreases. (miscicka2024ribosomalcollisionis pages 6-7, miscicka2024ribosomalcollisionis pages 8-9)

3. Subcellular localization and where ASCC2 acts

ASCC2 participates in both nuclear and cytoplasmic pathways:

Nuclear (DNA alkylation response): ASCC2 forms nuclear foci after alkylation damage and co-localizes with K63 ubiquitin signals and DNA-repair module components; recruitment depends on ubiquitin binding by ASCC2. (brickner2019activationandregulation pages 139-144, lombardi2022theascc2cue pages 4-7)
Cytoplasmic/ribosome-associated (RQC): ASCC2 functions within the hRQT/ASCC ribosome splitting machinery (ASCC3–ASCC2–TRIP4), acting on ubiquitinated stalled translation complexes. (hashimoto2020identificationofa pages 1-2, miscicka2024ribosomalcollisionis pages 1-1)

These dual roles are consistent with ASCC2 operating as a shared ubiquitin-sensing module that targets the same ASCC3 motor core to distinct substrates (damaged transcription-associated nucleic acids vs ubiquitinated ribosomes). (jia2023extendeddnathreading pages 2-3)

4. Recent developments and latest research (prioritizing 2023–2024)

4.1 2023: complex modularity and mutually exclusive ASCC3 assemblies

Jia et al. (2023) emphasize that ASCC3 can form distinct functional sub-complexes: TRIP4 and ALKBH3 bind ASCC3 mutually exclusively, supporting a model where ASCC3 is directed to either RQC-related functions (TRIP4-containing RQT complex) or DNA alkylation repair (ALKBH3-containing repair complex). ASCC2 is present in both the canonical ASCC and the RQT complex and is explicitly described as containing a K63-linked ubiquitin chain-binding CUE domain, aligning ASCC2’s biochemical specialization with pathway selection by ubiquitin signals. (jia2023extendeddnathreading pages 2-3)

4.2 2024: reconstitution-level rules for ASCC-mediated splitting + expert synthesis

The Miścicka et al. (2024) study provides experimentally defined rules (mRNA length and ubiquitin-chain requirements) that sharpen the mechanistic understanding of how ASCC (and, by extension, ASCC2’s ubiquitin recognition) triggers ribosome splitting across multiple ribosomal states. (miscicka2024ribosomalcollisionis pages 1-1, miscicka2024ribosomalcollisionis pages 12-13)

Ford et al. (2024) then integrate these mechanistic insights into a broader framework of ubiquitin-dependent translation control, including the role of ASCC2’s CUE domain in recruiting the splitting machinery to ubiquitylated uS10/eS10. (ford2024ubiquitindependenttranslationcontrol pages 4-6)

5. Applications and real-world implementations

5.1 DNA repair context: potential relevance to alkylating chemotherapy

Because ASCC2 is required for effective recruitment of ALKBH3–ASCC to alkylation lesions and alkylation tolerance, ASCC2 (and especially the ASCC2–ASCC3 interface and CUE domain) is conceptually relevant to cancer cell responses to alkylating DNA damage (including clinically used alkylating agents). Mechanistic cancer-mutation studies explicitly connect reduced ASCC2–ASCC3 affinity to a plausible weakening of alkylation repair at nuclear foci. (jia2020theinteractionof pages 9-10, soll2018rnaligaselikedomain pages 1-2)

However, direct clinical implementation (e.g., validated ASCC2 biomarker assays in routine care) was not demonstrated in the retrieved primary sources.

ASCC2’s participation in RQC suggests a role in proteostasis and stress responses, which is frequently implicated in neurodegeneration. OpenTargets reports ASCC2 associations with neurodegenerative disease and diabetes traits largely through GWAS credible sets and a neuronal CRISPRi screen implicating lipid peroxidation phenotypes, but these represent hypothesis-generating associations rather than established clinical use. (OpenTargets Search: -ASCC2)

5.3 Cancer omics: prognostic associations and pathway-level biomarkers

A pan-cancer analysis across 10,967 tumors reports ASCC2 altered in ~1.8% of patients, with certain tumor-type enrichments (e.g., endometrial cancer >5%), and notes survival associations (e.g., ACC OS p=0.016; DFS associations in ACC/STAD/THYM). The same study also reports tumor-specific ASCC2 phosphorylation changes (e.g., T157 hyperphosphorylation across multiple tumors), which could be explored as biomarkers, although causal mechanisms remain unclear. (pan2025pancanceranalysisreveals pages 2-3, pan2025pancanceranalysisreveals pages 3-5)

A prostate cancer ceRNA study proposes that ASCC2 can sit downstream of an lncRNA/miRNA axis (TCONS_00027385/miR-874-5p/ASCC2) affecting proliferation and apoptosis, implying possible biomarker/target hypotheses in that cancer type; this evidence is preprint-level and should be treated cautiously. (han2021longnoncodingrna pages 1-5)

6. Expert opinions and analysis (authoritative synthesis)

6.1 Mechanistic consensus: ASCC2 as a ubiquitin reader coupling K63-Ub to motor action

Across DNA repair and RQC contexts, the strongest mechanistic consensus is that ASCC2’s primary biochemical specialization is ubiquitin binding with K63 linkage preference, positioning ASCC2 as the “reader” that couples a K63-ubiquitin signal to deployment of the ASCC3 motor (DNA unwinding or ribosome splitting). This is supported by direct CUE-domain binding biophysics and by functional recruitment phenotypes, and reiterated by recent review synthesis in the RQC field. (lombardi2022theascc2cue pages 2-4, ford2024ubiquitindependenttranslationcontrol pages 4-6)

6.2 Interface mutations as a disease mechanism principle

The ASCC2–ASCC3 interface is exceptionally tight (nanomolar) and structurally conserved; cancer-associated substitutions that weaken this interface are proposed to disrupt proper localization at nuclear damage foci (without necessarily changing ASCC3’s intrinsic helicase activity), providing a concrete “molecular disease principle” (loss of scaffold coupling rather than catalytic inactivity). (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 9-10)

6.3 Reconciling in vivo vs in vitro requirements of ASCC2 ubiquitin binding in RQC

Authoritative review synthesis highlights a tension: some cellular rescue studies suggest partial dispensability of ASCC2’s CUE domain in vivo, while biochemical splitting assays support a strong requirement for ASCC2 ubiquitin recognition for recruitment/splitting. A parsimonious interpretation is context dependence (cell type, stall substrate, ubiquitin architecture), which aligns with reconstitution results showing chain length/linkage and mRNA geometry constraints. (ford2024ubiquitindependenttranslationcontrol pages 2-4, miscicka2024ribosomalcollisionis pages 12-13)

7. Key statistics and quantitative data (selected)

7.1 Ubiquitin-binding affinities (ASCC2 CUE)

MonoUb: Kd = 57.1 ± 5.0 μM (ITC). (lombardi2022theascc2cue pages 1-2)
K63Ub2: Kd ≈ 8.7–10.4 μM (isolated CUE); 8.8 ± 0.9 μM (full-length ASCC2). (lombardi2022theascc2cue pages 2-4)
K48Ub2: Kd ≈ 98 μM; M1 diUb: Kd ≈ 400 μM. (lombardi2022theascc2cue pages 2-4)
Example mutant impacts (K63Ub2 binding): E467A weakens binding 3.6–5×; S470R Kd ≈ 90.9 ± 23.1 μM; E467R/S470R Kd ≈ 92.6 ± 20.9 μM. (lombardi2022theascc2cue pages 4-7)

7.2 ASCC2–ASCC3 affinity and determinants

ASCC2FL–ASCC3NTR: Kd = 3.5 ± 0.4 nM. (jia2020theinteractionof pages 4-5)
ASCC2(1–434)–ASCC3(1–197): Kd = 3.8 ± 1.2 nM. (jia2020theinteractionof pages 5-6)
Truncations weaken binding: ASCC2(1–434)–ASCC3(1–161) Kd 47.7 ± 14.9 nM; ASCC2(1–434)–ASCC3(16–197) Kd 483.0 ± 260.2 nM; deletion of the ASCC3 N‑arm abolishes binding. (jia2020theinteractionof pages 5-6, jia2020theinteractionof pages 3-4)

7.3 RQC splitting constraints (Miścicka 2024)

Requirement: ≥30–35 nt of 3′ mRNA downstream of the P site for ASCC-mediated splitting. (miscicka2024ribosomalcollisionis pages 1-1, miscicka2024ribosomalcollisionis pages 12-13)
Poly(A) stalling construct: A39 (39 consecutive A; 13 AAA Lys codons). (miscicka2024ribosomalcollisionis pages 6-7)
ZNF598 ubiquitination levels: ~90% uS10 polyubiquitination under WT/K63-only ubiquitin conditions; K63R yields 1–4 Ub attachments; with K63R, ASCC still releases ~50% of leading ribosomes in one assay context. (miscicka2024ribosomalcollisionis pages 6-7, miscicka2024ribosomalcollisionis pages 8-9)

7.4 Disease-associated cohort statistics

COSMIC (v91, Apr 2020) mutation counts: ASCC2 223, ASCC3 652 somatic mutations. (jia2020theinteractionof pages 1-2)
Pan-cancer cohort: 10,967 tumors; ASCC2 altered ~1.8%; ASCC1/2/3 alterations in 754 cases (~7%). (pan2025pancanceranalysisreveals pages 2-3, pan2025pancanceranalysisreveals pages 1-2)

8. Summary table (evidence-backed)

Functional module/process	ASCC2 molecular role	Key interacting partners	Subcellular localization	Key mechanistic details	Quantitative data	Key citations
DNA alkylation damage response	Ubiquitin-binding adaptor/sensor in the ALKBH3–ASCC repair pathway; recruits/helps recruit ASCC3 and ALKBH3 to alkylation-damage foci through its CUE domain (brickner2019activationandregulation pages 139-144, lombardi2022theascc2cue pages 1-2, fahrer2023dnaalkylationdamage pages 12-14)	ASCC3, ALKBH3, RNF113A-dependent K63-polyubiquitin, spliceosomal factors including BRR2/PRP8; broader ASCC complex includes ASCC1 and TRIP4/ASC1 (brickner2019activationandregulation pages 139-144, soll2019theroleof pages 27-34, soll2018rnaligaselikedomain pages 1-2, fahrer2023dnaalkylationdamage pages 12-14, jia2020theinteractionof pages 1-2)	Predominantly cytoplasmic at steady state, then accumulates in the nucleus and forms nuclear foci after alkylation stress; foci co-localize with K63-Ub, elongating RNA Pol II, and spliceosomal proteins (brickner2019activationandregulation pages 139-144, soll2019theroleof pages 90-95, soll2019theroleof pages 27-34)	ASCC2 CUE domain (aa ~465–521; UniProt domain annotation consistent) preferentially recognizes K63-linked polyubiquitin; N-terminal region of ASCC2 (aa 1–434) binds ASCC3 N-terminus, positioning ASCC3 to help generate ssDNA for ALKBH3 access to lesions such as N1-methyladenine and N3-methylcytosine during transcription-associated repair (lombardi2022theascc2cue pages 4-7, lombardi2022theascc2cue pages 1-2, lombardi2022theascc2cue pages 2-4, jia2020theinteractionof pages 4-5, fahrer2023dnaalkylationdamage pages 12-14)	Kd: monoubiquitin 57.1 ± 5.0 μM; K63-Ub2 8.7–10.4 μM for isolated CUE and 8.8 ± 0.9 μM for full-length ASCC2; K48-Ub2 ~98 μM; linear diUb ~400 μM; E467A weakens binding 3.6–5.0× (Kd ~46.9–65.4 μM); S470R Kd ~90.9 ± 23.1 μM; E467R/S470R Kd ~92.6 ± 20.9 μM; ASCC2(1–434)-ASCC3(1–197) Kd 3.8 ± 1.2 nM; full-length ASCC2-ASCC3 NTR Kd 3.5 ± 0.4 nM (lombardi2022theascc2cue pages 4-7, lombardi2022theascc2cue pages 1-2, lombardi2022theascc2cue pages 2-4, jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4, jia2020theinteractionof pages 5-6)	Lombardi et al., 2022, J Biol Chem, https://doi.org/10.1016/j.jbc.2021.101545; Jia et al., 2020, Nat Commun, https://doi.org/10.1038/s41467-020-19221-x; Fahrer & Christmann, 2023, Int J Mol Sci, https://doi.org/10.3390/ijms24054684 (lombardi2022theascc2cue pages 1-2, jia2020theinteractionof pages 4-5, fahrer2023dnaalkylationdamage pages 12-14)
Ribosome-associated quality control (RQC) / hRQT	Ubiquitin-recognition subunit of the mammalian hRQT/ASCC ribosome-splitting machinery; helps target ASCC3/TRIP4 to ubiquitinated stalled ribosomes (hashimoto2020identificationofa pages 5-7, hashimoto2020identificationofa pages 3-5, hashimoto2020identificationofa pages 1-2)	ASCC3, TRIP4; upstream ZNF598-dependent K63-linked ubiquitination on small-subunit proteins (reported in Hashimoto for eS10; Miścicka shows ZNF598-dependent uS10/eS10 ubiquitination supports ASCC activity) (hashimoto2020identificationofa pages 3-5, hashimoto2020identificationofa pages 1-2, miscicka2024ribosomalcollisionis pages 11-12)	Cytoplasmic/ribosome-associated functional context; acts on stalled 80S monosomes, polysomes, and even 48S complexes once appropriately ubiquitinated (hashimoto2020identificationofa pages 5-7, miscicka2024ribosomalcollisionis pages 11-12)	hRQT is composed of ASCC3-ASCC2-TRIP4; ASCC2 ubiquitin-binding activity is required/crucial for efficient RQC, while ASCC3 ATPase/helicase activity powers subunit dissociation. Recent reconstitution work shows ASCC can dissociate ubiquitinated ribosomal complexes without obligatory ribosome collision, provided ZNF598-dependent K63-linked ubiquitination and sufficient mRNA extension are present (hashimoto2020identificationofa pages 5-7, hashimoto2020identificationofa pages 3-5, hashimoto2020identificationofa pages 1-2, miscicka2024ribosomalcollisionis pages 11-12)	Functional KD evidence: ASCC3 KD abolishes RQC; ASCC2 KD partially impairs RQC; TRIP4 KD partially impairs RQC; ASCC1 not required (hashimoto2020identificationofa pages 2-3). Miścicka 2024: ASCC can dissociate complexes with ≥30–35 nt 3' mRNA downstream of the P site; polysome stalling assays used 39 A residues/13 AAA Lys codons; ZNF598 generated near-complete eS10 and ~90% uS10 polyubiquitination with WT/K63-only Ub, whereas K63R Ub yielded only 1–4 Ub attachments (miscicka2024ribosomalcollisionis pages 11-12, miscicka2024ribosomalcollisionis pages 6-7)	Hashimoto et al., 2020, Sci Rep, https://doi.org/10.1038/s41598-020-60241-w; Miścicka et al., 2024, Nucleic Acids Res, https://doi.org/10.1093/nar/gkae087 (hashimoto2020identificationofa pages 5-7, hashimoto2020identificationofa pages 1-2, miscicka2024ribosomalcollisionis pages 11-12, miscicka2024ribosomalcollisionis pages 6-7)
ASCC2–ASCC3 structural module relevant to both pathways	High-affinity scaffold interface that physically links the ubiquitin-sensing ASCC2 subunit to the ASCC3 motor/helicase subunit, enabling downstream DNA-repair and ribosome-quality-control activities (jia2020theinteractionof pages 9-10, jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4)	ASCC3 N-terminal region (especially first ~16 aa and broader 1–197/207 region); cancer-associated substitutions in both ASCC2 and ASCC3 map to the interface (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 1-2, jia2020theinteractionof pages 10-11)	Applicable to nuclear DNA-damage complexes and cytoplasmic hRQT/ribosome complexes because the same ASCC2–ASCC3 core interaction is reused across functions (jia2020theinteractionof pages 10-11)	ASCC2(1–434) forms a compact helical unit clasped by ASCC3(1–207); ASCC3 R5 and R11 contact acidic residues in ASCC2 (D103, D63, D92). The interface is evolutionarily conserved, and cancer mutations can weaken or abolish binding, suggesting disease-relevant destabilization of the core module (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4, jia2020theinteractionof pages 1-2)	ASCC3 minimal 1–22 peptide binds ASCC2(1–434) with Kd 2.0 μM; ASCC2(1–434)-ASCC3(1–161) Kd 47.7 ± 14.9 nM; truncation of ASCC3 N-terminus to aa 16–197 weakens to 483.0 ± 260.2 nM; deleting the N-arm abolishes detectable binding; ASCC3 R5L/G weaken affinity ~8–11×, R5H/C >20×, and R11H/C abolish binding (jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4, jia2020theinteractionof pages 5-6)	Jia et al., 2020, Nat Commun, https://doi.org/10.1038/s41467-020-19221-x; Jia et al., 2023, Nat Commun, https://doi.org/10.1038/s41467-023-37528-3 (context mainly for ASCC3/TRIP4 module update) (jia2020theinteractionof pages 9-10, jia2020theinteractionof pages 4-5, jia2020theinteractionof pages 3-4, jia2020theinteractionof pages 5-6)

Table: This table summarizes the best-supported functional annotation for human ASCC2 across its two main mechanistic contexts: DNA alkylation repair and ribosome-associated quality control. It highlights domain function, partners, localization, mechanism, and quantitative measurements from primary studies, with 2023-2024 sources emphasized where available.

9. References (URLs and publication dates)

Key recent/authoritative sources used:

Miścicka A. et al. “Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC.” Nucleic Acids Research (Feb 2024). https://doi.org/10.1093/nar/gkae087 (miscicka2024ribosomalcollisionis pages 1-1)
Ford P.W. et al. “Ubiquitin-dependent translation control mechanisms: Degradation and beyond.” Cell Reports (Dec 2024). https://doi.org/10.1016/j.celrep.2024.115050 (ford2024ubiquitindependenttranslationcontrol pages 4-6)
Jia J. et al. “Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex.” Nature Communications (Apr 2023). https://doi.org/10.1038/s41467-023-37528-3 (jia2023extendeddnathreading pages 2-3)
Fahrer J., Christmann M. “DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways.” International Journal of Molecular Sciences (Feb 2023). https://doi.org/10.3390/ijms24054684 (fahrer2023dnaalkylationdamage pages 12-14)

Foundational mechanistic sources:

Lombardi P.M. et al. “The ASCC2 CUE domain in the ALKBH3–ASCC DNA repair complex recognizes adjacent ubiquitins in K63-linked polyubiquitin.” Journal of Biological Chemistry (Feb 2022). https://doi.org/10.1016/j.jbc.2021.101545 (lombardi2022theascc2cue pages 1-2)
Jia J. et al. “The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations.” Nature Communications (May 2020). https://doi.org/10.1038/s41467-020-19221-x (jia2020theinteractionof pages 4-5)
Hashimoto S. et al. “Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells.” Scientific Reports (Feb 2020). https://doi.org/10.1038/s41598-020-60241-w (hashimoto2020identificationofa pages 1-2)
Soll J.M. et al. “RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage.” Journal of Biological Chemistry (Aug 2018). https://doi.org/10.1074/jbc.ra117.000114 (soll2018rnaligaselikedomain pages 1-2)

Disease/target association platform:

Open Targets Platform (ASCC2 disease associations) (platform resource; accessed via tool output). https://platform.opentargets.org/ (OpenTargets Search: -ASCC2)

References

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(hashimoto2020identificationofa pages 1-2): Satoshi Hashimoto, Takato Sugiyama, Reina Yamazaki, Risa Nobuta, and Toshifumi Inada. Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific Reports, Feb 2020. URL: https://doi.org/10.1038/s41598-020-60241-w, doi:10.1038/s41598-020-60241-w. This article has 125 citations and is from a peer-reviewed journal.
(soll2018rnaligaselikedomain pages 1-2): Jennifer M. Soll, Joshua R. Brickner, Miranda C. Mudge, and Nima Mosammaparast. Rna ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ascc1) regulates ascc complex function during alkylation damage. Journal of Biological Chemistry, 293:13524-13533, Aug 2018. URL: https://doi.org/10.1074/jbc.ra117.000114, doi:10.1074/jbc.ra117.000114. This article has 39 citations and is from a domain leading peer-reviewed journal.
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(jia2020theinteractionof pages 3-4): Junqiao Jia, Eva Absmeier, Nicole Holton, Agnieszka J. Pietrzyk-Brzezinska, Philipp Hackert, Katherine E. Bohnsack, Markus T. Bohnsack, and Markus C. Wahl. The interaction of dna repair factors ascc2 and ascc3 is affected by somatic cancer mutations. Nature Communications, May 2020. URL: https://doi.org/10.1038/s41467-020-19221-x, doi:10.1038/s41467-020-19221-x. This article has 29 citations and is from a highest quality peer-reviewed journal.
(lombardi2022theascc2cue pages 2-4): Patrick M. Lombardi, Sara Haile, Timur Rusanov, Rebecca Rodell, Rita Anoh, Julia G. Baer, Kate A. Burke, Lauren N. Gray, Abigail R. Hacker, Kayla R. Kebreau, Christine K. Ngandu, Hannah A. Orland, Emmanuella Osei-Asante, Dhane P. Schmelyun, Devin E. Shorb, Shaheer H. Syed, Julianna M. Veilleux, Ananya Majumdar, Nima Mosammaparast, and Cynthia Wolberger. The ascc2 cue domain in the alkbh3–ascc dna repair complex recognizes adjacent ubiquitins in k63-linked polyubiquitin. Journal of Biological Chemistry, 298:101545, Feb 2022. URL: https://doi.org/10.1016/j.jbc.2021.101545, doi:10.1016/j.jbc.2021.101545. This article has 11 citations and is from a domain leading peer-reviewed journal.
(lombardi2022theascc2cue pages 4-7): Patrick M. Lombardi, Sara Haile, Timur Rusanov, Rebecca Rodell, Rita Anoh, Julia G. Baer, Kate A. Burke, Lauren N. Gray, Abigail R. Hacker, Kayla R. Kebreau, Christine K. Ngandu, Hannah A. Orland, Emmanuella Osei-Asante, Dhane P. Schmelyun, Devin E. Shorb, Shaheer H. Syed, Julianna M. Veilleux, Ananya Majumdar, Nima Mosammaparast, and Cynthia Wolberger. The ascc2 cue domain in the alkbh3–ascc dna repair complex recognizes adjacent ubiquitins in k63-linked polyubiquitin. Journal of Biological Chemistry, 298:101545, Feb 2022. URL: https://doi.org/10.1016/j.jbc.2021.101545, doi:10.1016/j.jbc.2021.101545. This article has 11 citations and is from a domain leading peer-reviewed journal.
(ford2024ubiquitindependenttranslationcontrol pages 4-6): Pierce W. Ford, Mythreyi Narasimhan, and Eric J. Bennett. Ubiquitin-dependent translation control mechanisms: degradation and beyond. Cell reports, 43 12:115050, Dec 2024. URL: https://doi.org/10.1016/j.celrep.2024.115050, doi:10.1016/j.celrep.2024.115050. This article has 17 citations and is from a highest quality peer-reviewed journal.
(hashimoto2020identificationofa pages 5-7): Satoshi Hashimoto, Takato Sugiyama, Reina Yamazaki, Risa Nobuta, and Toshifumi Inada. Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific Reports, Feb 2020. URL: https://doi.org/10.1038/s41598-020-60241-w, doi:10.1038/s41598-020-60241-w. This article has 125 citations and is from a peer-reviewed journal.
(jia2020theinteractionof pages 1-2): Junqiao Jia, Eva Absmeier, Nicole Holton, Agnieszka J. Pietrzyk-Brzezinska, Philipp Hackert, Katherine E. Bohnsack, Markus T. Bohnsack, and Markus C. Wahl. The interaction of dna repair factors ascc2 and ascc3 is affected by somatic cancer mutations. Nature Communications, May 2020. URL: https://doi.org/10.1038/s41467-020-19221-x, doi:10.1038/s41467-020-19221-x. This article has 29 citations and is from a highest quality peer-reviewed journal.
(brickner2019activationandregulation pages 139-144): Joshua R. Brickner. Activation and regulation of the alkbh3-ascc alkylation repair pathway. ArXiv, 2019. URL: https://doi.org/10.7936/gavm-wj49, doi:10.7936/gavm-wj49. This article has 0 citations.
(miscicka2024ribosomalcollisionis pages 1-1): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(hashimoto2020identificationofa pages 3-5): Satoshi Hashimoto, Takato Sugiyama, Reina Yamazaki, Risa Nobuta, and Toshifumi Inada. Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific Reports, Feb 2020. URL: https://doi.org/10.1038/s41598-020-60241-w, doi:10.1038/s41598-020-60241-w. This article has 125 citations and is from a peer-reviewed journal.
(ford2024ubiquitindependenttranslationcontrol pages 2-4): Pierce W. Ford, Mythreyi Narasimhan, and Eric J. Bennett. Ubiquitin-dependent translation control mechanisms: degradation and beyond. Cell reports, 43 12:115050, Dec 2024. URL: https://doi.org/10.1016/j.celrep.2024.115050, doi:10.1016/j.celrep.2024.115050. This article has 17 citations and is from a highest quality peer-reviewed journal.
(miscicka2024ribosomalcollisionis pages 12-13): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(miscicka2024ribosomalcollisionis pages 11-11): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(miscicka2024ribosomalcollisionis pages 6-7): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(miscicka2024ribosomalcollisionis pages 8-9): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(jia2023extendeddnathreading pages 2-3): Junqiao Jia, Tarek Hilal, Katherine E. Bohnsack, Aleksandar Chernev, Ning Tsao, Juliane Bethmann, Aruna Arumugam, Lane Parmely, Nicole Holton, Bernhard Loll, Nima Mosammaparast, Markus T. Bohnsack, Henning Urlaub, and Markus C. Wahl. Extended dna threading through a dual-engine motor module of the activating signal co-integrator 1 complex. Nature Communications, Apr 2023. URL: https://doi.org/10.1038/s41467-023-37528-3, doi:10.1038/s41467-023-37528-3. This article has 13 citations and is from a highest quality peer-reviewed journal.
(jia2020theinteractionof pages 9-10): Junqiao Jia, Eva Absmeier, Nicole Holton, Agnieszka J. Pietrzyk-Brzezinska, Philipp Hackert, Katherine E. Bohnsack, Markus T. Bohnsack, and Markus C. Wahl. The interaction of dna repair factors ascc2 and ascc3 is affected by somatic cancer mutations. Nature Communications, May 2020. URL: https://doi.org/10.1038/s41467-020-19221-x, doi:10.1038/s41467-020-19221-x. This article has 29 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: -ASCC2): Open Targets Query (-ASCC2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(pan2025pancanceranalysisreveals pages 2-3): Yimin Pan, Jun Tan, Changwu Wu, Chunbo Liu, Zheng Chen, Yongye Zhu, Fushu Luo, and Qing Liu. Pan-cancer analysis reveals ascc family promotes the cancer progression of lung adenocarcinoma. Scientific Reports, Jul 2025. URL: https://doi.org/10.1038/s41598-025-03946-0, doi:10.1038/s41598-025-03946-0. This article has 1 citations and is from a peer-reviewed journal.
(pan2025pancanceranalysisreveals pages 3-5): Yimin Pan, Jun Tan, Changwu Wu, Chunbo Liu, Zheng Chen, Yongye Zhu, Fushu Luo, and Qing Liu. Pan-cancer analysis reveals ascc family promotes the cancer progression of lung adenocarcinoma. Scientific Reports, Jul 2025. URL: https://doi.org/10.1038/s41598-025-03946-0, doi:10.1038/s41598-025-03946-0. This article has 1 citations and is from a peer-reviewed journal.
(han2021longnoncodingrna pages 1-5): jianxin han, Ning Tao, Zhenlei Zhao, Yanpei Gu, Fan Xue, Yali Yan, Lihuan Chen, Hongrui Xiao, Ruiying Qiu, Ying Zhang, Hengqing An, and Wei Li. Long noncoding rna tcons_00027385 acts as a mir-874-5p sponge to suppress the progression of prostate cancer through regulating ascc2 expression. Unknown journal, Jul 2021. URL: https://doi.org/10.21203/rs.3.rs-728951/v1, doi:10.21203/rs.3.rs-728951/v1. This article has 0 citations.
(jia2020theinteractionof pages 5-6): Junqiao Jia, Eva Absmeier, Nicole Holton, Agnieszka J. Pietrzyk-Brzezinska, Philipp Hackert, Katherine E. Bohnsack, Markus T. Bohnsack, and Markus C. Wahl. The interaction of dna repair factors ascc2 and ascc3 is affected by somatic cancer mutations. Nature Communications, May 2020. URL: https://doi.org/10.1038/s41467-020-19221-x, doi:10.1038/s41467-020-19221-x. This article has 29 citations and is from a highest quality peer-reviewed journal.
(pan2025pancanceranalysisreveals pages 1-2): Yimin Pan, Jun Tan, Changwu Wu, Chunbo Liu, Zheng Chen, Yongye Zhu, Fushu Luo, and Qing Liu. Pan-cancer analysis reveals ascc family promotes the cancer progression of lung adenocarcinoma. Scientific Reports, Jul 2025. URL: https://doi.org/10.1038/s41598-025-03946-0, doi:10.1038/s41598-025-03946-0. This article has 1 citations and is from a peer-reviewed journal.
(soll2019theroleof pages 27-34): Jennifer M. Soll. The role of the ascc complex in the alkylation damage response. ArXiv, 2019. URL: https://doi.org/10.7936/05nr-fv98, doi:10.7936/05nr-fv98. This article has 0 citations.
(soll2019theroleof pages 90-95): Jennifer M. Soll. The role of the ascc complex in the alkylation damage response. ArXiv, 2019. URL: https://doi.org/10.7936/05nr-fv98, doi:10.7936/05nr-fv98. This article has 0 citations.
(miscicka2024ribosomalcollisionis pages 11-12): Anna Miścicka, Alexander G Bulakhov, Kazushige Kuroha, Alexandra Zinoviev, Christopher U T Hellen, and Tatyana V Pestova. Ribosomal collision is not a prerequisite for znf598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ascc. Nucleic Acids Research, 52:4627-4643, Feb 2024. URL: https://doi.org/10.1093/nar/gkae087, doi:10.1093/nar/gkae087. This article has 21 citations and is from a highest quality peer-reviewed journal.
(hashimoto2020identificationofa pages 2-3): Satoshi Hashimoto, Takato Sugiyama, Reina Yamazaki, Risa Nobuta, and Toshifumi Inada. Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific Reports, Feb 2020. URL: https://doi.org/10.1038/s41598-020-60241-w, doi:10.1038/s41598-020-60241-w. This article has 125 citations and is from a peer-reviewed journal.
(jia2020theinteractionof pages 10-11): Junqiao Jia, Eva Absmeier, Nicole Holton, Agnieszka J. Pietrzyk-Brzezinska, Philipp Hackert, Katherine E. Bohnsack, Markus T. Bohnsack, and Markus C. Wahl. The interaction of dna repair factors ascc2 and ascc3 is affected by somatic cancer mutations. Nature Communications, May 2020. URL: https://doi.org/10.1038/s41467-020-19221-x, doi:10.1038/s41467-020-19221-x. This article has 29 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

fahrer2023dnaalkylationdamage pages 12-14
jia2023extendeddnathreading pages 2-3
ford2024ubiquitindependenttranslationcontrol pages 4-6
han2021longnoncodingrna pages 1-5
jia2020theinteractionof pages 4-5
jia2020theinteractionof pages 5-6
miscicka2024ribosomalcollisionis pages 6-7
jia2020theinteractionof pages 1-2
hashimoto2020identificationofa pages 2-3
jia2020theinteractionof pages 10-11
miscicka2024ribosomalcollisionis pages 1-1
hashimoto2020identificationofa pages 1-2
soll2018rnaligaselikedomain pages 1-2
jia2020theinteractionof pages 3-4
hashimoto2020identificationofa pages 5-7
brickner2019activationandregulation pages 139-144
hashimoto2020identificationofa pages 3-5
ford2024ubiquitindependenttranslationcontrol pages 2-4
miscicka2024ribosomalcollisionis pages 12-13
miscicka2024ribosomalcollisionis pages 11-11
miscicka2024ribosomalcollisionis pages 8-9
jia2020theinteractionof pages 9-10
pan2025pancanceranalysisreveals pages 2-3
pan2025pancanceranalysisreveals pages 3-5
pan2025pancanceranalysisreveals pages 1-2
soll2019theroleof pages 27-34
soll2019theroleof pages 90-95
miscicka2024ribosomalcollisionis pages 11-12
https://doi.org/10.1016/j.jbc.2021.101545;
https://doi.org/10.1038/s41467-020-19221-x;
https://doi.org/10.3390/ijms24054684
https://doi.org/10.1038/s41598-020-60241-w;
https://doi.org/10.1093/nar/gkae087
https://doi.org/10.1038/s41467-023-37528-3
https://doi.org/10.1016/j.celrep.2024.115050
https://doi.org/10.1016/j.jbc.2021.101545
https://doi.org/10.1038/s41467-020-19221-x
https://doi.org/10.1038/s41598-020-60241-w
https://doi.org/10.1074/jbc.ra117.000114
https://platform.opentargets.org/
https://doi.org/10.1016/j.jbc.2021.101545,
https://doi.org/10.1038/s41467-020-19221-x,
https://doi.org/10.1038/s41598-020-60241-w,
https://doi.org/10.1074/jbc.ra117.000114,
https://doi.org/10.3390/ijms24054684,
https://doi.org/10.1016/j.celrep.2024.115050,
https://doi.org/10.7936/gavm-wj49,
https://doi.org/10.1093/nar/gkae087,
https://doi.org/10.1038/s41467-023-37528-3,
https://doi.org/10.1038/s41598-025-03946-0,
https://doi.org/10.21203/rs.3.rs-728951/v1,
https://doi.org/10.7936/05nr-fv98,

📚 Additional Documentation

Notes

(ASCC2-notes.md)

ASCC2 notes

2026-06-03 Proteostasis PN batch review

Fetched human ASCC2 with just fetch-gene human ASCC2; GOA seeded 38 review
annotations from 39 GOA rows. Refreshed PMID caching successfully. Falcon deep
research was attempted with perplexity-lite fallback; Falcon timed out after
600 seconds and the fallback failed with a Perplexity API quota 401, so no
provider deep-research file was created. This review therefore uses the cached
primary literature, UniProt, Reactome, and the PN projection report directly.

Core synthesis: ASCC2 is a CUE-domain ubiquitin-binding subunit used in two
well-supported ASCC contexts. In the nucleus, ASCC2 recognizes K63-linked
polyubiquitin signals during alkylation damage and helps recruit ASCC repair
machinery PMID:29144457. Loss of ASCC2 impairs
repair kinetics PMID:29144457.

In the proteostasis/RQC context, ASCC2 works with ASCC3 and TRIP4 as the human
RQC-trigger complex. Hashimoto et al. identify the trimeric hRQT complex
PMID:32099016.
Juszkiewicz et al. show ASCC disassembles collided ribosomes PMID:32579943. Narita et al.
connect this to K63-polyubiquitinated uS10 and ASCC2 ubiquitin binding
PMID:36302773.

PN projection decision: the PN report projects ASCC2 to GO:0072344 rescue of stalled cytosolic ribosome as already present, and to GO:0006515 protein quality control for misfolded or incompletely synthesized proteins as a
candidate new-to-GOA group-level RQC annotation
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv
"ASCC2 Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal
rescue"]. I treated the projection conservatively: keep and support the specific
RQC annotations (GO:0072344, GO:0032790, GO:1990116, GO:0180022,
GO:0070530), but do not propose adding broad GO:0006515 because the existing
specific GO annotations already capture ASCC2's proteostasis role.

Annotation decisions:

GO:0043130 ubiquitin binding: MODIFY to GO:0070530 K63-linked polyubiquitin modification-dependent protein binding.
GO:0005515 protein binding: remove or mark over-annotated depending on
whether the interaction is high-throughput-only or mechanistically meaningful
ASCC2-ASCC3 complex evidence.
GO:0006260 DNA replication: REMOVE; the cited evidence supports DNA
alkylation repair, not ASCC2 involvement in DNA replication.
Transcription regulation annotations: KEEP_AS_NON_CORE; the ASC-1 complex
evidence is real PMID:12077347, but not the core PN-relevant role.

Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep-research report was generated on 2026-06-07
(the 2026-06-03 attempt had failed). It does not overturn any existing
annotation decision; it adds mechanistic depth and several primary references
that strengthen the two established core functions. Distinguishing
CONFIRMS / NEW / PROVISIONAL below.

CONFIRMS (molecular function / CUE specificity): The K63-linkage preference of
the ASCC2 CUE domain is now backed by quantitative structural/biophysical work
beyond the references already cited. Lombardi et al. show the CUE domain binds
K63-linked diUb by contacting BOTH distal and proximal ubiquitin, with strong
linkage preference (ITC: monoUb Kd ~57 uM; K63Ub2 ~8.7-10.4 uM; K48Ub2 ~98 uM;
M1/linear diUb ~400 uM), and N-terminal alpha1-helix residues (E467, S470)
are required for recruitment to alkylation-damage foci
[PMID:34971705 (Lombardi 2022) "recognizes adjacent ubiquitins in K63-linked
polyubiquitin"]. Supports the existing GO:0070530 MODIFY/ACCEPT decisions; no
change needed, but adds a primary structural reference.
NEW (ASCC2-ASCC3 scaffold interface; disease principle): A dedicated
structural study maps the ASCC2 N-terminal region (~aa 1-434) as the
high-affinity (Kd ~3.5 nM) ASCC3-binding module, clasped by the ASCC3
N-terminal arms, and shows somatic cancer mutations at this evolutionarily
conserved interface reduce ASCC2-ASCC3 affinity -- a "loss of scaffold
coupling" disease principle rather than loss of helicase catalysis
[PMID:33139697 (Jia 2020) "interaction of DNA repair factors ASCC2 and ASCC3
is affected by somatic cancer mutations"]. This is mechanistic context for the
ASCC2-ASCC3 interaction (relevant to the GO:0005515 MARK_AS_OVER_ANNOTATED
decision on PMID:29997253) and to GO:1990391 DNA repair complex. Does not
change actions; supports representing the interaction via complex/process
terms rather than generic protein binding.
NEW (pathway selection / complex modularity): TRIP4 and ALKBH3 bind ASCC3
mutually exclusively, so the ASCC3 motor is directed either to RQC (TRIP4 /
RQT complex) or to DNA alkylation repair (ALKBH3 complex); ASCC2 is shared by
both assemblies as the K63-Ub reader [PMID:37019967 (Jia 2023) "TRIP4 binds
ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3"]. This
reinforces, with a mechanistic basis, why ASCC2 has dual nuclear-repair and
cytosolic-RQC roles in the review.
NEW (RQC mechanism refinement): In vitro reconstitution shows ribosomal
collision is NOT strictly required for ZNF598 ubiquitination or ASCC-mediated
disassembly; ASCC can split monosomes, polysome queues, and even 48S
complexes given (i) >=30-35 nt of 3' mRNA downstream of the P site and (ii)
sufficiently long K63-linked ubiquitin chains on uS10/eS10
[PMID:38366554 (Miscicka 2024) "Ribosomal collision is not a prerequisite for
ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes
by ASCC"]. Consistent with existing GO:0032790 / GO:0072344 / GO:0070530
decisions; sharpens the mechanism but does not change any action.
CONFIRMS (RQC synthesis / in vivo vs in vitro tension): A 2024 review
reiterates ASCC2 CUE-mediated K63-Ub recognition as the recruitment step for
ASCC ribosome splitting, and notes context-dependence between strong in vitro
requirement and partial in vivo dispensability of ASCC2 ubiquitin binding
[PMID:39661518 (Ford 2024) "Ubiquitin-dependent translation control
mechanisms: Degradation and beyond"]. Supports the existing suggested question
about whether CUE binding is required under endogenous conditions.
PROVISIONAL / LOW-CONFIDENCE (disease associations, NOT used to change
annotations): A pan-cancer analysis reports ASCC2 altered in ~1.8% of 10,967
tumors with tumor-type enrichments and survival associations
[PMID(unresolved): Pan et al. 2025, Sci Rep, doi:10.1038/s41598-025-03946-0];
a prostate-cancer lncRNA/miRNA ceRNA axis (TCONS_00027385/miR-874-5p/ASCC2) is
preprint-level (doi:10.21203/rs.3.rs-728951/v1) and treated as
hypothesis-generating only. Open Targets neurodegeneration/diabetes
associations are GWAS/credible-set level. None of these are used to alter GO
annotations.

References added to ASCC2-ai-review.yaml (statement-only findings, full text not
fetched): PMID:33139697, PMID:34971705, PMID:37019967, PMID:38366554,
PMID:39661518, PMID:36902118. The Brickner 2019 and Soll 2019 ArXiv/thesis items
and the Soll 2018 JBC paper (already represented as ASCC1 work via PMID:29997253)
were left in notes only. PMIDs for Pan 2025 and the Han 2021 preprint were not
reliably resolved to PubMed IDs and are kept in notes only.

Pn Notes

(ASCC2-pn-notes.md)

ASCC2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9H1I8
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1373)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ASCC2/ASCC2-ai-review.yaml
AIGR review HTML: present - genes/human/ASCC2/ASCC2-ai-review.html
Gene notes: present - genes/human/ASCC2/ASCC2-notes.md
GOA TSV: present - genes/human/ASCC2/ASCC2-goa.tsv
UniProt record: present - genes/human/ASCC2/ASCC2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ASCC2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ASCC2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ASCC2/ASCC2-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 29; KEEP_AS_NON_CORE: 2; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 2; REMOVE: 4

PN Consistency Summary

Consistency: Fully consistent. Deep research, notes, review YAML agree ASCC2 is the CUE-domain K63-polyUb reader serving BOTH (1) nuclear ASCC-ALKBH3 alkylation repair and (2) cytosolic hRQT/RQC. Both PN rows map onto these two arms cleanly. Review holds GO:0070530 (K63-linked polyUb-dependent binding) as the MF for both core_functions, plus full RQC term set.
PN story / NEW pressure: Row1 RQC role already captured by specific terms (GO:0072344, GO:0032790, GO:1990116, GO:0180022 ACCEPT; GO:0043130 ubiquitin binding MODIFY→GO:0070530). Notes correctly decline broad GO:0006515 as redundant. Row2 (UPS CUE / ubiquitin-reader) is honestly mapped no_mapping at leaf and context_only above (GO:0140036 ubiquitin-modified protein reader) — the actual reader function is captured more specifically by GO:0070530 in the review. Conclude: already captured. No NEW term needed.
Evidence alignment: PN rows carry no reference titles. Review CUE/K63 evidence (PMID:29144457, PMID:36302773, PMID:34971705 Lombardi, PMID:33139697 Jia ASCC2-ASCC3 interface) and RQC (PMID:32099016, PMID:32579943) align with both PN arms. No citation conflicts.
Verdict: Consistent and well-supported across both PN branches; specific GO:0070530 + RQC terms already capture the story. Broad projections correctly declined. No edits warranted.

Full Consistency Review

UniProt: Q9H1I8 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE (Falcon DR present)
PN placement: TWO rows. Row1 Translation|...|Ribosome-associated QC|Ribosomal rescue (type=mapped/ok GO:0072344 already_in_goa_exact; group=mapped/ok GO:0006515 new_to_goa). Row2 Ubiquitin Proteasome System|Ubiquitin and UBL binding|translation|ribosome QC & DNA repair|CUE (subtype/type=no_mapping; group/class context_only GO:0006412 / GO:0140036). Signature domain IPR003892 (CUE).
Consistency: Fully consistent. Deep research, notes, review YAML agree ASCC2 is the CUE-domain K63-polyUb reader serving BOTH (1) nuclear ASCC-ALKBH3 alkylation repair and (2) cytosolic hRQT/RQC. Both PN rows map onto these two arms cleanly. Review holds GO:0070530 (K63-linked polyUb-dependent binding) as the MF for both core_functions, plus full RQC term set.
PN story / NEW pressure: Row1 RQC role already captured by specific terms (GO:0072344, GO:0032790, GO:1990116, GO:0180022 ACCEPT; GO:0043130 ubiquitin binding MODIFY→GO:0070530). Notes correctly decline broad GO:0006515 as redundant. Row2 (UPS CUE / ubiquitin-reader) is honestly mapped no_mapping at leaf and context_only above (GO:0140036 ubiquitin-modified protein reader) — the actual reader function is captured more specifically by GO:0070530 in the review. Conclude: already captured. No NEW term needed.
Mapping strategy: ASCC2 supports both nodes but drives neither toward change. Broad GO:0006515 (RQC node) and GO:0140036 (UPS class) are both broader than the review's GO:0070530 — the TOMM20/HSPA8/RAB7A "too broad" precedent applies; do not project. Row2 leaf no_mapping is the right call.
Evidence alignment: PN rows carry no reference titles. Review CUE/K63 evidence (PMID:29144457, PMID:36302773, PMID:34971705 Lombardi, PMID:33139697 Jia ASCC2-ASCC3 interface) and RQC (PMID:32099016, PMID:32579943) align with both PN arms. No citation conflicts.
Verdict: Consistent and well-supported across both PN branches; specific GO:0070530 + RQC terms already capture the story. Broad projections correctly declined. No edits warranted.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ASCC2/ASCC2-ai-review.yaml
PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Ribosomal rescue

UniProt: Q9H1I8
In branches: TR, UPS
PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0072344 rescue of stalled cytosolic ribosome]
  rationale: This PN RQC type denotes rescue of stalled cytosolic ribosomes. The matching GO process term is the direct target.
- [group] Translation|Cytosolic translation|Ribosome-associated QC
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
  rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | translation | ribosome QC & DNA repair | CUE

UniProt: Q9H1I8
In branches: TR, UPS
Signature domains: IPR003892
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|translation|ribosome QC & DNA repair|CUE
  status=no_mapping scope= GO=[]
  rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|translation|ribosome QC & DNA repair
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: This PN group captures ubiquitin/UBL-binding factors assigned to translation-related contexts. The relationship to translation is real, but the group mixes heterogeneous subcontexts including repression, nascent-peptide binding, ribosome maturation, and ribosome-quality- control-adjacent roles.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
GO:0072344 rescue of stalled cytosolic ribosome | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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

ASCC2

Gene Description

Existing Annotations Review

Core Functions

K63-linked polyubiquitin-dependent adaptor/subunit function in the nuclear ASCC DNA alkylation repair pathway.

K63-polyubiquitin-dependent hRQT/RQC-trigger complex role in resolving collided or stalled cytosolic ribosomes.

References

Suggested Questions for Experts

Suggested Experiments

Tags

Deep Research

Falcon

Research Report: Human ASCC2 (UniProt Q9H1I8) Functional Annotation

0. Target verification (critical disambiguation)

1. Key concepts and definitions (current understanding)

1.1 ASCC/ASC-1 complex and ASCC2’s role

1.2 CUE domain and linkage specificity (ubiquitin recognition)

1.3 hRQT/ASC-1 in ribosome-associated quality control (RQC)

2. Molecular function, biological processes, and pathways

2.1 DNA alkylation damage response: ubiquitin-directed recruitment of ALKBH3–ASCC

Pathway concept

ASCC2’s specific role

Domain/function evidence (mechanistic)

ASCC2–ASCC3 interface: transmitting the ubiquitin signal to a motor

2.2 Ribosome-associated quality control (RQC): ubiquitin-directed ribosome splitting

Core concept

ASCC2’s specific role

Recent mechanistic advance (2024): collision independence and quantitative constraints

3. Subcellular localization and where ASCC2 acts

4. Recent developments and latest research (prioritizing 2023–2024)

4.1 2023: complex modularity and mutually exclusive ASCC3 assemblies

4.2 2024: reconstitution-level rules for ASCC-mediated splitting + expert synthesis

5. Applications and real-world implementations

5.1 DNA repair context: potential relevance to alkylating chemotherapy

5.2 Translation quality control: mechanistic target for proteostasis-related disease hypotheses

5.3 Cancer omics: prognostic associations and pathway-level biomarkers

6. Expert opinions and analysis (authoritative synthesis)

6.1 Mechanistic consensus: ASCC2 as a ubiquitin reader coupling K63-Ub to motor action

6.2 Interface mutations as a disease mechanism principle

6.3 Reconciling in vivo vs in vitro requirements of ASCC2 ubiquitin binding in RQC

7. Key statistics and quantitative data (selected)

7.1 Ubiquitin-binding affinities (ASCC2 CUE)

7.2 ASCC2–ASCC3 affinity and determinants

7.3 RQC splitting constraints (Miścicka 2024)

7.4 Disease-associated cohort statistics

8. Summary table (evidence-backed)

9. References (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

ASCC2 notes

2026-06-03 Proteostasis PN batch review

Falcon deep research findings (2026-06-07)

Pn Notes

ASCC2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Ribosomal rescue

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | translation | ribosome QC & DNA repair | CUE

Projected GO annotations (2)

Note

📄 View Raw YAML