Affinage

ASCC2

Activating signal cointegrator 1 complex subunit 2 · UniProt Q9H1I8

Length
757 aa
Mass
86.4 kDa
Annotated
2026-06-09
16 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASCC2 is the ubiquitin-sensing subunit of the Activating Signal Cointegrator Complex (ASCC) that couples K63-linked polyubiquitin signals to the recruitment of the ASCC3 helicase across DNA repair, replication-stress, and ribosome quality-control pathways (PMID:29144457, PMID:32099016). Its CUE domain selectively recognizes K63-linked diubiquitin by simultaneously contacting both the distal and proximal ubiquitin moieties, with unique contacts made by residues in the N-terminal portion of its α1 helix; mutation of these residues abolishes recruitment to damage sites (PMID:34971705). In the nucleus, this ubiquitin-binding activity—downstream of the E3 ligase RNF113A—directs the ASCC repair complex specifically to alkylation DNA damage, and ASCC2 loss slows alkylation adduct repair and sensitizes cells to alkylating agents (PMID:29144457). ASCC2 binds ASCC3 directly through a conserved interface clasped by ASCC3's extended arms, an interaction weakened by somatic cancer mutations (PMID:33139697). Beyond DNA repair, ASCC2/ASCC3 together with TRIP4 constitute the human RQC-trigger (hRQT) complex, where ASCC2 ubiquitin recognition of stalled ribosomes is essential to trigger ribosomal subunit dissociation (PMID:32099016), and the same activity recruits ASCC3 to stalled replication forks in a PCNA-K164-polyubiquitylation-dependent manner to enable fork unwinding and SMARCAL1 recruitment (PMID:41785087).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2017 High

    Established that ASCC2 acts as a ubiquitin reader linking a specific ubiquitin signal to targeted DNA repair, answering how the ASCC complex is recruited selectively to alkylation lesions.

    Evidence Cell-based foci assays, CUE domain binding experiments, alkylation sensitivity assays, and RNF113A epistasis

    PMID:29144457

    Open questions at the time
    • Did not resolve atomic basis of K63-linkage selectivity
    • Did not address ASCC2 roles outside alkylation repair
  2. 2020 High

    Defined the structural architecture of the ASCC2–ASCC3 interaction, showing how the two subunits assemble and that cancer mutations destabilize the complex.

    Evidence Crystal structure of the ASCC2–ASCC3 interface with affinity quantification of cancer-mutation variants

    PMID:33139697

    Open questions at the time
    • Did not capture full-length complex or ubiquitin-bound state
    • Functional consequence of weakened binding in cells not measured
  3. 2020 High

    Extended ASCC2 function beyond DNA repair by showing it forms the hRQT complex with ASCC3 and TRIP4, using ubiquitin recognition to trigger dissociation of stalled ribosomes.

    Evidence Reciprocal Co-IP for complex composition, ubiquitin-binding mutants tested in cell-based RQC assays, genetic complementation

    PMID:32099016

    Open questions at the time
    • Did not define the ribosomal ubiquitin substrate recognized by ASCC2
    • Mechanism of subunit dissociation by ASCC3 not resolved
  4. 2019 Medium

    Genetically placed ASCC2/ASCC3 as the most potent modifiers of ribosome-stalling toxicity acting downstream of HBS1L, independently corroborating the RQC role.

    Evidence Genome-wide CRISPRi screen and epistasis experiments with PF8503 stalling compound

    PMID:30875366

    Open questions at the time
    • Pathway placement lacked orthogonal biochemical validation
    • Did not distinguish ASCC2 vs ASCC3 specific contributions
  5. 2018 Medium

    Identified ASCC1 as a coordinator of ASCC2 co-recruitment with ASCC3 to alkylation damage, refining the assembly logic of the nuclear repair complex.

    Evidence Co-IP, confocal foci imaging, and CRISPR knockout epistasis

    PMID:29997253

    Open questions at the time
    • Single-lab study
    • Molecular basis of ASCC1-dependent co-recruitment not defined
  6. 2021 High

    Resolved the structural basis of K63-linkage selectivity, explaining how the CUE domain discriminates K63 chains by contacting both distal and proximal ubiquitins.

    Evidence Structural/biochemical analysis of CUE–diubiquitin, mutagenesis, and cell-based recruitment assays

    PMID:34971705

    Open questions at the time
    • Did not test selectivity in the context of full ASCC complex
    • In vivo chain-type specificity at damage sites not directly imaged
  7. 2026 Medium

    Demonstrated a distinct ASCC2 role at stalled replication forks, where ubiquitin-binding and PCNA-K164 polyubiquitylation recruit ASCC3 to drive fork unwinding and SMARCAL1 loading.

    Evidence Fork recruitment assays, ASCC2 ubiquitin-binding mutants, in vitro DNA unwinding, and epistasis with PCNA E3 ligases

    PMID:41785087

    Open questions at the time
    • Single-lab study
    • Relationship between fork and alkylation-repair functions of ASCC2 unresolved
  8. 2026 Low

    Implicated ASCC2 nuclear translocation in cancer, with lncRNA DLEU1 promoting ASCC2–ALKBH3 interaction to support alkylation repair.

    Evidence RNA-protein interaction assays, localization western blots, and co-targeting in organoid/xenograft models

    PMID:41484982

    Open questions at the time
    • Mechanism of ASCC2 translocation relies on co-localization without deep dissection
    • Direct ASCC2–ALKBH3 contact not structurally defined
    • Single-lab cancer-context study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASCC2 ubiquitin recognition is partitioned and regulated across its nuclear DNA-repair, replication-fork, and cytoplasmic ribosome-quality-control functions remains unresolved.
  • No unifying model for context-specific deployment of one ubiquitin reader
  • Cytoplasmic vs nuclear ASCC2 pools not delineated
  • Regulation of CUE-domain accessibility unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1
Partners
ALKBH3ASCC1ASCC3PCNARNF113ATRIP4
Complex memberships
ASCC (Activating Signal Cointegrator Complex)human RQC-trigger (hRQT) complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 The CUE domain of ASCC2 recognizes K63-linked polyubiquitin chains, and this recognition is required for recruitment of the ASCC repair complex to nuclear foci specifically upon alkylation damage. Loss of ASCC2 impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents but not other DNA damage types. The E3 ligase RNF113A is responsible for upstream ubiquitin signalling in this pathway. Cell-based foci formation assays, domain-specific binding experiments (CUE domain), alkylation damage sensitivity assays, epistasis with RNF113A Nature High 29144457
2021 The ASCC2 CUE domain selectively binds K63-linked diubiquitin by contacting both the distal and proximal ubiquitin simultaneously. The distal ubiquitin is contacted similarly to other CUE domains, while residues in the N-terminal portion of the ASCC2 α1 helix make unique contacts with the proximal ubiquitin. Mutation of these N-terminal α1 helix residues decreases ASCC2 recruitment to alkylation damage sites. Structural/biochemical analysis of CUE–diubiquitin interaction, mutagenesis of binding residues, cell-based recruitment assays The Journal of biological chemistry High 34971705
2020 ASCC2 and ASCC3 directly interact; the ASCC3 fragment comprises a central helical domain and terminal extended arms that clasp the compact ASCC2 unit. This interface is evolutionarily conserved, and somatic cancer mutations at the interface reduce ASCC2–ASCC3 binding affinity. ASCC3 shows similar domain organization and regulation to the spliceosomal RNA helicase Brr2. Structural analysis (crystal structure), interaction mapping, affinity quantification of cancer mutation variants Nature communications High 33139697
2020 ASCC2 and ASCC3 form the human RQC-trigger (hRQT) complex together with TRIP4, functioning as orthologs of the yeast RQT complex (Slh1/Cue3/yKR023W). The ubiquitin-binding activity of ASCC2 is crucial for triggering ribosome-associated quality control (RQC), specifically recognition of ubiquitinated stalled ribosomes to facilitate subunit dissociation. Co-immunoprecipitation to define complex composition, functional assays measuring RQC efficiency upon loss of ASCC2 ubiquitin-binding activity, genetic complementation Scientific reports High 32099016
2019 In a genome-wide CRISPRi screen, ASCC2 and ASCC3 were the two most potent genetic modifiers protecting cells from toxic effects of the ribosome-stalling compound PF8503. Genetic interaction experiments showed ASCC3 acts together with ASCC2 and functions downstream of HBS1L in the ribosome quality control pathway. Genome-wide CRISPRi screen, genetic interaction (epistasis) experiments PLoS genetics Medium 30875366
2018 ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit. Loss of ASCC2 from ASCC3 foci (when ASCC1 is absent) indicates ASCC1 coordinates proper co-recruitment of ASCC2 with ASCC3 during alkylation damage. ASCC1 is present at nuclear speckle foci prior to damage but leaves in response to alkylation. Co-immunoprecipitation, confocal microscopy of nuclear foci, CRISPR/Cas9 knockout with epistasis analysis The Journal of biological chemistry Medium 29997253
2026 ASCC2 recruits ASCC3 to stalled replication forks; this recruitment requires both ASCC2 ubiquitin-binding activity and polyubiquitylation of PCNA at K164 catalyzed by SHPRH, HLTF, and RFWD3. At stalled forks, ASCC3 unwinds DNA in a manner required for SMARCAL1 recruitment, restrained fork progression, and fork degradation in BRCA1/BRCA2-deficient cells. Protein recruitment assays at stalled forks, ubiquitin-binding mutants of ASCC2, in vitro DNA unwinding assays, genetic epistasis with PCNA ubiquitin E3 ligases Cell reports Medium 41785087
2026 lncRNA DLEU1 promotes ASCC2 nuclear translocation and its interaction with ALKBH3 in gastric cancer cells, thereby facilitating alkylation DNA repair and stabilizing E2F1 mRNA. Co-targeting DLEU1 and ASCC2 synergizes with G6PD inhibition to impair cancer cell viability. RNA-protein interaction assays, western blotting for localization, functional co-targeting experiments in organoids and xenograft models Biomarker research Low 41484982

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature 87 29144457
2020 Identification of a novel trigger complex that facilitates ribosome-associated quality control in mammalian cells. Scientific reports 84 32099016
2019 Cellular response to small molecules that selectively stall protein synthesis by the ribosome. PLoS genetics 28 30875366
2018 RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage. The Journal of biological chemistry 27 29997253
2018 Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures. Journal of medical genetics 27 30327447
2020 The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. Nature communications 21 33139697
2021 A Dual Systems Genetics Approach Identifies Common Genes, Networks, and Pathways for Type 1 and 2 Diabetes in Human Islets. Frontiers in genetics 19 33777101
2023 Sensogenomics of music and Alzheimer's disease: An interdisciplinary view from neuroscience, transcriptomics, and epigenomics. Frontiers in aging neuroscience 15 36819725
2022 Whole-genome characterization of myoepithelial carcinomas of the soft tissue. Cold Spring Harbor molecular case studies 9 36577525
2021 Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3. HGG advances 9 35047834
2021 The ASCC2 CUE domain in the ALKBH3-ASCC DNA repair complex recognizes adjacent ubiquitins in K63-linked polyubiquitin. The Journal of biological chemistry 8 34971705
2025 Integrative multi-omics analysis and machine learning reveal the unique role of ASCC3 in combination with various immune-related genes in rectal adenocarcinoma. Frontiers in genetics 2 40881169
2026 Ski2-like helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses. Cell reports 1 41785087
2025 Pan-cancer analysis reveals ASCC family promotes the cancer progression of lung adenocarcinoma. Scientific reports 1 40594069
2026 Histone modification-regulated LncRNA DLEU1 interacts with ASCC2/ALKBH3 complex to drive DNA repair, antioxidant homeostasis and glucose metabolism in gastric cancer. Biomarker research 0 41484982
2025 The Ski2 helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses. bioRxiv : the preprint server for biology 0 40777259

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