Affinage

ASCC3

Activating signal cointegrator 1 complex subunit 3 · UniProt Q8N3C0

Round 2 corrected
Length
2202 aa
Mass
251.5 kDa
Annotated
2026-04-28
42 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASCC3 is a Ski2-like 3′-to-5′ DNA/RNA helicase that serves as the catalytic engine of the Activating Signal Cointegrator Complex, coupling nucleic acid unwinding to alkylation damage repair, replication fork protection, and ribosome-associated quality control. As the largest ASCC subunit, ASCC3 generates single-stranded DNA substrates for the demethylase ALKBH3 to remove 1-methyladenine and 3-methylcytosine lesions, and it is recruited to stalled replication forks via ASCC2-mediated recognition of polyubiquitylated PCNA, where its helicase activity promotes fork reversal, RPA loading, ATR activation, and suppression of RAD51-dependent recombination (PMID:22055184, PMID:41785087). ASCC3 also disassembles collided ribosomes—recruited by FMRP—to maintain translational homeostasis and permit ALKBH3-mediated mRNA demethylation; loss of this function triggers stress responses and ribosome collision accumulation at UUA sense codons (PMID:34217309, PMID:41061044). Biallelic loss-of-function variants in ASCC3 cause a human neuromuscular syndrome with developmental delay, and disease-associated missense variants disrupt FMRP interaction and ribosome association (PMID:35047834, PMID:41061044).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2011 High

    Discovery that ASCC3 is a 3′-to-5′ DNA helicase within the ALKBH3 complex resolved how single-stranded DNA is generated for alkylation damage repair, establishing ASCC3's first known enzymatic activity and linking it to genomic integrity.

    Evidence Affinity purification of ALKBH3 complex, in vitro helicase assay, siRNA knockdown with alkylation sensitivity and DNA damage marker readouts in human cancer cell lines

    PMID:22055184

    Open questions at the time
    • Structural basis of helicase activity and substrate specificity not resolved
    • How ASCC3 is recruited to sites of alkylation damage was unknown
    • Whether ASCC3 acts on RNA substrates in vivo was not addressed
  2. 2020 High

    Structural determination of the ASCC2-ASCC3 interface revealed a conserved dual-cassette Ski2-like helicase architecture and showed that somatic cancer mutations cluster at the binding surface, explaining how the complex is assembled and why certain cancer variants are loss-of-function.

    Evidence X-ray crystallography of ASCC2-ASCC3 interacting regions, quantitative binding assays, cancer variant mutagenesis

    PMID:33139697

    Open questions at the time
    • Full-length ASCC3 structure and mechanism of helicase processivity not determined
    • How ASCC2-ASCC3 disruption by cancer mutations affects repair in cells was not tested
    • No structure of ASCC3 bound to nucleic acid substrates
  3. 2021 Medium

    Two parallel advances linked ASCC3 to ribosome quality control and human disease: ASCC3 was shown to disassemble collided ribosomes to allow ALKBH3-mediated mRNA demethylation, while independent genetic studies identified biallelic ASCC3 variants as causative for a neuromuscular syndrome with genotype-severity correlation.

    Evidence SILAC proteomics of mRNA-binding proteins after MMS, quantitative mRNA methylbase measurement, P-body assays (ribosome role); exome/genome sequencing across seven unrelated families with clinical phenotyping (disease genetics)

    PMID:34217309 PMID:35047834

    Open questions at the time
    • Mechanism by which ASCC3 disassembles collided ribosomes was not reconstituted in vitro
    • No functional assay linking patient variants to helicase activity or ribosome disassembly defects at this stage
    • How mRNA demethylation defects contribute to neuromuscular pathology was unknown
  4. 2023 Medium

    An unexpected signaling role was uncovered: ASCC3 stabilizes STAT3 by recruiting CAND1 to inhibit ubiquitin-mediated STAT3 degradation, suppressing type I interferon signaling and promoting immunosuppression in non-small cell lung cancer.

    Evidence Reciprocal Co-IP/mass spectrometry for CAND1 interaction, RNA-seq, flow cytometry for immune cell populations, in vivo mouse tumor models with ASCC3 knockdown and anti-PD-1 combination

    PMID:38148115

    Open questions at the time
    • Whether STAT3 stabilization depends on ASCC3 helicase activity or is independent was not tested
    • Generalizability to other cancer types not established
    • Mechanism by which ASCC3-CAND1 interaction blocks STAT3 ubiquitylation is unclear
  5. 2025 High

    Two studies completed the mechanistic picture at replication forks and collided ribosomes: ASCC3 was shown to be recruited to stalled forks via ASCC2/polyubiquitylated-PCNA to drive fork reversal, RPA loading, and ATR activation while antagonizing RAD51 recombination; separately, FMRP was identified as the factor that recruits ASCC3 to collided ribosomes, with disease-associated ASCC3 variants disrupting FMRP binding and ribosome association, and ASCC3 restoration rescuing Fragile X phenotypes in Fmr1 KO mice.

    Evidence In vitro fork remodeling and DNA unwinding, iPOND, genetic epistasis with SHPRH/HLTF/RFWD3/BRCA pathway (fork role); Co-IP of ASCC3-FMRP, ribosome profiling in iPSC-neurons, CRISPRa-AAV rescue of behavioral deficits in Fmr1 KO mice, disease variant mutagenesis (ribosome role)

    PMID:41061044 PMID:41785087

    Open questions at the time
    • Whether the fork remodeling and ribosome QC functions are coordinated or independently regulated is unknown
    • Structural basis of ASCC3 engagement with collided ribosomes or reversed forks not resolved
    • Whether ASCC3-mediated fork reversal operates in normal replication or only under replication stress is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how ASCC3's helicase activity is regulated to switch between DNA repair, replication fork protection, and ribosome quality control functions, whether the STAT3-stabilizing role depends on the same protein interfaces as its canonical repair/QC roles, and what structural basis underlies ASCC3's engagement with diverse nucleoprotein substrates.
  • No full-length structure of ASCC3 or ASCC3-substrate complex available
  • Regulatory logic governing substrate-specific engagement (DNA forks vs. collided ribosomes) not defined
  • Contribution of each ASCC3 function to the human neuromuscular phenotype remains unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 3 GO:0003677 DNA binding 2 GO:0140097 catalytic activity, acting on DNA 2 GO:0003723 RNA binding 1
Localization
GO:0005840 ribosome 3 GO:0005634 nucleus 2 GO:0005694 chromosome 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 2 R-HSA-162582 Signal Transduction 1 R-HSA-69306 DNA Replication 1
Partners
ALKBH3ASCC2CAND1FMRPPCNARPASTAT3
Complex memberships
ASCC (Activating Signal Cointegrator Complex)RQC trigger complex (ribosome quality control)

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ASCC3 is the largest subunit of the Activating Signal Cointegrator Complex (ASCC) and encodes a 3'-5' DNA helicase whose unwinding activity generates single-stranded DNA upon which the demethylase ALKBH3 preferentially acts to repair N-alkylated nucleotides (3-methylcytosine and 1-methyladenine). Loss of ASCC3 leads to increased 3-methylcytosine, reduced cancer cell proliferation, and formation of pH2A.X and 53BP1 foci, indicating a role in maintaining genomic integrity. Affinity purification of ALKBH3 complex, in vitro helicase assay, siRNA knockdown with alkylation damage resistance assays, immunofluorescence for DNA damage markers Molecular cell High 22055184
2020 The ASCC3 subunit functions as a dual-cassette Ski2-like nucleic acid helicase. The ASCC2-ASCC3 interaction interface was structurally characterized: the ASCC3 fragment comprises a central helical domain and terminal extended arms that clasp the compact ASCC2 unit. This interface is evolutionarily conserved and harbors numerous somatic cancer mutation sites; cancer-associated mutations reduce ASCC2-ASCC3 binding affinity. ASCC3 domain organization is similar to that of the spliceosomal RNA helicase Brr2. X-ray crystallography of ASCC2-ASCC3 interacting regions, binding affinity quantification, mutational analysis of cancer variants Nature communications High 33139697
2021 ASCC3 promotes disassembly of collided ribosomes as part of the ribosome quality control (RQC) trigger complex. ASCC3-deficient cells display delayed removal of MMS-induced 1-methyladenosine (m1A) and 3-methylcytosine (m3C) from mRNA and impaired formation of MMS-induced P-bodies. ASCC3 also shows increased mRNA binding after MMS treatment, and its role in ribosome disassembly is proposed to allow access of ALKBH3 for demethylation of aberrant mRNA methylbases. Quantitative SILAC mass spectrometry of mRNA-binding proteome, ASCC3 knockdown with quantitative measurement of mRNA methylbases, P-body formation assay by immunofluorescence Journal of translational medicine Medium 34217309
2021 Biallelic loss-of-function variants in ASCC3 cause a neuromuscular syndrome in humans ranging from severe developmental delay to muscle fatigue, establishing ASCC3 as a disease gene. Genotype-phenotype correlation was observed: homozygous missense variants cause milder phenotypes, while compound heterozygotes for missense and presumed LOF variants are more severely affected, and no biallelic presumed LOF individuals are found, suggesting this genotype may be lethal. Exome/genome sequencing of seven unrelated families, clinical phenotyping, gnomAD population analysis HGG advances Medium 35047834
2023 ASCC3 stabilizes STAT3 signaling by recruiting CAND1, which inhibits ubiquitin-mediated proteasomal degradation of STAT3, thereby impairing the type I interferon response in non-small cell lung cancer cells and promoting immunosuppression. ASCC3 overexpression decreases CD8+ T cells, NK cells and dendritic cells and increases regulatory T cells in the tumor microenvironment. Immunoprecipitation, mass spectrometry, RNA sequencing, immunofluorescence, flow cytometry, in vivo mouse tumor models with ASCC3 knockdown and anti-PD-1 combination Journal for immunotherapy of cancer Medium 38148115
2025 ASCC3 is recruited to stalled replication forks by its binding partner ASCC2, whose fork recruitment requires ubiquitin-binding activity and polyubiquitylation of PCNA at K164 by E3 ligases SHPRH, HLTF, and RFWD3. Upon replication stress, ASCC3 helicase activity unwinds DNA at stalled forks, remodeling gap-containing fork substrates and promoting fork reversal. ASCC3 also interacts with RPA and stimulates RPA accumulation on ssDNA to promote ATR activation, antagonizes RAD51-mediated recombination, and prevents chromosome breaks/gaps and mis-segregation. In vitro DNA unwinding/fork remodeling assays, co-immunoprecipitation, iPOND (isolation of proteins on nascent DNA), genetic epistasis with SHPRH/HLTF/RFWD3/BRCA1/BRCA2, RPA accumulation assays, ATR activation assays, chromosome break quantification Cell reports High 41785087
2025 FMRP (fragile X messenger ribonucleoprotein) regulates collided ribosomes by recruiting ASCC3 to collided ribosomes. Loss of FMRP reduces ASCC3 abundance. ASCC3 overexpression in fetal Fmr1 KO mouse brains promotes neuronal migration, and CRISPR-mediated activation of ASCC3 via AAV injection ameliorates synaptic defects, locomotor, cognitive, obsessive-compulsive-like, and social interaction deficits in Fmr1 KO mice. Disease-associated ASCC3 variants that disrupt ASCC3-FMRP interaction are also defective in ribosome association and handling of collided ribosomes. Co-immunoprecipitation of ASCC3-FMRP, ribosome association assays in cell lines and iPSC-derived neurons, Fmr1 KO mouse model with ASCC3 overexpression or CRISPRa-AAV, behavioral testing, mutagenesis of disease-associated variants Science translational medicine High 41061044
2024 ASCC3, as a key factor for ribosome rescue, suppresses ribosome collisions that arise constitutively at UUA sense codons due to transient eRF1 misreading. Depletion of ASCC3 leads to accumulation of disomes at UUA codons and triggers stress responses including induction of the stress transcription factor ATF3, indicating ASCC3 is required for translation homeostasis. Disome-Seq (ribosome profiling of collided ribosomes) with ASCC3 depletion, stress response gene expression analysis bioRxivpreprint Medium bio_10.1101_2024.09.01.610654

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2014 Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 445 25231870
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2020 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. Med (New York, N.Y.) 291 32838362
2000 Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. EMBO reports 281 11256614
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2017 Ubiquitination of stalled ribosome triggers ribosome-associated quality control. Nature communications 260 28757607
2004 Functional proteomics mapping of a human signaling pathway. Genome research 247 15231748
2018 Mapping the Genetic Landscape of Human Cells. Cell 225 30033366
2015 Structure and assembly pathway of the ribosome quality control complex. Molecular cell 194 25578875
2012 NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Molecular cell 174 23022380
2011 DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. Molecular cell 173 22055184
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
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 24 38148115
2020 The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. Nature communications 20 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 19 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 8 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
2025 The Ski2 helicase ASCC3 unwinds DNA upon fork stalling to control replication stress responses. bioRxiv : the preprint server for biology 0 40777259