Affinage

ASCC3

Activating signal cointegrator 1 complex subunit 3 · UniProt Q8N3C0

Length
2202 aa
Mass
251.5 kDa
Annotated
2026-06-09
13 papers in source corpus 9 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

ASCC3 is a 3'-5' DNA/RNA helicase and the largest subunit of the Activating Signal Cointegrator Complex (ASCC) that operates across DNA repair, replication stress, and translation quality control (PMID:22055184, PMID:41785087, PMID:40777259). In dealkylation repair, its unwinding activity generates the single-stranded substrate on which the partner demethylase ALKBH3 acts, and loss of ASCC3 elevates 3-methylcytosine, induces pH2A.X/53BP1 foci, and impairs proliferation; this activity also clears m1A and m3C from damaged mRNA, consistent with disassembly of collided ribosomes to permit demethylation (PMID:22055184, PMID:34217309). Within the complex, ASCC3 binds ASCC2 through a structurally defined interface, and ASCC2's ubiquitin-binding activity recruits ASCC3 to stalled replication forks in a manner dependent on SHPRH/HLTF/RFWD3-mediated polyubiquitylation of PCNA at K164; there ASCC3's helicase activity drives SMARCAL1 recruitment, fork remodeling, RPA accumulation and ATR activation, and antagonizes RAD51-mediated recombination to preserve genome stability (PMID:33139697, PMID:41785087, PMID:40777259). In translation surveillance ASCC3 acts as an early ribosome-associated quality control factor recruited to collided ribosomes by FMRP, and disease-associated variants that disrupt the ASCC3-FMRP interaction are defective in ribosome handling (PMID:41061044). Distinct from its genome-maintenance roles, ASCC3 stabilizes STAT3 by recruiting CAND1 to block STAT3 ubiquitination, dampening the type I interferon response (PMID:38148115).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Established the founding biochemical function of ASCC3 by showing its helicase generates the ssDNA substrate required for ALKBH3-dependent dealkylation, linking the ASCC complex to active reversal of N-alkylation damage.

    Evidence Affinity purification/MS, in vitro helicase assay, and siRNA knockdown with alkylation-resistance and DNA-damage-foci readouts

    PMID:22055184

    Open questions at the time
    • Did not resolve how ASCC3 helicase activity is coupled to ALKBH3 catalysis structurally
    • Scope of substrate (DNA vs RNA) not fully delineated
  2. 2020 High

    Defined the physical basis of the ASCC2-ASCC3 interaction at atomic resolution, showing the interface is conserved and disrupted by cancer mutations, and that ASCC3 is organized like the Brr2 RNA helicase.

    Evidence X-ray crystallography of the interacting regions with quantitative binding affinity and cancer-variant mutagenesis

    PMID:33139697

    Open questions at the time
    • Functional consequence of weakened ASCC2-ASCC3 binding in cells not tested here
    • Full-length complex architecture not resolved
  3. 2021 Medium

    Extended ASCC3's dealkylation role from DNA to mRNA, showing it is needed to clear m1A/m3C methylbases from transcripts and to form MMS-induced P-bodies.

    Evidence MS quantification of mRNA methylbases plus SILAC-MS of the mRNA-bound proteome after alkylation, with knockdown readouts

    PMID:34217309

    Open questions at the time
    • Direct ribosome-disassembly activity inferred but not reconstituted here
    • Single-lab study without orthogonal genetic confirmation
  4. 2023 Medium

    Revealed a genome-maintenance-independent role: ASCC3 recruits CAND1 to protect STAT3 from ubiquitin-mediated degradation, dampening type I interferon signaling and promoting tumor immunosuppression.

    Evidence Co-IP/MS identification of CAND1, plus knockdown with STAT3 stability, ubiquitination, interferon, and in vivo tumor readouts in NSCLC

    PMID:38148115

    Open questions at the time
    • Whether ASCC3 acts here as a helicase or scaffold is unresolved
    • Direct vs indirect nature of CAND1 recruitment not structurally defined
  5. 2025 High

    Placed ASCC3 in the replication stress response, defining a recruitment pathway (PCNA-K164 polyubiquitylation by SHPRH/HLTF/RFWD3 → ASCC2 → ASCC3) and a helicase-dependent role in fork remodeling, ATR activation, and suppression of RAD51 recombination.

    Evidence In vitro fork-substrate unwinding, iPOND/proximity ligation, epistasis with E3-ligase/PCNA mutants, and chromosome-instability phenotyping

    PMID:40777259 PMID:41785087

    Open questions at the time
    • How ASCC3 selects fork vs dealkylation substrates is unclear
    • Mechanism of RAD51 antagonism at the molecular level not defined
  6. 2025 High

    Identified ASCC3 as an early RQC factor recruited to collided ribosomes by FMRP, with disease-associated variants disrupting this interaction, and demonstrated therapeutic rescue in Fragile X models.

    Evidence Reciprocal co-IP, ribosome-association assays, variant mutagenesis, and in vivo AAV-CRISPR activation in Fmr1 KO mice with synaptic/behavioral readouts

    PMID:41061044

    Open questions at the time
    • Structural basis of the ASCC3-FMRP interaction unresolved
    • How ASCC3 mechanically resolves collided ribosomes not reconstituted
  7. 2024 Medium

    Extended ASCC3's translation surveillance role to suppression of ribosome collisions arising from eRF1 misrecognition at UUA sense codons, coupling its loss to ATF3 stress induction.

    Evidence Disome-Seq and ribosome profiling with ASCC3 depletion plus stress-response gene expression (preprint)

    PMID:bio_10.1101_2024.09.01.610654

    Open questions at the time
    • Single-method preprint not independently confirmed
    • Mechanistic link between ASCC3 and 4EHP at collision sites not established
  8. 2026 Medium

    Connected ASCC3 to chemotherapy response, showing it promotes glycolytic metabolic reprogramming and PERK-mediated apoptotic signaling that sensitizes colorectal cells to replication-stress agents.

    Evidence siRNA knockdown with RNA-seq, extracellular flux, isotope tracing, and PERK/CHOP/caspase-3 Western blotting under drug treatment

    PMID:41844711

    Open questions at the time
    • Whether metabolic and PERK effects are direct ASCC3 functions or downstream consequences is unclear
    • Single-lab, single-context study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single helicase is partitioned among its DNA dealkylation, replication-fork remodeling, ribosome quality control, and STAT3-stabilizing roles, and what determines context-specific recruitment, remains unresolved.
  • No unified model of substrate/partner selection across pathways
  • Structural basis for FMRP and CAND1 recruitment undefined
  • Catalytic vs scaffolding requirements not separated for each role

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0098772 molecular function regulator activity 2 GO:0140097 catalytic activity, acting on DNA 2 GO:0140657 ATP-dependent activity 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005840 ribosome 2
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-162582 Signal Transduction 1 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1
Partners
ALKBH3ASCC2CAND1FMRPPCNASMARCAL1
Complex memberships
ASCC complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ASCC3, the largest subunit of the Activating Signal Cointegrator Complex (ASCC), encodes a 3'-5' DNA helicase whose unwinding activity generates single-stranded DNA upon which ALKBH3 preferentially functions for dealkylation of N-alkylated nucleotides. ASCC3 and ALKBH3 form a complex (purified by co-immunoprecipitation/mass spectrometry), and loss of ASCC3 leads to increased 3-methylcytosine levels, pH2A.X and 53BP1 foci formation, and reduced cell proliferation. Complex purification (affinity purification/mass spectrometry), in vitro helicase assay, siRNA knockdown with alkylation damage resistance and proliferation readouts, immunofluorescence for DNA damage markers Molecular cell High 22055184
2020 ASCC2 and ASCC3 directly interact via a structurally defined interface: the ASCC3 fragment contains a central helical domain and terminal extended arms that clasp the compact ASCC2 unit. This interface is evolutionarily conserved, and somatic cancer mutations at this interface reduce ASCC2-ASCC3 binding affinity. Functional dissection revealed ASCC3 has similar organization and regulation to the spliceosomal RNA helicase Brr2. X-ray crystallography / structural analysis of interacting regions, quantitative binding affinity measurements, mutagenesis of cancer-associated variants Nature communications High 33139697
2021 ASCC3 promotes removal of MMS-induced 1-methyladenosine (m1A) and 3-methylcytosine (m3C) from mRNA. ASCC3-deficient cells show delayed clearance of these aberrant mRNA methylbases and impaired formation of MMS-induced P-bodies. ASCC3 binds mRNA after alkylation damage (increased mRNA association detected by SILAC-MS), consistent with a role in disassembly of collided ribosomes to allow ALKBH3-mediated demethylation. Quantitative mass spectrometry of mRNA methylbases, SILAC-MS for mRNA-binding proteome, siRNA knockdown of ASCC3 with mRNA modification and P-body formation readouts Journal of translational medicine Medium 34217309
2025 ASCC3 is recruited to stalled replication forks by its binding partner ASCC2. ASCC2 recruitment to stalled forks requires its ubiquitin-binding activity and polyubiquitylation of PCNA at K164 catalyzed by SHPRH, HLTF, and RFWD3. Upon replication stress, ASCC3's DNA unwinding activity is required for SMARCAL1 recruitment, restrained fork progression, fork degradation in BRCA1/BRCA2-deficient cells, and RPA accumulation on ssDNA to promote ATR activation. ASCC3 remodels gap-containing fork substrates in vitro and antagonizes RAD51-mediated recombination, preventing chromosome breaks/gaps and mis-segregation. In vitro DNA unwinding assay with fork substrates, iPOND/proximity ligation for fork recruitment, epistasis with SHPRH/HLTF/RFWD3/PCNA mutants, siRNA/CRISPR knockdown with fork progression, ATR activation, and chromosome instability readouts Cell reports High 40777259 41785087
2025 ASCC3 is an early-acting ribosome-associated quality control (RQC) factor that is recruited to collided ribosomes by FMRP. FMRP recruits ASCC3 to collided ribosomes, and disease-associated ASCC3 variants that perturb ASCC3-FMRP interaction are defective in ribosome association and handling of collided ribosomes. ASCC3 overexpression in Fmr1 KO mice promoted neuronal migration, and CRISPR-mediated ASCC3 activation ameliorated synaptic defects and behavioral deficits in FXS mouse models. Co-immunoprecipitation (ASCC3-FMRP interaction), ribosome association assays, mutagenesis of disease-associated variants, in vivo AAV-CRISPR activation in Fmr1 KO mice with behavioral and synaptic readouts Science translational medicine High 41061044
2024 ASCC3 (along with 4EHP) suppresses ribosome collisions at UUA sense codons caused by transient eRF1 misrecognition. Depletion of ASCC3 leads to accumulation of ribosomes stalled at UUA codons and triggers stress responses including upregulation of the stress-induced transcription factor ATF3, establishing ASCC3 as a factor that suppresses aberrant ribosome collisions from sense codon misrecognition. Disome-Seq with ASCC3 depletion, ribosome profiling, stress response gene expression analysis bioRxivpreprint Medium bio_10.1101_2024.09.01.610654
2023 ASCC3 stabilizes STAT3 signaling by recruiting CAND1, which inhibits ubiquitin-mediated degradation of STAT3, thereby impairing the type I interferon response and promoting immunosuppression in NSCLC. This was demonstrated by co-immunoprecipitation and mass spectrometry identifying CAND1 as an ASCC3-interacting protein. Co-immunoprecipitation, mass spectrometry, immunofluorescence, siRNA knockdown with STAT3 stability, ubiquitination, and interferon response readouts; in vivo mouse tumor models Journal for immunotherapy of cancer Medium 38148115
2026 ASCC3 promotes sensitivity to replication stress-inducing chemotherapeutic agents (5-fluorouracil, cisplatin, hydroxyurea) in colorectal cancer cells. ASCC3 loss causes increased chemoresistance despite enhanced DNA damage accumulation. ASCC3 reprograms energy metabolism toward glycolysis and is required for PERK production upon ER stress; impaired PERK production upon ASCC3 loss is associated with reduced CHOP and caspase 3 levels, indicating ASCC3 promotes PERK-mediated cell death in response to chemotherapy. ASCC3 siRNA knockdown, RNA-seq, extracellular flux assays, stable isotope tracer analysis, Western blotting for PERK/CHOP/caspase 3 upon drug treatment Scientific reports Medium 41844711

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Molecular cell 175 22055184
2023 ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3. Journal for immunotherapy of cancer 25 38148115
2020 The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. Nature communications 21 33139697
2021 ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA. Journal of translational medicine 20 34217309
1986 Molecular cloning and in vitro transcription of rat 4.5S RNAH genes. Nucleic acids research 13 3951991
2021 Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3. HGG advances 9 35047834
2015 Correlations between ASCC3 Gene Polymorphisms and Chronic Hepatitis B in a Chinese Han Population. PloS one 3 26536629
2007 Mouse nucleolin binds to 4.5S RNAh, a small noncoding RNA. Biochemical and biophysical research communications 3 17971306
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 CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice. Science translational medicine 1 41061044
2026 ASCC3 promotes chemosensitivity in colorectal cancer cells. Scientific reports 0 41844711
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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