Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: ASCC1 is a nuclear ASC-1/ASCC complex subunit, and both transcriptional coactivation and alkylation-damage functions occur in the nucleus. Reason: Nuclear localization is supported by the original ASC-1 complex study, the ASCC1 disease paper, UniProt, and the ASCC alkylation-damage literature. Supporting Evidence: PMID:12077347 Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei PMID:26924529 encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex.
GO:0006355 regulation of DNA-templated transcription	IBA GO_REF:0000033	ACCEPT	Summary: ASCC1 is part of the ASC-1 transcription coactivator complex and supports transcriptional activation by several transcription factors. Reason: The original ASC-1 complex paper directly supports an endogenous transcription coactivation role, and later human genetics work also frames ASCC1 as a subunit of a nuclear transcriptional coactivator complex. Supporting Evidence: PMID:12077347 these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation PMID:26924529 Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.
GO:0003723 RNA binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: ASCC1 has a predicted RNA-binding/RNA-ligase-like region, but the ASCC1-specific evidence available here supports an RNA-related domain requirement rather than direct ASCC1 RNA-binding activity. Reason: The strongest ASCC alkylation-damage papers show RNA dependence of ASCC foci and direct ssRNA binding by ASCC3, while the earlier ASCC1 paper only described a putative RNA-binding motif. A later structural study (PMID:38750793) now provides direct EMSA evidence that ASCC1 binds sequence-selectively to CGCG-containing RNA via its KH GXXG motif, so ASCC1 RNA binding is a genuine molecular activity. It is retained as non-core here because the physiological endogenous RNA targets remain undefined and the in-cell functional contribution of ASCC1 RNA binding to transcription/repair is not yet established; the action is unchanged pending that evidence. Supporting Evidence: PMID:29997253 a function that appears to depend on a putative RNA-binding motif near the ASCC1 C terminus. PMID:29144457 Purified ASCC3 bound to ssRNA in vitro
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: UniProt-derived nuclear localization is consistent with multiple experimental reports for ASCC1/ASC-1 complex biology. Reason: ASCC1 functions in nuclear transcriptional coactivation and in nuclear alkylation-damage signaling. Supporting Evidence: PMID:12077347 Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei PMID:29144457 We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents.
GO:0016607 nuclear speck	IEA GO_REF:0000044	ACCEPT	Summary: ASCC1 is reported at nuclear speckle foci before alkylation damage and redistributes after damage. Reason: The UniProt mapping is backed by the ASCC1-specific alkylation-damage paper. Supporting Evidence: PMID:29997253 ASCC1 is present at nuclear speckle foci prior to damage, but leaves the foci in response to alkylation.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This high-throughput binary interactome annotation reports an ASCC1 protein interaction but does not identify a specific ASCC1 molecular function. Reason: Generic protein binding is not informative for ASCC1. The curated model is better captured by ASC-1/ASCC complex membership, transcriptional coactivation, and alkylation-damage repair. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions.
GO:0005515 protein binding	IPI PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	MARK AS OVER ANNOTATED	Summary: ASCC1 interacts with ASCC3 in the ASCC complex, but the generic protein binding term obscures the repair-complex function. Reason: The interaction is real and important, but GO:0005515 is too broad. The same evidence is used more informatively for ASCC complex recruitment and DNA alkylation repair. Supporting Evidence: PMID:29997253 ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: BioPlex AP-MS provides interactome context but does not define a specific ASCC1 molecular function beyond complex association. Reason: Proteome-scale AP-MS is useful supporting context for physical proximity and complex membership, but generic protein binding should not be carried as a core ASCC1 function. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: The U2OS multimodal cell map integrates AP-MS and imaging data, but the resulting generic protein-binding annotation is not a specific ASCC1 function. Reason: This large-scale resource can support complex/proximity hypotheses, but ASCC1 curation should use specific ASC-1/ASCC transcription and DNA repair evidence instead of generic protein binding. Supporting Evidence: PMID:40205054 Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells.
GO:0016607 nuclear speck	EXP PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	ACCEPT	Summary: ASCC1 localizes to nuclear speckle foci before alkylation damage. Reason: This is directly reported in the ASCC1-specific alkylation-damage paper and is consistent with the RNA/splicing-associated ASCC damage response. Supporting Evidence: PMID:29997253 ASCC1 is present at nuclear speckle foci prior to damage, but leaves the foci in response to alkylation.
GO:0005634 nucleus	IDA PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	ACCEPT	Summary: ASCC1 is nuclear in the context of the ALKBH3-ASCC alkylation damage response. Reason: The ASCC complex forms nuclear foci after alkylation damage, and ASCC1 is a subunit of this nuclear repair complex. Supporting Evidence: PMID:29144457 We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents.
GO:0006260 DNA replication	NAS PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	REMOVE	Summary: The ASCC1/ASCC literature supports alkylation-damage signaling and repair, not a direct ASCC1 role in DNA replication. Reason: PMID:29997253 describes ASCC1 regulation of ASCC recruitment during alkylation damage. A related ASCC study notes that foci are largely in G1/early S phase and distinct from PCNA, which argues against curating a direct DNA replication process annotation from this evidence. Supporting Evidence: PMID:29997253 our results identify a critical regulator of the ALKBH3-ASCC alkylation damage signaling pathway PMID:29144457 These foci were largely limited to G1/early S-phase of the cell cycle PMID:29144457 These foci were also distinct from GFP-PCNA or BMI-1
GO:0006307 DNA alkylation repair	NAS PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	ACCEPT	Summary: ASCC1 regulates ASCC complex function during alkylation damage and loss of ASCC1 causes alkylation damage sensitivity. Reason: ASCC1 is not the catalytic dealkylase or helicase, but it is a required accessory/regulatory subunit for proper ASCC complex recruitment and function in the ALKBH3-linked DNA alkylation repair pathway. Supporting Evidence: PMID:29997253 ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation damage sensitivity in a manner epistatic with ASCC3. PMID:29144457 Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage PMID:22055184 Our data provide a molecular mechanism by which ALKBH3 collaborates with ASCC to maintain genomic integrity in a cell-type specific manner.
GO:1990391 DNA repair complex	IPI PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	ACCEPT	Summary: ASCC1 is a subunit of the ASCC/ALKBH3 alkylation-damage repair complex. Reason: Multiple papers place ASCC1 with ASCC2 and ASCC3 in a complex that recruits/coordinates ALKBH3-dependent repair of alkylated nucleotides. Supporting Evidence: PMID:29997253 ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit. PMID:29144457 Mass spectrometric analysis of ASCC2-associated proteins revealed the constitutive association of ASCC3 and ASCC1 PMID:22055184 Besides ALKBH3 itself, we identified numerous peptides corresponding to three subunits of the Activating Signal Co-integrator Complex
GO:0005634 nucleus	IDA PMID:12077347 Novel transcription coactivator complex containing activatin...	ACCEPT	Summary: The original ASC-1 complex study identified ASCC1/p50 in a nuclear steady-state complex. Reason: This directly supports nuclear localization for the transcriptional coactivator complex containing ASCC1. Supporting Evidence: PMID:12077347 Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei
GO:0005634 nucleus	IDA PMID:26924529 Mutations in Subunits of the Activating Signal Cointegrator ...	ACCEPT	Summary: The ASCC1 disease paper describes ASCC1 as a subunit of the nuclear ASC-1 complex. Reason: Nuclear localization is consistent with ASCC1's transcriptional coactivator role and its ASCC alkylation-damage function. Supporting Evidence: PMID:26924529 encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-112123	ACCEPT	Summary: Reactome places ALKBH3/ASCC-dependent oxidative demethylation of 1-meA damaged DNA in the nucleoplasm. Reason: This Reactome catalytic event represents ALKBH3-mediated oxidative demethylation of 1-meA damaged dsDNA in the nucleoplasm; ASCC participation is through the helicase complex that provides an appropriate DNA substrate. Supporting Evidence: Reactome:R-HSA-112123 The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-112124	ACCEPT	Summary: Reactome places ALKBH3/ASCC-dependent oxidative demethylation of 3-meC damaged DNA in the nucleoplasm. Reason: This Reactome catalytic event represents ALKBH3-mediated oxidative demethylation of 3-meC damaged dsDNA in the nucleoplasm; ASCC participation is through the helicase complex that provides an appropriate DNA substrate. Supporting Evidence: Reactome:R-HSA-112124 The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-112125	ACCEPT	Summary: Reactome places ALKBH3/ASCC-dependent oxidative dealkylation of 1-etA damaged DNA in the nucleoplasm. Reason: This Reactome catalytic event represents ALKBH3-mediated oxidative dealkylation of 1-etA damaged dsDNA in the nucleoplasm; ASCC participation is through the helicase complex that provides an appropriate DNA substrate. Supporting Evidence: Reactome:R-HSA-112125 The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-activator complex
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5657617	ACCEPT	Summary: Reactome models ALKBH3 associated with ASCC1:ASCC2:ASCC3 binding 3-meC-containing alkylated dsDNA. Reason: This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on 3-meC-containing alkylated dsDNA before the ALKBH3 catalytic repair step. Supporting Evidence: Reactome:R-HSA-5657617 ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5657637	ACCEPT	Summary: Reactome models ALKBH3 associated with ASCC1:ASCC2:ASCC3 binding 1-meA-containing alkylated dsDNA. Reason: This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on 1-meA-containing alkylated dsDNA before the ALKBH3 catalytic repair step. Supporting Evidence: Reactome:R-HSA-5657637 ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5657642	ACCEPT	Summary: Reactome models ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binding 1-etA-containing alkylated DNA. Reason: This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on 1-etA-containing alkylated DNA before the ALKBH3 catalytic repair step. Supporting Evidence: Reactome:R-HSA-5657642 ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing 1-etA
GO:0005667 transcription regulator complex	IDA PMID:12077347 Novel transcription coactivator complex containing activatin...	ACCEPT	Summary: ASCC1/p50 is part of the ASC-1 transcription coactivator complex. Reason: The original ASC-1 complex study identifies ASCC1/p50 as a component of a nuclear complex that promotes AP-1, SRF, and NF-kappaB transactivation. Supporting Evidence: PMID:12077347 Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. PMID:12077347 Here we report that ASC-1 exists as a steady-state complex associated with three polypeptides, P200, P100, and P50, in HeLa nuclei
GO:0006355 regulation of DNA-templated transcription	IDA PMID:12077347 Novel transcription coactivator complex containing activatin...	ACCEPT	Summary: ASCC1 is an ASC-1 complex subunit required for efficient activation of multiple transcription-factor outputs. Reason: Microinjection/complex-disruption experiments in the original paper support the conclusion that the endogenous hASC-1 complex is needed for AP-1, SRF, and NF-kappaB transactivation. Supporting Evidence: PMID:12077347 neutralization of endogenous P50 by single-cell microinjection of a P50 antibody inhibits AP-1 transactivation PMID:12077347 these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation
GO:0060090 molecular adaptor activity	IDA PMID:29997253 RNA ligase-like domain in activating signal cointegrator 1 c...	NEW	Summary: Proposed new molecular-function annotation for ASCC1's accessory role in coordinating ASCC complex recruitment during alkylation damage. Reason: ASCC1 interacts with ASCC3 and regulates proper ASCC complex recruitment during alkylation damage. The available evidence does not support ASCC1 as the catalytic helicase or dealkylase, so molecular adaptor activity is the most conservative molecular-function representation for this complex coordination role. Supporting Evidence: PMID:29997253 ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit. PMID:29997253 ASCC1 coordinates the proper recruitment of the ASCC complex during alkylation
GO:0003713 transcription coactivator activity	IDA PMID:12077347 Novel transcription coactivator complex containing activatin...	NEW	Summary: Proposed new molecular-function annotation for ASCC1/p50 contributing to the ASC-1 transcription coactivator complex. Reason: The original ASC-1 complex paper identifies the complex containing ASCC1/p50 as a transcriptional coactivator that enhances AP-1, SRF, and NF-kappaB transactivation. A contributes_to qualifier is more precise than asserting ASCC1 independently enables this complex-level activity, and is more informative than generic protein binding. Supporting Evidence: PMID:12077347 Human activating signal cointegrator 1 (hASC-1) was originally isolated as a transcriptional coactivator of nuclear receptors. PMID:12077347 these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation

Core Functions

ASCC1 is an accessory/regulatory subunit of the ASCC alkylation-damage response. Through association with ASCC3 and the ASCC complex, ASCC1 helps coordinate proper ASCC complex recruitment and assembly in the ALKBH3-linked repair pathway for alkylated nucleotides.

Molecular Function:

molecular adaptor activity

Directly Involved In:

DNA alkylation repair

Cellular Locations:

nucleus nuclear speck

In Complex:

DNA repair complex

Supporting Evidence:

PMID:29997253
ASCC1 coordinates the proper recruitment of the ASCC complex during alkylation
PMID:29997253
ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation damage sensitivity in a manner epistatic with ASCC3.
PMID:29144457
Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage

ASCC1/p50 is a subunit of the nuclear ASC-1 transcription coactivator complex. The complex enhances transcriptional activation by AP-1, SRF, and NF-kappaB and participates in signal-dependent gene-expression responses, including gastrin/IL-8-induced SERPINB2/PAI-2 expression.

Directly Involved In:

regulation of DNA-templated transcription

Cellular Locations:

nucleus

In Complex:

transcription regulator complex

Supporting Evidence:

PMID:12077347
these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation
PMID:19074642
Silencing at least two subunits of ASC-1, p50 and p65, inhibited gastrin-stimulated PAI-2 expression, indicating that ASC-1 acts as a transcription activator complex to regulate transcription.

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.

Identified ASCC1/p50 as part of a nuclear ASC-1 complex required for AP-1, SRF, and NF-kappaB transactivation.

"these results suggest that the endogenous hASC-1 complex appears to play an essential role in AP-1, SRF, and NF-kappaB transactivation"

PMID:19074642

Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1.

Supports a context-specific transcriptional role for ASC-1/p50 in gastrin-triggered PAI-2/SERPINB2 induction.

"Silencing at least two subunits of ASC-1, p50 and p65, inhibited gastrin-stimulated PAI-2 expression, indicating that ASC-1 acts as a transcription activator complex to regulate transcription."

PMID:22055184

DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation.

Establishes the ASCC complex as an ALKBH3-associated alkylation repair complex.

"Our data provide a molecular mechanism by which ALKBH3 collaborates with ASCC to maintain genomic integrity in a cell-type specific manner."

PMID:25416956

A proteome-scale map of the human interactome network.

High-throughput interactome resource; useful for PPI context but not sufficient to define ASCC1 core molecular function.

"Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions."

PMID:26924529

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

Human ASCC1 loss-of-function variants disrupt neuromuscular development and support ASCC1 as a nuclear ASC-1 complex subunit.

"We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex."

PMID:29144457

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

Defines a ubiquitin-dependent ASCC alkylation-damage pathway and places ASCC1 in the ASCC2/ASCC3-associated repair complex.

"Mass spectrometric analysis of ASCC2-associated proteins revealed the constitutive association of ASCC3 and ASCC1"

PMID:29997253

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

ASCC1 interacts with ASCC3, regulates ASCC complex recruitment during alkylation damage, and is required for resistance to alkylation damage.

"ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation damage sensitivity in a manner epistatic with ASCC3."

PMID:33961781

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

BioPlex AP-MS is useful large-scale interaction context but should not drive a generic protein-binding core annotation.

"Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks."

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

U2OS multimodal cell-map evidence is broad interaction/localization context rather than ASCC1-specific mechanistic evidence.

"Here we construct a global map of human subcellular architecture through joint measurement of biophysical interactions and immunofluorescence images for over 5,100 proteins in U2OS osteosarcoma cells."

PMID:37092320

The ASC-1 complex promotes translation initiation by scanning ribosomes.

The ASC-1/ASCC complex (including ASCC1) associates with scanning ribosomes and promotes translation initiation on a subset of transcripts; the experimentally emphasized motor activity is ASCC3-dependent.

PMID:37455927

Investigating the role of ASCC1 in the causation of bone fragility.

In a SMABF2 patient and in hMSCs, loss/knockdown of ASCC1 suppresses osteoblast differentiation and increases adipogenesis, with reduced RUNX2/SERPINF1 expression and TGF-beta/SMAD3 signaling, identifying ASCC1 as a pro-osteoblastogenic and anti-adipogenic regulator.

PMID:38366554

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

In a reconstituted system, ASCC-mediated disassembly of ubiquitinated ribosomal complexes does not strictly require ribosomal collision; ASCC1 is dispensable for the cytoplasmic ribosome-splitting step while remaining required for the nuclear ASCC DNA-repair function.

PMID:38750793

ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix RNA-binding motif linked to a two-histidine phosphodiesterase.

Crystal and SAXS structures define ASCC1 as a coupled KH-like (helix-clasp-helix) RNA-binding domain and a two-histidine phosphodiesterase domain; ASCC1 binds sequence-selectively to CGCG-containing RNA in a manner dependent on the KH GXXG motif.
No phosphodiesterase activity was detected on a tested 2-5A substrate, and an atypical active-site histidine rotamer implies a noncanonical substrate, so a specific catalytic reaction for ASCC1 cannot be asserted.

Reactome:R-HSA-112123

Oxidative demethylation of 1-meA damaged DNA By ALKBH3

Reactome event for ALKBH3/ASCC-dependent oxidative demethylation of 1-meA damaged DNA.

"The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex"

Reactome:R-HSA-112124

Oxidative demethylation of 3-meC damaged DNA By ALKBH3

Reactome event for ALKBH3/ASCC-dependent oxidative demethylation of 3-meC damaged DNA.

"The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-integrator complex"

Reactome:R-HSA-112125

Oxidative dealkylation of 1-EtA damaged DNA by ABH3

Reactome event for ALKBH3/ASCC-dependent oxidative dealkylation of 1-etA damaged DNA.

"The reversal of alkylating damage of dsDNA by ALKBH3 requires the presence of DNA helicase ASCC3, a component of the activating signal co-activator complex"

Reactome:R-HSA-5657617

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

Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on 3-meC-containing alkylated DNA.

"ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3"

Reactome:R-HSA-5657637

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

Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on 1-meA-containing alkylated DNA.

"ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator complex, which unwinds dsDNA, providing an appropriate substrate for ALKBH3"

Reactome:R-HSA-5657642

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

Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on 1-etA-containing alkylated DNA.

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

Suggested Experiments

Experiment: Perform ASCC1 CLIP-seq or purified-protein RNA-binding assays with wild-type ASCC1 and mutations in the C-terminal motif, coupled to rescue of ASCC2/ASCC3 foci formation after MMS treatment.

Hypothesis: ASCC1 directly binds RNA through its C-terminal RNA-ligase-like/KH region and this binding contributes to ASCC recruitment during alkylation damage.

Type: RNA-binding assay

Experiment: Compare ASCC1 knockout/rescue cells with known RQC factors in reporters for nonstop, no-go, and collided-ribosome substrates, while controlling for indirect DNA-damage and transcriptional stress effects.

Hypothesis: ASCC1 does not directly participate in cytosolic ribosome rescue despite the PN projection to ribosome-associated QC.

Type: ribosome-stalling reporter assay

Experiment: Perform ASCC1 eCLIP/PAR-CLIP in cells with and without alkylation damage, using KH GXXG-motif mutants as binding-dead controls, to define endogenous RNA targets and test whether RNA binding is required for ASCC speckle localization and damage-response recruitment.

Hypothesis: The sequence-selective CGCG RNA binding shown for ASCC1 in vitro reflects binding to specific endogenous transcripts that target ASCC complex activity to particular RNA contexts.

Type: in-cell RNA crosslinking and target identification

Deep Research

Falcon

(ASCC1-deep-research-falcon.md)

Research report: Human **ASCC1** (UniProt Q8N9N2) functional annotation Falcon Edison Scientific Literature 47 citations 2 artifacts 2026-06-07T04:50:18.620353

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000061 I have extracted Figure 1, which details ASCC1 overexpression and its correlation with poor survival in pancreatic cancer (PAAD, Pa (image/png)

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.

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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.

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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 ASCC1 (UniProt Q8N9N2) functional annotation

1. Target verification (gene/protein identity)

The UniProt accession Q8N9N2 corresponds to human ASCC1, described as “Activating signal cointegrator 1 complex subunit 1” and historically referred to as ASC-1 complex subunit p50 (P50) within the ASC-1/ASCC complex. Primary purification of the nuclear ASC-1 complex identified a “P50” subunit that contains a KH motif and is required for AP-1 transactivation, aligning with ASCC1’s KH-type RNA-binding features. (jung2002noveltranscriptioncoactivator pages 1-2, jung2002noveltranscriptioncoactivator pages 5-6)

2. Key concepts and definitions (current understanding)

2.1 The ASC-1/ASCC complex

ASC-1 was originally characterized as a transcriptional coactivator, and a steady-state ASC-1 complex purified from HeLa nuclei was shown to support transcriptional activation by multiple transcription factors (SRF, AP-1, NF-κB). (jung2002noveltranscriptioncoactivator pages 1-2)

In more recent DNA damage and translation-quality-control literature, “ASCC/ASC-1 complex” refers to a multi-subunit assembly containing ASCC1, ASCC2, ASCC3, and TRIP4/ASC-1, with context-dependent functions spanning transcriptional regulation, DNA alkylation-damage responses (via ALKBH3), and ribosome quality control. (soll2018rnaligaselikedomain pages 1-2, kito2023theasc‐1complex pages 1-2, miscicka2024ribosomalcollisionis pages 2-3)

2.2 ASCC1 domain architecture and terminology

ASCC1 is unusual in combining an N-terminal KH-like nucleic-acid-binding module with a C-terminal 2H phosphodiesterase (2H-PDE) / “RNA ligase-like” module containing two conserved HXT motifs (the hallmark of 2H phosphodiesterases). A 2024 structural study describes a previously unrecognized KH-associated structural element named a helix-clasp-helix (HCH) that contributes to nucleotide recognition, and it defines a V-shaped PDE active-site channel. (chinnam2024ascc1structuresand pages 1-2, chinnam2024ascc1structuresand pages 2-4)

3. Molecular function: what ASCC1 does (best-supported)

3.1 Molecular activity 1 (validated): sequence-selective RNA binding

The strongest direct biochemical activity currently demonstrated for ASCC1 is sequence-selective RNA binding. Using EMSA with a panel of short RNAs, ASCC1 bound specifically to CGCG-containing RNA under stringent salt conditions, with detectable binding at ~60 nM protein. Mutation of the KH GXXG motif (GXXG→GDDG) abolished binding, and the analogous DNA sequence did not show a mobility shift, supporting RNA-selective recognition. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 8-9)

Interpretation: ASCC1 likely functions as an RNA-binding regulatory subunit whose specificity and binding geometry may target the ASC-1/ASCC machinery to particular RNA contexts (e.g., specific sequence motifs or structured regions), but the physiologic endogenous RNA targets remain to be defined. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 14-15)

3.2 Molecular activity 2 (structurally plausible but not yet substrate-validated): 2H phosphodiesterase-like chemistry

ASCC1’s C-terminal domain is structurally homologous to 2H phosphodiesterases, with two HXT motifs positioned in a V-shaped channel consistent with cyclic phosphate chemistry. (chinnam2024ascc1structuresand pages 1-2, chinnam2024ascc1structuresand pages 14-15)

However, direct enzymatic activity remains unresolved: a 2024 HPLC-based assay detected no cleavage of a tested 2-5A substrate (2′–5′ oligoadenylate analog) by human or Alvinella ASCC1, while a positive control PDE (rotavirus VP3-CTD) showed robust cleavage (>95%). This indicates either (i) a different physiological substrate, (ii) requirement for cofactors/partners, or (iii) a regulated/low-activity PDE state. (chinnam2024ascc1structuresand pages 9-11)

3.3 Key interaction partner: ASCC3 as a scaffold linking ASCC1 to ASCC2

In vitro pulldown and co-immunoprecipitation experiments support that ASCC1 binds ASCC3 directly, while ASCC1 and ASCC2 do not detectably bind each other in isolation; instead, ASCC3 mediates/scaffolds the ASCC1–ASCC2 association. (soll2018rnaligaselikedomain pages 1-2, soll2019theroleof pages 64-71)

4. Cellular localization and functional pathways

4.1 Nuclear speckles and alkylation damage response (ALKBH3–ASCC axis)

Subcellular localization: ASCC1 localizes constitutively to nuclear speckle-like foci and co-localizes with the spliceosomal component PRP8, supporting a nuclear role in RNA-linked processes. Upon alkylation damage (e.g., MMS), ASCC1 is removed from these foci. (soll2018rnaligaselikedomain pages 1-2, soll2019theroleof pages 64-71)

Functional role in alkylation damage response: Genetic and cell-biology evidence indicates ASCC1 is a regulator of ASCC complex recruitment/assembly during alkylation damage.

ASCC1 knockout increases MMS-induced ASCC3 foci formation yet many such foci lack ASCC2, indicating dysregulated complex assembly. (soll2018rnaligaselikedomain pages 6-7, soll2019theroleof pages 71-85)
ASCC1 knockout reduces ASCC2–ASCC3 association in co-IP assays and decreases ASCC2/ASCC3 co-localization after damage. (soll2019theroleof pages 71-85)
ASCC1 knockout increases sensitivity to MMS in a manner epistatic with ASCC3, consistent with ASCC1 functioning within the same pathway rather than in a parallel repair route. (soll2019theroleof pages 71-85)

Mechanistic implication: ASCC1 appears to coordinate correct ASCC2–ASCC3 recruitment to damage-associated loci and thereby supports ALKBH3-coupled alkylation repair (where ALKBH3 reverses lesions such as 1-methyladenine and 3-methylcytosine on ssDNA/RNA), but ASCC1 itself is not the dealkylase. (soll2018rnaligaselikedomain pages 6-7, chinnam2024ascc1structuresand pages 1-2)

4.2 Transcriptional coactivation (historical “primary” function of ASC-1 complex)

A canonical primary study demonstrated that the nuclear ASC-1 complex stimulates transcriptional activation by SRF, AP-1, and NF-κB, and directly tested the necessity of the P50 subunit (ASCC1) for AP-1 activation in vivo.

Specifically, microinjection of an anti-P50 antibody nearly abolished TPA-induced AP-1 reporter activation; this inhibition was rescued by expressing wild-type P50, but not by a KH-mutant P50 that fails to interact properly within the complex. This provides direct functional evidence that ASCC1/P50 is required for AP-1 transactivation and that its RNA-binding KH region is functionally important. (jung2002noveltranscriptioncoactivator pages 5-6)

4.3 Ribosome quality control (RQC) and translation initiation (recent expansion of function)

RQC (ribosome splitting) context: The ASCC complex is now recognized as a key effector downstream of ZNF598-mediated ubiquitination of stalled/collided ribosomes. A 2024 reconstitution study emphasizes that ASCC-mediated dissociation can occur without ribosome collision provided ribosomes are ubiquitinated and have adequate 3′ mRNA overhang. (miscicka2024ribosomalcollisionis pages 2-3)

ASCC1’s role within this cytoplasmic RQC function appears limited: ASCC1 is reported as dispensable for dissociation of stalled ribosomes, while being essential for ASCC’s nuclear DNA-repair function. (miscicka2024ribosomalcollisionis pages 2-3)

Translation initiation/scanning: A 2023 EMBO Journal study reported that the ASC-1/ASCC complex associates with scanning ribosomes. Proteomics identified ASCC1 along with other ASCC components in eIF4A1-bound scanning ribosome preparations, supporting a physical presence of ASCC1 within scanning-ribosome-associated complexes, even though functional experiments highlighted ASCC3 knockdown effects on scanning dynamics. (kito2023theasc‐1complex pages 1-2)

5. Recent developments (prioritizing 2023–2024)

5.1 2024: ASCC1 structural and biochemical mechanism (RNA-binding motif + 2H-PDE active site)

A 2024 Journal of Biological Chemistry paper provided high-resolution structures and SAXS evidence defining ASCC1 as the first solved protein with a linked KH and 2H-PDE module in a relatively rigid arrangement. It also experimentally established CGCG RNA sequence preference and identified structural constraints suggesting a noncanonical PDE substrate (including an atypical conserved histidine rotamer in the second HXT motif). (chinnam2024ascc1structuresand pages 2-4, chinnam2024ascc1structuresand pages 9-11)

5.2 2024: ASCC-mediated RQC does not require collision (and ASCC1 is dispensable for ribosome splitting)

A 2024 Nucleic Acids Research study reconstituted ASCC activity and concluded that ribosome collision is not strictly required for ZNF598-mediated ubiquitination or for ASCC-mediated dissociation. Importantly for functional annotation, this work explicitly distinguishes ASCC1 as dispensable for the ribosome-splitting activity while noting its necessity for nuclear DNA repair function. (miscicka2024ribosomalcollisionis pages 2-3)

5.3 2023: ASCC1 in human bone biology and SMABF2 mechanism

A 2023 Frontiers in Endocrinology study investigated ASCC1 in the context of SMABF2, integrating patient genetics with functional assays. Key quantitative results included:

In an SMABF2 case with a homozygous ASCC1 deletion, ASCC1 RNA and protein were “hardly expressed” in fibroblasts. (voraberger2023investigatingtherole pages 1-2)
RUNX2 and SERPINF1 expression were reduced by >50% (p < 0.05), and TGF-β/SMAD signaling showed >40% reduction in SMAD3 phosphorylation after ligand stimulation (p < 0.01). (voraberger2023investigatingtherole pages 8-9)
ASCC1 knockdown in human MSCs suppressed osteoblast differentiation with >90% reduction in incorporated calcium by day 25 and increased adipogenesis with ~50% more Oil Red O–positive cells, including 2.5-fold increase in PPARG expression at day 17. (voraberger2023investigatingtherole pages 8-9)
The bone microenvironment showed marked marrow adiposity (adipocytes covering 19.9% of marrow area) and ~50% reduction in trabecular bone volume versus reference. (voraberger2023investigatingtherole pages 4-6)

These results support a model where ASCC1 is a pro-osteoblastogenic and anti-adipogenic regulator, linking a molecular defect in a transcription/RNA-associated complex to a bone fragility phenotype. (voraberger2023investigatingtherole pages 1-2, voraberger2023investigatingtherole pages 8-9)

6. Human genetics, disease associations, and real-world implementation

6.1 SMABF2 diagnosis and variant interpretation

ASCC1 biallelic loss-of-function variants cause spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a severe congenital disorder.

Clinical genetics implementation is well established in case reports/series:

Whole-exome sequencing identified a homozygous frameshift (c.157dupG; p.Glu53Glyfs*19) and segregation confirmed autosomal recessive inheritance. (oliveira2017thenewneuromuscular pages 5-8)
Whole genome sequencing plus parental cDNA studies were used to functionally validate a novel intronic splice-altering variant, demonstrating integration of sequencing with transcript-level assays in diagnosis. (rosano2021biallelicascc1variants pages 1-2)

A 2021 review summarized that ASCC1 mutations had been reported in 7 families (12 patients) and that congenital bone fractures were part of the phenotype in all ASCC1-mutated patients described. (meunier2021inheriteddefectsof pages 5-6, meunier2021inheriteddefectsof pages 11-12)

A 2023 SMABF2-focused cohort summary reported 18 SMABF2 patients (17 with congenital bone fractures) from 13 unrelated families, indicating growing case ascertainment and providing context for clinical interpretation of new ASCC1 variants. (voraberger2023investigatingtherole pages 2-3)

6.2 Cancer expression and prognosis (exploratory/biomarker-level)

A 2024 JBC study used TCGA-scale analyses (~7000 tumor samples) and reported that ASCC1 mRNA levels were significantly higher in tumors than matched controls in 7/15 tumor types examined. In pancreatic adenocarcinoma, high ASCC1 expression was associated with worse survival, with a reported hazard ratio ~3.7 for poor prognosis in the high-expression group. (chinnam2024ascc1structuresand pages 2-4)

These analyses support ASCC1 as a candidate prognostic marker in some tumor contexts; however, they remain bioinformatic associations rather than a clinically qualified biomarker. (chinnam2024ascc1structuresand pages 2-4)

7. Expert synthesis and open questions

7.1 Primary function (most defensible functional phrasing)

Across the best-supported literature, ASCC1 is most defensibly annotated as a regulatory RNA-binding subunit of the ASC-1/ASCC complex that:

1) contributes to transcriptional coactivation (notably AP-1), (jung2002noveltranscriptioncoactivator pages 5-6)
2) regulates nuclear ASCC complex organization during the ALKBH3-associated alkylation damage response, (soll2018rnaligaselikedomain pages 1-2, soll2019theroleof pages 71-85)
3) participates (as a component of the larger complex) in translation-linked processes (scanning ribosomes), while being dispensable for the core ribosome-splitting step in some RQC reconstitution settings. (kito2023theasc‐1complex pages 1-2, miscicka2024ribosomalcollisionis pages 2-3)

7.2 Enzymology caution

Although ASCC1’s C-terminus has strong structural signatures of a 2H phosphodiesterase, the absence of activity on a tested substrate and the predicted noncanonical active-site configuration argue against asserting a specific catalytic reaction or substrate specificity at present. The most evidence-based statement is that ASCC1 contains a 2H-PDE-like domain with unresolved physiological substrate, and that its validated activity is RNA binding (CGCG preference). (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 14-15)

8. Visual evidence from recent primary literature

TCGA expression and survival association (including pancreatic adenocarcinoma survival curves) and supporting panels are shown in Chinnam et al. 2024 Figure 1. (chinnam2024ascc1structuresand media 43f11e65)
KH/PDE domain organization and structural framework are shown in Chinnam et al. 2024 structural figures (domain architecture). (chinnam2024ascc1structuresand media 8de0a236)
EMSA evidence for sequence-specific RNA binding (CGCG) and related structural panels are shown in Chinnam et al. 2024 Figure 6. (chinnam2024ascc1structuresand media e9b370fb)

9. Evidence map (quick reference)

Aspect	Current best-supported conclusion	Key evidence (brief)	Representative primary sources (with year, journal)	URL/DOI
Identity / aliases	Human ASCC1 encodes activating signal cointegrator 1 complex subunit 1, also known as ASC-1 complex subunit p50; it is a subunit of the ASC-1/ASCC complex rather than an independently validated catalytic repair enzyme. (jung2002noveltranscriptioncoactivator pages 1-2, soll2018rnaligaselikedomain pages 1-2)	Original purification identified a steady-state ASC-1 complex from HeLa nuclei containing P200, P100, and P50; later DNA-damage work defines ASCC as containing ASCC1, ASCC2, ASCC3 associated with ALKBH3. (jung2002noveltranscriptioncoactivator pages 1-2, brickner2019activationandregulation pages 22-26, soll2018rnaligaselikedomain pages 1-2)	Jung et al., 2002, Mol Cell Biol; Soll et al., 2018, J Biol Chem	https://doi.org/10.1128/MCB.22.14.5203-5211.2002; https://doi.org/10.1074/jbc.RA117.000114
Domain architecture (KH/HCH + 2H-PDE)	ASCC1 has an N-terminal KH-like RNA-binding domain that includes a newly defined helix-clasp-helix (HCH) nucleotide-binding motif, fused to a C-terminal two-histidine phosphodiesterase (2H-PDE)/RNA ligase-like domain with two HXT motifs. (chinnam2024ascc1structuresand pages 1-2, chinnam2024ascc1structuresand pages 2-4, chinnam2024ascc1structuresand pages 5-8)	Crystal structures and SAXS in 2024 showed a compact KH–PDE arrangement with limited flexibility; the PDE forms a V-shaped channel with two HXT motifs and unusual active-site geometry. (chinnam2024ascc1structuresand pages 1-2, chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 8-9)	Chinnam et al., 2024, J Biol Chem	https://doi.org/10.1016/j.jbc.2024.107368
Molecular activities: RNA binding specificity	Best-supported direct biochemical activity is sequence-selective RNA binding, with preference for CGCG-containing RNA; binding depends on the KH GXXG motif. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 1-2)	EMSA with eight 12-nt RNAs found binding only to the CGCG-containing RNA under stringent salt; binding detectable at ~60 nM protein; GXXG→GDDG mutation abolished binding; corresponding DNA did not shift. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 8-9)	Chinnam et al., 2024, J Biol Chem	https://doi.org/10.1016/j.jbc.2024.107368
Molecular activities: PDE activity status	ASCC1’s C-terminal domain is structurally a 2H-PDE, but direct phosphodiesterase activity is not yet validated for the physiological substrate; tested cleavage of 2-5A was negative, implying a different or regulated substrate. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 1-2)	HPLC assays showed no detectable cleavage of 2-5A by human or A. pompejana ASCC1, while positive control VP3-CTD cleaved >95%; structural analysis still supports cyclic-phosphate chemistry potential. (chinnam2024ascc1structuresand pages 9-11, chinnam2024ascc1structuresand pages 14-15)	Chinnam et al., 2024, J Biol Chem	https://doi.org/10.1016/j.jbc.2024.107368
Complex membership / partners	ASCC1 is a component of the ASC-1/ASCC complex with ASCC2, ASCC3, and TRIP4/ASC-1; in alkylation repair it functionally connects to the ALKBH3–ASCC pathway. Direct binding is strongest for ASCC3, which scaffolds ASCC1–ASCC2 association. (soll2019theroleof pages 64-71, soll2018rnaligaselikedomain pages 1-2, kito2023theasc‐1complex pages 1-2)	Recombinant pulldown: His-ASCC3 binds GST-ASCC1; ASCC1 and ASCC2 do not bind each other directly; co-IPs show ASCC3 bridges ASCC1 with ASCC2. Kito et al. detected ASCC1, ASCC2, ASCC3, TRIP4 on scanning ribosomes. (soll2019theroleof pages 64-71, soll2018rnaligaselikedomain pages 1-2, kito2023theasc‐1complex pages 1-2)	Soll et al., 2018, J Biol Chem; Kito et al., 2023, EMBO J	https://doi.org/10.1074/jbc.RA117.000114; https://doi.org/10.15252/embj.2022112869
Subcellular localization and dynamics	ASCC1 is predominantly nuclear, localizes constitutively to nuclear speckles that overlap with PRP8, and leaves these foci after alkylation damage; unlike ASCC2/ASCC3, its basal speckle localization precedes damage. (soll2018rnaligaselikedomain pages 1-2, soll2019theroleof pages 64-71, soll2019theroleof pages 71-85)	IF microscopy showed HA-ASCC1 in nuclear speckles before damage and reduced speckle localization after MMS; ASCC1 KO increases ASCC3 foci yet reduces ASCC2–ASCC3 co-localization, indicating a regulatory role in assembly/recruitment. (soll2019theroleof pages 64-71, soll2019theroleof pages 95-99, soll2019theroleof pages 71-85)	Soll et al., 2018, J Biol Chem	https://doi.org/10.1074/jbc.RA117.000114
Pathway: alkylation damage response	ASCC1 acts as a regulatory/accessory factor in the ALKBH3–ASCC alkylation damage response, helping proper recruitment/organization of ASCC2–ASCC3 at damaged sites rather than directly catalyzing dealkylation. (soll2019theroleof pages 64-71, soll2019theroleof pages 71-85, soll2018rnaligaselikedomain pages 6-7)	ASCC1 KO causes MMS hypersensitivity and is epistatic with ASCC3; loss of ASCC1 increases ASCC3 foci but many lack ASCC2; HXT-motif/C-terminal mutants fail to rescue proper ASCC2–ASCC3 co-localization. (soll2019theroleof pages 95-99, brickner2019activationandregulation pages 94-105, soll2019theroleof pages 71-85)	Soll et al., 2018, J Biol Chem; Dango et al., 2011, Mol Cell (pathway context for ALKBH3-ASCC)	https://doi.org/10.1074/jbc.RA117.000114; https://doi.org/10.1016/j.molcel.2011.08.039
Pathway: transcriptional coactivation	The strongest classical evidence supports ASCC1/P50 as a transcriptional coactivator component required for AP-1 transactivation, within an ASC-1 complex that also stimulates SRF and NF-κB signaling. (jung2002noveltranscriptioncoactivator pages 1-2, jung2002noveltranscriptioncoactivator pages 5-6, meunier2021inheriteddefectsof pages 6-8)	Anti-P50 microinjection nearly abolished TPA-induced AP-1 reporter activation; rescue occurred with WT P50 but not KH-mutant P50, arguing ASCC1 is functionally required in vivo for AP-1 transactivation. (jung2002noveltranscriptioncoactivator pages 5-6)	Jung et al., 2002, Mol Cell Biol	https://doi.org/10.1128/MCB.22.14.5203-5211.2002
Pathway: ribosome quality control (RQC)	ASCC participates in mammalian RQC, but current evidence indicates ASCC1 is dispensable for ribosome splitting/stall resolution in at least some cytoplasmic settings, whereas ASCC3 helicase and likely ASCC2 ubiquitin interactions are the core required activities. (miscicka2024ribosomalcollisionis pages 2-3, meunier2021inheriteddefectsof pages 8-9, meunier2021inheriteddefectsof pages 6-8)	2024 NAR and prior review evidence state ASCC1 is essential for nuclear DNA-repair function but dispensable for stalled-ribosome dissociation; ASCC can split ubiquitinated queues, monosomes, and 48S complexes when mRNA overhang and ubiquitin requirements are met. (miscicka2024ribosomalcollisionis pages 2-3)	Miścicka et al., 2024, Nucleic Acids Res; Meunier et al., 2021, Int J Mol Sci	https://doi.org/10.1093/nar/gkae087; https://doi.org/10.3390/ijms22116039
Pathway: translation initiation / scanning	A 2023 advance suggests the ASC-1/ASCC complex also promotes translation initiation by scanning ribosomes on a subset of transcripts; ASCC1 is present in the scanning-ribosome-associated complex, although ASCC3 is the experimentally emphasized motor subunit. (kito2023theasc‐1complex pages 1-2, miscicka2024ribosomalcollisionis pages 2-3)	Sel-TCP-MS identified ASCC1, ASCC2, ASCC3, and TRIP4 on eIF4A1-bound scanning ribosomes; ASCC3 knockdown impaired 43S loading/scanning dynamics and reduced translation efficiency for selected transcripts. (kito2023theasc‐1complex pages 1-2)	Kito et al., 2023, EMBO J	https://doi.org/10.15252/embj.2022112869
Human disease: SMABF2	Biallelic loss-of-function ASCC1 variants cause SMABF2 (spinal muscular atrophy with congenital bone fractures 2), a severe congenital neuromuscular/bone fragility disorder. (voraberger2023investigatingtherole pages 1-2, rosano2021biallelicascc1variants pages 1-2, meunier2021inheriteddefectsof pages 11-12)	WES/WGS and cDNA studies identified nonsense, frameshift, splice, and deletion alleles; patient fibroblasts showed near-absent ASCC1; functional work supports impaired osteoblastogenesis and enhanced adipogenesis. (rosano2021biallelicascc1variants pages 1-2, voraberger2023investigatingtherole pages 1-2)	Knierim et al., 2016, Am J Hum Genet; Rosano et al., 2021, Am J Med Genet A; Voraberger et al., 2023, Front Endocrinol	https://doi.org/10.1016/j.ajhg.2016.01.006; https://doi.org/10.1002/ajmg.a.62219; https://doi.org/10.3389/fendo.2023.1137573
Cancer / prognostic biomarker data	ASCC1 is not an established clinical biomarker, but recent analyses suggest it may have prognostic value, especially in pancreatic cancer and some other tumor types; interpretation remains exploratory. (chinnam2024ascc1structuresand pages 2-4)	TCGA analysis across ~7000 tumor samples found ASCC1 mRNA higher in tumors in 7/15 tumor types and lower in 3/15; in pancreatic adenocarcinoma, high ASCC1 expression associated with poorer survival with hazard ratio ~3.7. (chinnam2024ascc1structuresand pages 2-4)	Chinnam et al., 2024, J Biol Chem	https://doi.org/10.1016/j.jbc.2024.107368
Key quantitative statistics	Frequently cited current quantitative anchors: CGCG RNA binding detectable at ~60 nM; 2-5A cleavage undetectable for ASCC1 in HPLC assay; 7/15 tumor types with higher ASCC1 expression; PAAD HR ~3.7 for high ASCC1; 18 SMABF2 patients from 13 families summarized in 2023 review context; in hMSCs, ASCC1 knockdown caused >90% reduction in mineralization, ~50% increase in adipogenesis, >40% reduction in SMAD3 phosphorylation, and >50% downregulation of RUNX2/SERPINF1. (chinnam2024ascc1structuresand pages 9-11, voraberger2023investigatingtherole pages 8-9, voraberger2023investigatingtherole pages 2-3, chinnam2024ascc1structuresand pages 2-4)	These values come from biochemical EMSA/HPLC, TCGA survival/expression analysis, and disease-mechanism studies in patient cells/hMSCs. (chinnam2024ascc1structuresand pages 9-11, voraberger2023investigatingtherole pages 8-9, chinnam2024ascc1structuresand pages 2-4)	Chinnam et al., 2024, J Biol Chem; Voraberger et al., 2023, Front Endocrinol	https://doi.org/10.1016/j.jbc.2024.107368; https://doi.org/10.3389/fendo.2023.1137573

Table: This table summarizes the best-supported functional annotation for human ASCC1 (UniProt Q8N9N2), including molecular function, complexes, pathways, disease relevance, and recent quantitative findings. It is designed as a concise evidence map for rapid reference in the full report.

Key sources (URLs; publication dates)

Chinnam NB et al. ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix RNA-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry. Jun 2024. https://doi.org/10.1016/j.jbc.2024.107368 (chinnam2024ascc1structuresand pages 2-4)
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 2-3)
Voraberger B et al. Investigating the role of ASCC1 in the causation of bone fragility. Frontiers in Endocrinology. 30 Jun 2023. https://doi.org/10.3389/fendo.2023.1137573 (voraberger2023investigatingtherole pages 1-2)
Kito Y et al. The ASC-1 complex promotes translation initiation by scanning ribosomes. The EMBO Journal. 24 Apr 2023 (online). https://doi.org/10.15252/embj.2022112869 (kito2023theasc‐1complex pages 1-2)
Soll JM et al. RNA ligase-like domain in 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)
Jung D-J et al. Novel Transcription Coactivator Complex Containing Activating Signal Cointegrator 1. Molecular and Cellular Biology. Jul 2002. https://doi.org/10.1128/MCB.22.14.5203-5211.2002 (jung2002noveltranscriptioncoactivator pages 1-2)
Knierim E et al. Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures. American Journal of Human Genetics. Mar 2016. https://doi.org/10.1016/j.ajhg.2016.01.006 (knierim2016mutationsinsubunits pages 8-9)

References

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(chinnam2024ascc1structuresand pages 1-2): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand pages 2-4): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand pages 9-11): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand pages 8-9): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand pages 14-15): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(soll2019theroleof pages 64-71): 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.
(soll2018rnaligaselikedomain pages 6-7): 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.
(soll2019theroleof pages 71-85): 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.
(voraberger2023investigatingtherole pages 1-2): Barbara Voraberger, Johannes A. Mayr, Nadja Fratzl-Zelman, Stéphane Blouin, Suma Uday, Robert Kopajtich, Marijke Koedam, Helena Hödlmayr, Saskia B. Wortmann, Bernhard Csillag, Holger Prokisch, Bram C. J. van der Eerden, Ahmed El-Gazzar, and Wolfgang Högler. Investigating the role of ascc1 in the causation of bone fragility. Frontiers in Endocrinology, Jun 2023. URL: https://doi.org/10.3389/fendo.2023.1137573, doi:10.3389/fendo.2023.1137573. This article has 8 citations.
(voraberger2023investigatingtherole pages 8-9): Barbara Voraberger, Johannes A. Mayr, Nadja Fratzl-Zelman, Stéphane Blouin, Suma Uday, Robert Kopajtich, Marijke Koedam, Helena Hödlmayr, Saskia B. Wortmann, Bernhard Csillag, Holger Prokisch, Bram C. J. van der Eerden, Ahmed El-Gazzar, and Wolfgang Högler. Investigating the role of ascc1 in the causation of bone fragility. Frontiers in Endocrinology, Jun 2023. URL: https://doi.org/10.3389/fendo.2023.1137573, doi:10.3389/fendo.2023.1137573. This article has 8 citations.
(voraberger2023investigatingtherole pages 4-6): Barbara Voraberger, Johannes A. Mayr, Nadja Fratzl-Zelman, Stéphane Blouin, Suma Uday, Robert Kopajtich, Marijke Koedam, Helena Hödlmayr, Saskia B. Wortmann, Bernhard Csillag, Holger Prokisch, Bram C. J. van der Eerden, Ahmed El-Gazzar, and Wolfgang Högler. Investigating the role of ascc1 in the causation of bone fragility. Frontiers in Endocrinology, Jun 2023. URL: https://doi.org/10.3389/fendo.2023.1137573, doi:10.3389/fendo.2023.1137573. This article has 8 citations.
(oliveira2017thenewneuromuscular pages 5-8): Jorge Oliveira, Márcia Martins, R. P. Leite, M. Sousa, and Rosário Santos. The new neuromuscular disease related with defects in the asc‐1 complex: report of a second case confirms ascc1 involvement. Clinical Genetics, 92:434-439, Oct 2017. URL: https://doi.org/10.1111/cge.12997, doi:10.1111/cge.12997. This article has 43 citations and is from a peer-reviewed journal.
(rosano2021biallelicascc1variants pages 1-2): Kristen K. Rosano, Daniel J. Wegner, Marwan Shinawi, Dustin Baldridge, Robert C. Bucelli, Sonika Dahiya, Frances V. White, Marcia C. Willing, William McAllister, Ryan J. Taft, Krista Bluske, Amanda Buchanan, Francis Sessions Cole, and Jennifer A. Wambach. Biallelic ascc1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (smabf2). American Journal of Medical Genetics Part A, 185:2190-2197, May 2021. URL: https://doi.org/10.1002/ajmg.a.62219, doi:10.1002/ajmg.a.62219. This article has 15 citations.
(meunier2021inheriteddefectsof pages 5-6): Justine Meunier, Rocio-Nur Villar-Quiles, Isabelle Duband-Goulet, and Ana Ferreiro. Inherited defects of the asc-1 complex in congenital neuromuscular diseases. International Journal of Molecular Sciences, 22:6039, Jun 2021. URL: https://doi.org/10.3390/ijms22116039, doi:10.3390/ijms22116039. This article has 18 citations.
(meunier2021inheriteddefectsof pages 11-12): Justine Meunier, Rocio-Nur Villar-Quiles, Isabelle Duband-Goulet, and Ana Ferreiro. Inherited defects of the asc-1 complex in congenital neuromuscular diseases. International Journal of Molecular Sciences, 22:6039, Jun 2021. URL: https://doi.org/10.3390/ijms22116039, doi:10.3390/ijms22116039. This article has 18 citations.
(voraberger2023investigatingtherole pages 2-3): Barbara Voraberger, Johannes A. Mayr, Nadja Fratzl-Zelman, Stéphane Blouin, Suma Uday, Robert Kopajtich, Marijke Koedam, Helena Hödlmayr, Saskia B. Wortmann, Bernhard Csillag, Holger Prokisch, Bram C. J. van der Eerden, Ahmed El-Gazzar, and Wolfgang Högler. Investigating the role of ascc1 in the causation of bone fragility. Frontiers in Endocrinology, Jun 2023. URL: https://doi.org/10.3389/fendo.2023.1137573, doi:10.3389/fendo.2023.1137573. This article has 8 citations.
(chinnam2024ascc1structuresand media 43f11e65): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand media 8de0a236): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(chinnam2024ascc1structuresand media e9b370fb): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(brickner2019activationandregulation pages 22-26): 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.
(chinnam2024ascc1structuresand pages 5-8): Naga babu Chinnam, Roopa Thapar, Andrew S. Arvai, Altaf H. Sarker, Jennifer M. Soll, Tanmoy Paul, Aleem Syed, Daniel J. Rosenberg, Michal Hammel, Albino Bacolla, Panagiotis Katsonis, Abhishek Asthana, Miaw-Sheue Tsai, Ivaylo Ivanov, Olivier Lichtarge, Robert H. Silverman, Nima Mosammaparast, Susan E. Tsutakawa, and John A. Tainer. Ascc1 structures and bioinformatics reveal a novel helix-clasp-helix rna-binding motif linked to a two-histidine phosphodiesterase. Journal of Biological Chemistry, 300:107368, Jun 2024. URL: https://doi.org/10.1016/j.jbc.2024.107368, doi:10.1016/j.jbc.2024.107368. This article has 7 citations and is from a domain leading peer-reviewed journal.
(soll2019theroleof pages 95-99): 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.
(brickner2019activationandregulation pages 94-105): 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.
(meunier2021inheriteddefectsof pages 6-8): Justine Meunier, Rocio-Nur Villar-Quiles, Isabelle Duband-Goulet, and Ana Ferreiro. Inherited defects of the asc-1 complex in congenital neuromuscular diseases. International Journal of Molecular Sciences, 22:6039, Jun 2021. URL: https://doi.org/10.3390/ijms22116039, doi:10.3390/ijms22116039. This article has 18 citations.
(meunier2021inheriteddefectsof pages 8-9): Justine Meunier, Rocio-Nur Villar-Quiles, Isabelle Duband-Goulet, and Ana Ferreiro. Inherited defects of the asc-1 complex in congenital neuromuscular diseases. International Journal of Molecular Sciences, 22:6039, Jun 2021. URL: https://doi.org/10.3390/ijms22116039, doi:10.3390/ijms22116039. This article has 18 citations.
(knierim2016mutationsinsubunits pages 8-9): Ellen Knierim, Hiromi Hirata, Nicole I. Wolf, Susanne Morales-Gonzalez, Gudrun Schottmann, Yu Tanaka, Sabine Rudnik-Schöneborn, Mickael Orgeur, Klaus Zerres, Stefanie Vogt, Anne van Riesen, Esther Gill, Franziska Seifert, Angelika Zwirner, Janbernd Kirschner, Hans Hilmar Goebel, Christoph Hübner, Sigmar Stricker, David Meierhofer, Werner Stenzel, and Markus Schuelke. Mutations in subunits of the activating signal cointegrator 1 complex are associated with prenatal spinal muscular atrophy and congenital bone fractures. American journal of human genetics, 98 3:473-489, Mar 2016. URL: https://doi.org/10.1016/j.ajhg.2016.01.006, doi:10.1016/j.ajhg.2016.01.006. This article has 94 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

jung2002noveltranscriptioncoactivator pages 1-2
soll2019theroleof pages 71-85
jung2002noveltranscriptioncoactivator pages 5-6
miscicka2024ribosomalcollisionis pages 2-3
voraberger2023investigatingtherole pages 1-2
voraberger2023investigatingtherole pages 8-9
voraberger2023investigatingtherole pages 4-6
oliveira2017thenewneuromuscular pages 5-8
voraberger2023investigatingtherole pages 2-3
soll2018rnaligaselikedomain pages 1-2
knierim2016mutationsinsubunits pages 8-9
soll2019theroleof pages 64-71
soll2018rnaligaselikedomain pages 6-7
meunier2021inheriteddefectsof pages 5-6
meunier2021inheriteddefectsof pages 11-12
brickner2019activationandregulation pages 22-26
soll2019theroleof pages 95-99
brickner2019activationandregulation pages 94-105
meunier2021inheriteddefectsof pages 6-8
meunier2021inheriteddefectsof pages 8-9
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https://doi.org/10.1016/j.jbc.2024.107368
https://doi.org/10.1074/jbc.RA117.000114;
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https://doi.org/10.15252/embj.2022112869,
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https://doi.org/10.1016/j.ajhg.2016.01.006,

📚 Additional Documentation

Notes

(ASCC1-notes.md)

ASCC1 review notes

Deep research status

Attempted just deep-research-falcon human ASCC1 --fallback perplexity-lite on
2026-06-03. Falcon timed out after the wrapper's 600-second provider timeout, and
the configured perplexity-lite fallback failed with a Perplexity API 401 quota
error. No ASCC1-deep-research-falcon.md or fallback provider report was
created. This review therefore uses the cached primary literature, UniProt/GOA,
Reactome entries, and the PN projection report directly.

Summary

ASCC1 encodes the p50 subunit of the human ASC-1/ASCC complex. The strongest
evidence supports two connected nuclear roles:

transcription coactivation as part of ASC-1, with the endogenous complex
required for AP-1, SRF, and NF-kappaB transactivation PMID:12077347.
accessory/regulatory participation in ALKBH3-ASCC DNA alkylation repair,
where ASCC1 interacts through ASCC3 and coordinates proper ASCC recruitment
during alkylation damage PMID:29997253.

Human loss-of-function genetics supports biological importance in neuromuscular
development, but the immediate molecular interpretation remains ASC-1/ASCC
complex dysfunction rather than an independent developmental signaling activity
PMID:26924529.

Proteostasis PN projection

The PN projection report proposes two candidate additions for ASCC1:
GO:0006515 protein quality control for misfolded or incompletely synthesized
proteins and GO:0072344 rescue of stalled cytosolic ribosome, from
Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
"ASCC1 GO:0072344 rescue of stalled cytosolic ribosome"].

I did not promote these to ASCC1 GO annotations. The ASCC1-specific literature
reviewed here supports nuclear ASCC transcription and alkylation-damage repair,
not cytosolic ribosome rescue. The key ASCC alkylation-damage paper says ASCC1
loss affects ASCC3/ASCC2 recruitment and MMS sensitivity PMID:29997253. The broader ASCC pathway paper ties ASCC
foci to alkylated nucleotides, elongating RNA polymerase II, splicing factors,
and K63-linked ubiquitin signaling rather than ribosome rescue PMID:29144457.

Conservative PN decision: treat the ASCC1 ribosomal-rescue/RQC projection as
unsupported by ASCC1-specific evidence in this review. It remains a suggested
expert question rather than a proposed annotation.

Annotation decisions

Accepted nuclear and nuclear-speck localization. PMID:29997253 directly says
ASCC1 is present at nuclear speckle foci before damage and leaves those foci
after alkylation PMID:29997253.
Accepted DNA alkylation repair and DNA repair complex participation. PMID
22055184 establishes ALKBH3 association with ASCC and a repair mechanism
PMID:22055184. PMID:29144457 establishes an alkylation-specific ubiquitin pathway
and ASCC1/ASCC3 complex association PMID:29144457.
Removed DNA replication. The cited ASCC1 paper supports alkylation damage
repair, not DNA replication. The related ASCC pathway paper reports foci in
G1/early S and distinct from PCNA, which is insufficient for direct DNA
replication curation PMID:29144457.
Marked generic protein binding annotations as over-annotated. ASCC1 physical
interactions are real, especially with ASCC3, but GO:0005515 is less useful
than ASCC complex membership and DNA alkylation repair PMID:29997253.
Marked RNA binding as over-annotated rather than core. PMID:29997253 supports
a putative RNA-binding motif requirement, but does not itself demonstrate
direct ASCC1 RNA binding PMID:29997253. PMID:29144457 shows
direct ssRNA binding for ASCC3, not ASCC1 PMID:29144457.

Falcon deep research findings (2026-06-07)

A Falcon (Edison Scientific) deep research report was generated on 2026-06-07
(ASCC1-deep-research-falcon.md), superseding the earlier failed Falcon attempt
noted above. Synthesis of KEY findings, emphasizing what is NEW relative to the
existing COMPLETE review:

NEW (most material): Direct, sequence-selective RNA binding by ASCC1 is now
experimentally demonstrated. Chinnam et al. 2024 (PMID:38750793, J Biol Chem)
solved crystal/SAXS structures and showed by EMSA that ASCC1 binds
CGCG-containing RNA (detectable at ~60 nM), abolished by a KH GXXG->GDDG
mutation, with no shift on the corresponding DNA. This is the first DIRECT
ASCC1 RNA-binding evidence and partially addresses the prior caveat that
only ASCC3 (not ASCC1) had shown direct nucleic-acid binding. The existing
GO:0003723 RNA binding annotation (currently MARK_AS_OVER_ANNOTATED) is now
better supported as a genuine molecular activity, though physiological
endogenous RNA targets remain undefined. Note PMID:38750793 is not in the
local publications cache, so it is added as a statement-only reference and
NOT used to flip the existing IEA annotation's action.
NEW (domain architecture): ASCC1 uniquely couples an N-terminal KH-like domain
(with a newly named helix-clasp-helix / HCH nucleotide-binding motif) to a
C-terminal two-histidine (2H) phosphodiesterase (PDE) / "RNA ligase-like"
module with two HXT motifs PMID:38750793. This sharpens the prior generic
"RNA-ligase-like region" description into a defined KH-HCH + 2H-PDE
architecture.
PROVISIONAL/CAUTION (enzymology): The 2H-PDE domain is structurally present
but NO catalytic activity was detected on a tested 2-5A substrate by human or
Alvinella ASCC1 (positive control VP3-CTD cleaved >95%); an atypical conserved
active-site histidine rotamer implies a noncanonical substrate
PMID:38750793. Do NOT assert a specific PDE reaction/substrate. No GO
catalytic-activity annotation is warranted at present.
CONFIRMS: ASCC1 is a regulatory/accessory subunit of the ASC-1/ASCC complex
(with ASCC2, ASCC3, TRIP4); ASCC3 directly binds ASCC1 and scaffolds the
ASCC1-ASCC2 association (ASCC1 and ASCC2 do not bind directly). ASCC1 localizes
to nuclear speckles (co-localizing with PRP8) and leaves foci on alkylation
damage; ASCC1 loss dysregulates ASCC2/ASCC3 recruitment and causes MMS
hypersensitivity epistatic with ASCC3 (Soll 2018, PMID:29997253; Soll 2019
thesis). All already captured in the review.
NEW (pathway context, complex-level): The ASC-1/ASCC complex has expanding
translation-linked roles. Kito et al. 2023 (PMID:37092320, EMBO J) found ASCC
(ASCC1/2/3, TRIP4) associates with scanning ribosomes and promotes translation
initiation on a subset of transcripts (ASCC3-driven). Miscicka et al. 2024
(PMID:38366554, Nucleic Acids Res) reconstituted ASCC-mediated ribosome
disassembly downstream of ZNF598 ubiquitination and report ASCC1 is
DISPENSABLE for the cytoplasmic ribosome-splitting step while remaining
essential for the nuclear DNA-repair function. This is complex-level / ASCC3-
and ASCC2-centric evidence and supports the existing conservative decision NOT
to add cytosolic ribosome-rescue (RQC) GO annotations to ASCC1 specifically;
it strengthens the suggested expert question on this point.
NEW (disease mechanism): Voraberger et al. 2023 (PMID:37455927, Front
Endocrinol) gives a SMABF2 bone-mechanism: ASCC1 knockdown in hMSCs suppresses
osteoblastogenesis (>90% reduced mineralization) and increases adipogenesis,
with downregulation of RUNX2/SERPINF1 and reduced TGF-beta/SMAD3 signaling,
framing ASCC1 as a pro-osteoblastogenic / anti-adipogenic regulator. This is
downstream/pleiotropic disease-phenotype data; it elaborates the SMABF2 link
(PMID:26924529) but does not by itself justify a new core molecular-function
GO annotation. Captured as a reference and supporting context only.
PROVISIONAL (biomarker): Chinnam 2024 TCGA analysis (~7000 tumors) reports
ASCC1 mRNA overexpression in 7/15 tumor types and a poor-prognosis association
in pancreatic adenocarcinoma (HR ~3.7) PMID:38750793. Exploratory
bioinformatic association only; not annotation-relevant.

Net curation effect: add four genuinely-new primary references (PMID:38750793,
PMID:37092320, PMID:38366554, PMID:37455927) as statement-only entries
(full_text_unavailable), refine the GO:0003723 RNA binding review.reason to note
the now-direct CGCG RNA-binding evidence (without changing the action), and add
targeted suggested questions/experiments. No existing annotation action changed.

Pn Notes

(ASCC1-pn-notes.md)

ASCC1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8N9N2
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1370)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ASCC1/ASCC1-ai-review.yaml
AIGR review HTML: present - genes/human/ASCC1/ASCC1-ai-review.html
Gene notes: present - genes/human/ASCC1/ASCC1-notes.md
GOA TSV: present - genes/human/ASCC1/ASCC1-goa.tsv
UniProt record: present - genes/human/ASCC1/ASCC1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ASCC1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ASCC1.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/ASCC1/ASCC1-deep-research-falcon.md

AIGR Review Snapshot

Description: ASCC1 encodes the p50 subunit of the nuclear activating signal cointegrator 1 complex. The protein acts with TRIP4/ASC-1, ASCC2, and ASCC3 in a transcription coactivator complex that supports AP-1, SRF, NF-kappaB, and context-specific gene-expression responses. ASCC1 also functions as an accessory/regulatory subunit of the ASCC alkylation-damage response, where it interacts with ASCC3 and helps coordinate recruitment and assembly of the ALKBH3-ASCC repair complex at nuclear alkylation-damage foci. ASCC1 localizes mainly to the nucleus and nuclear speckles; loss-of-function variants disrupt neuromuscular development and cause spinal muscular atrophy with congenital bone fractures.
Existing/core annotation action counts: ACCEPT: 18; MARK_AS_OVER_ANNOTATED: 5; NEW: 2; REMOVE: 1

PN Consistency Summary

Consistency: Internally consistent but PN placement is contradicted by the gene's own evidence. Deep research, notes, and review YAML all frame ASCC1 as a nuclear ASC-1/ASCC subunit (transcription coactivation + ALKBH3-linked alkylation-damage repair); none place ASCC1 in cytosolic ribosome rescue. The notes explicitly flag the RQC projection as a workbook propagation artifact and cite PMID:38366554 that ASCC1 is dispensable for the cytoplasmic ribosome-splitting step. GOA confirms no RQC term on ASCC1.
PN story / NEW pressure: The PN asserts a ribosomal-rescue/RQC role not in GO and not supported by ASCC1-specific data. GO:0072344 and GO:0006515 are real terms, but projecting them to ASCC1 over-reaches: the RQC role belongs to the ASCC complex via ASCC3/ASCC2/TRIP4, with ASCC1 dispensable. Conclude: over-reaches (do not project to ASCC1). No defensible NEW GO term for ASCC1 from the PN node; the review already proposes the correct NEWs (GO:0060090 molecular adaptor; GO:0003713 transcription coactivator, contributes_to).
Evidence alignment: PN row carries no reference titles; the review's RQC-adjacent papers (PMID:37092320 translation initiation; PMID:38366554 disassembly) are complex/ASCC3-centric and were deliberately not used to add RQC terms to ASCC1. No PMID conflict — divergence is conceptual (node-level vs gene-level).
Verdict: Consistent review; PN RQC projection over-reaches for ASCC1 and is correctly rejected in-review. No edits needed beyond exempting ASCC1 from RQC propagation at the mapping layer.

Full Consistency Review

UniProt: Q8N9N2 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE (rich; Falcon DR present)
PN placement: Translation|Cytosolic translation|Ribosome-associated QC|Ribosomal rescue ; PN-node mapping: type=mapped/ok GO:0072344 (rescue of stalled cytosolic ribosome); group=mapped/ok GO:0006515; class/branch context_only. Both projected terms new_to_goa.
Consistency: Internally consistent but PN placement is contradicted by the gene's own evidence. Deep research, notes, and review YAML all frame ASCC1 as a nuclear ASC-1/ASCC subunit (transcription coactivation + ALKBH3-linked alkylation-damage repair); none place ASCC1 in cytosolic ribosome rescue. The notes explicitly flag the RQC projection as a workbook propagation artifact and cite PMID:38366554 that ASCC1 is dispensable for the cytoplasmic ribosome-splitting step. GOA confirms no RQC term on ASCC1.
PN story / NEW pressure: The PN asserts a ribosomal-rescue/RQC role not in GO and not supported by ASCC1-specific data. GO:0072344 and GO:0006515 are real terms, but projecting them to ASCC1 over-reaches: the RQC role belongs to the ASCC complex via ASCC3/ASCC2/TRIP4, with ASCC1 dispensable. Conclude: over-reaches (do not project to ASCC1). No defensible NEW GO term for ASCC1 from the PN node; the review already proposes the correct NEWs (GO:0060090 molecular adaptor; GO:0003713 transcription coactivator, contributes_to).
Mapping strategy: This gene is a counter-example for the RQC node, not a driver. The type/group mappings (GO:0072344/GO:0006515) are biologically sound for the node but must not be auto-projected to ASCC1. Status/scope of the node need not change for other members; ASCC1 should be exempted from propagation.
Evidence alignment: PN row carries no reference titles; the review's RQC-adjacent papers (PMID:37092320 translation initiation; PMID:38366554 disassembly) are complex/ASCC3-centric and were deliberately not used to add RQC terms to ASCC1. No PMID conflict — divergence is conceptual (node-level vs gene-level).
Verdict: Consistent review; PN RQC projection over-reaches for ASCC1 and is correctly rejected in-review. No edits needed beyond exempting ASCC1 from RQC propagation at the mapping layer.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ASCC1/ASCC1-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q8N9N2
In branches: TR
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.

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=new_to_goa | 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: Q8N9N2
gene_symbol: ASCC1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ASCC1 encodes the p50 subunit of the nuclear activating signal cointegrator
  1 complex. The protein acts with TRIP4/ASC-1, ASCC2, and ASCC3 in a
  transcription coactivator complex that supports AP-1, SRF, NF-kappaB, and
  context-specific gene-expression responses. ASCC1 also functions as an
  accessory/regulatory subunit of the ASCC alkylation-damage response, where it
  interacts with ASCC3 and helps coordinate recruitment and assembly of the
  ALKBH3-ASCC repair complex at nuclear alkylation-damage foci. ASCC1 localizes
  mainly to the nucleus and nuclear speckles; loss-of-function variants disrupt
  neuromuscular development and cause spinal muscular atrophy with congenital
  bone fractures.
alternative_products:
- name: '1'
  id: Q8N9N2-1
- name: '2'
  id: Q8N9N2-2
  sequence_note: VSP_011007, VSP_011008
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      ASCC1 is a nuclear ASC-1/ASCC complex subunit, and both transcriptional
      coactivation and alkylation-damage functions occur in the nucleus.
    action: ACCEPT
    reason: >-
      Nuclear localization is supported by the original ASC-1 complex study,
      the ASCC1 disease paper, UniProt, and the ASCC alkylation-damage
      literature.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        Here we report that ASC-1 exists as a steady-state complex associated
        with three polypeptides, P200, P100, and P50, in HeLa nuclei
    - reference_id: PMID:26924529
      supporting_text: >-
        encode subunits of the nuclear activating signal cointegrator 1 (ASC-1)
        complex.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      ASCC1 is part of the ASC-1 transcription coactivator complex and supports
      transcriptional activation by several transcription factors.
    action: ACCEPT
    reason: >-
      The original ASC-1 complex paper directly supports an endogenous
      transcription coactivation role, and later human genetics work also frames
      ASCC1 as a subunit of a nuclear transcriptional coactivator complex.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        these results suggest that the endogenous hASC-1 complex appears to play
        an essential role in AP-1, SRF, and NF-kappaB transactivation
    - reference_id: PMID:26924529
      supporting_text: >-
        Our findings indicate that the dysfunction of a transcriptional
        coactivator complex can result in a clinical syndrome affecting the
        neuromuscular system.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      ASCC1 has a predicted RNA-binding/RNA-ligase-like region, but the
      ASCC1-specific evidence available here supports an RNA-related domain
      requirement rather than direct ASCC1 RNA-binding activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The strongest ASCC alkylation-damage papers show RNA dependence of ASCC
      foci and direct ssRNA binding by ASCC3, while the earlier ASCC1 paper only
      described a putative RNA-binding motif. A later structural study
      (PMID:38750793) now provides direct EMSA evidence that ASCC1 binds
      sequence-selectively to CGCG-containing RNA via its KH GXXG motif, so
      ASCC1 RNA binding is a genuine molecular activity. It is retained as
      non-core here because the physiological endogenous RNA targets remain
      undefined and the in-cell functional contribution of ASCC1 RNA binding to
      transcription/repair is not yet established; the action is unchanged
      pending that evidence.
    additional_reference_ids:
    - PMID:29997253
    - PMID:29144457
    - PMID:38750793
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        a function that appears to depend on a putative RNA-binding motif near
        the ASCC1 C terminus.
    - reference_id: PMID:29144457
      supporting_text: >-
        Purified ASCC3 bound to ssRNA in vitro
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt-derived nuclear localization is consistent with multiple
      experimental reports for ASCC1/ASC-1 complex biology.
    action: ACCEPT
    reason: >-
      ASCC1 functions in nuclear transcriptional coactivation and in nuclear
      alkylation-damage signaling.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        Here we report that ASC-1 exists as a steady-state complex associated
        with three polypeptides, P200, P100, and P50, in HeLa nuclei
    - reference_id: PMID:29144457
      supporting_text: >-
        We find that the alkylation repair complex ASCC (activating signal
        cointegrator complex) relocalizes to distinct nuclear foci specifically
        upon exposure of cells to alkylating agents.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      ASCC1 is reported at nuclear speckle foci before alkylation damage and
      redistributes after damage.
    action: ACCEPT
    reason: >-
      The UniProt mapping is backed by the ASCC1-specific alkylation-damage
      paper.
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 is present at nuclear speckle foci prior to damage, but leaves the
        foci in response to alkylation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      This high-throughput binary interactome annotation reports an ASCC1
      protein interaction but does not identify a specific ASCC1 molecular
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not informative for ASCC1. The curated model is
      better captured by ASC-1/ASCC complex membership, transcriptional
      coactivation, and alkylation-damage repair.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: >-
        Here, we describe a systematic map of ?14,000 high-quality human binary
        protein-protein interactions.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997253
  qualifier: enables
  review:
    summary: >-
      ASCC1 interacts with ASCC3 in the ASCC complex, but the generic protein
      binding term obscures the repair-complex function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction is real and important, but GO:0005515 is too broad. The
      same evidence is used more informatively for ASCC complex recruitment and
      DNA alkylation repair.
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      BioPlex AP-MS provides interactome context but does not define a specific
      ASCC1 molecular function beyond complex association.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Proteome-scale AP-MS is useful supporting context for physical proximity
      and complex membership, but generic protein binding should not be carried
      as a core ASCC1 function.
    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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: >-
      The U2OS multimodal cell map integrates AP-MS and imaging data, but the
      resulting generic protein-binding annotation is not a specific ASCC1
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This large-scale resource can support complex/proximity hypotheses, but
      ASCC1 curation should use specific ASC-1/ASCC transcription and DNA repair
      evidence instead of generic protein binding.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: >-
        Here we construct a global map of human subcellular architecture through
        joint measurement of biophysical interactions and immunofluorescence
        images for over 5,100 proteins in U2OS osteosarcoma cells.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: EXP
  original_reference_id: PMID:29997253
  qualifier: located_in
  review:
    summary: >-
      ASCC1 localizes to nuclear speckle foci before alkylation damage.
    action: ACCEPT
    reason: >-
      This is directly reported in the ASCC1-specific alkylation-damage paper
      and is consistent with the RNA/splicing-associated ASCC damage response.
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 is present at nuclear speckle foci prior to damage, but leaves the
        foci in response to alkylation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:29997253
  qualifier: located_in
  review:
    summary: >-
      ASCC1 is nuclear in the context of the ALKBH3-ASCC alkylation damage
      response.
    action: ACCEPT
    reason: >-
      The ASCC complex forms nuclear foci after alkylation damage, and ASCC1 is
      a subunit of this nuclear repair complex.
    additional_reference_ids:
    - PMID:29144457
    supported_by:
    - reference_id: PMID:29144457
      supporting_text: >-
        We find that the alkylation repair complex ASCC (activating signal
        cointegrator complex) relocalizes to distinct nuclear foci specifically
        upon exposure of cells to alkylating agents.
- term:
    id: GO:0006260
    label: DNA replication
  evidence_type: NAS
  original_reference_id: PMID:29997253
  qualifier: involved_in
  review:
    summary: >-
      The ASCC1/ASCC literature supports alkylation-damage signaling and repair,
      not a direct ASCC1 role in DNA replication.
    action: REMOVE
    reason: >-
      PMID:29997253 describes ASCC1 regulation of ASCC recruitment during
      alkylation damage. A related ASCC study notes that foci are largely in
      G1/early S phase and distinct from PCNA, which argues against curating a
      direct DNA replication process annotation from this evidence.
    additional_reference_ids:
    - PMID:29144457
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        our results identify a critical regulator of the ALKBH3-ASCC alkylation
        damage signaling pathway
    - reference_id: PMID:29144457
      supporting_text: >-
        These foci were largely limited to G1/early S-phase of the cell cycle
    - reference_id: PMID:29144457
      supporting_text: >-
        These foci were also distinct from GFP-PCNA or BMI-1
- term:
    id: GO:0006307
    label: DNA alkylation repair
  evidence_type: NAS
  original_reference_id: PMID:29997253
  qualifier: involved_in
  review:
    summary: >-
      ASCC1 regulates ASCC complex function during alkylation damage and loss of
      ASCC1 causes alkylation damage sensitivity.
    action: ACCEPT
    reason: >-
      ASCC1 is not the catalytic dealkylase or helicase, but it is a required
      accessory/regulatory subunit for proper ASCC complex recruitment and
      function in the ALKBH3-linked DNA alkylation repair pathway.
    additional_reference_ids:
    - PMID:22055184
    - PMID:29144457
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation
        damage sensitivity in a manner epistatic with ASCC3.
    - reference_id: PMID:29144457
      supporting_text: >-
        Together, our work reveals a previously unrecognized
        ubiquitin-dependent pathway induced specifically to repair alkylation
        damage
    - reference_id: PMID:22055184
      supporting_text: >-
        Our data provide a molecular mechanism by which ALKBH3 collaborates with
        ASCC to maintain genomic integrity in a cell-type specific manner.
- term:
    id: GO:1990391
    label: DNA repair complex
  evidence_type: IPI
  original_reference_id: PMID:29997253
  qualifier: part_of
  review:
    summary: >-
      ASCC1 is a subunit of the ASCC/ALKBH3 alkylation-damage repair complex.
    action: ACCEPT
    reason: >-
      Multiple papers place ASCC1 with ASCC2 and ASCC3 in a complex that
      recruits/coordinates ALKBH3-dependent repair of alkylated nucleotides.
    additional_reference_ids:
    - PMID:22055184
    - PMID:29144457
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit.
    - reference_id: PMID:29144457
      supporting_text: >-
        Mass spectrometric analysis of ASCC2-associated proteins revealed the
        constitutive association of ASCC3 and ASCC1
    - reference_id: PMID:22055184
      supporting_text: >-
        Besides ALKBH3 itself, we identified numerous peptides corresponding to
        three subunits of the Activating Signal Co-integrator Complex
- 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 ASCC1/p50 in a nuclear
      steady-state complex.
    action: ACCEPT
    reason: >-
      This directly supports nuclear localization for the transcriptional
      coactivator complex containing ASCC1.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        Here we report that ASC-1 exists as a steady-state complex associated
        with three polypeptides, P200, P100, and P50, in HeLa nuclei
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26924529
  qualifier: located_in
  review:
    summary: >-
      The ASCC1 disease paper describes ASCC1 as a subunit of the nuclear ASC-1
      complex.
    action: ACCEPT
    reason: >-
      Nuclear localization is consistent with ASCC1's transcriptional
      coactivator role and its ASCC alkylation-damage function.
    supported_by:
    - reference_id: PMID:26924529
      supporting_text: >-
        encode subunits of the nuclear activating signal cointegrator 1 (ASC-1)
        complex.
- 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-dependent oxidative demethylation of 1-meA
      damaged DNA in the nucleoplasm.
    action: ACCEPT
    reason: >-
      This Reactome catalytic event represents ALKBH3-mediated oxidative
      demethylation of 1-meA damaged dsDNA in the nucleoplasm; ASCC participation
      is through the helicase complex that provides an appropriate DNA substrate.
    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, a component of the activating signal
        co-integrator complex
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112124
  qualifier: located_in
  review:
    summary: >-
      Reactome places ALKBH3/ASCC-dependent oxidative demethylation of 3-meC
      damaged DNA in the nucleoplasm.
    action: ACCEPT
    reason: >-
      This Reactome catalytic event represents ALKBH3-mediated oxidative
      demethylation of 3-meC damaged dsDNA in the nucleoplasm; ASCC participation
      is through the helicase complex that provides an appropriate DNA substrate.
    supported_by:
    - reference_id: Reactome:R-HSA-112124
      supporting_text: >-
        The reversal of alkylating damage of dsDNA by ALKBH3 requires the
        presence of DNA helicase ASCC3, a component of the activating signal
        co-integrator complex
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-112125
  qualifier: located_in
  review:
    summary: >-
      Reactome places ALKBH3/ASCC-dependent oxidative dealkylation of 1-etA
      damaged DNA in the nucleoplasm.
    action: ACCEPT
    reason: >-
      This Reactome catalytic event represents ALKBH3-mediated oxidative
      dealkylation of 1-etA damaged dsDNA in the nucleoplasm; ASCC participation
      is through the helicase complex that provides an appropriate DNA substrate.
    supported_by:
    - reference_id: Reactome:R-HSA-112125
      supporting_text: >-
        The reversal of alkylating damage of dsDNA by ALKBH3 requires the
        presence of DNA helicase ASCC3, a component of the activating signal
        co-activator complex
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5657617
  qualifier: located_in
  review:
    summary: >-
      Reactome models ALKBH3 associated with ASCC1:ASCC2:ASCC3 binding
      3-meC-containing alkylated dsDNA.
    action: ACCEPT
    reason: >-
      This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on
      3-meC-containing alkylated dsDNA before the ALKBH3 catalytic repair step.
    supported_by:
    - reference_id: Reactome:R-HSA-5657617
      supporting_text: >-
        ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator
        complex, which unwinds dsDNA, providing an appropriate substrate for
        ALKBH3
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5657637
  qualifier: located_in
  review:
    summary: >-
      Reactome models ALKBH3 associated with ASCC1:ASCC2:ASCC3 binding
      1-meA-containing alkylated dsDNA.
    action: ACCEPT
    reason: >-
      This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on
      1-meA-containing alkylated dsDNA before the ALKBH3 catalytic repair step.
    supported_by:
    - reference_id: Reactome:R-HSA-5657637
      supporting_text: >-
        ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator
        complex, which unwinds dsDNA, providing an appropriate substrate for
        ALKBH3
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5657642
  qualifier: located_in
  review:
    summary: >-
      Reactome models ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binding
      1-etA-containing alkylated DNA.
    action: ACCEPT
    reason: >-
      This Reactome binding step places ASCC1:ASCC2:ASCC3 with ALKBH3 on
      1-etA-containing alkylated DNA before the ALKBH3 catalytic repair step.
    supported_by:
    - reference_id: Reactome:R-HSA-5657642
      supporting_text: >-
        ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing
        1-etA
- term:
    id: GO:0005667
    label: transcription regulator complex
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: part_of
  review:
    summary: >-
      ASCC1/p50 is part of the ASC-1 transcription coactivator complex.
    action: ACCEPT
    reason: >-
      The original ASC-1 complex study identifies ASCC1/p50 as a component of a
      nuclear complex that promotes AP-1, SRF, and NF-kappaB transactivation.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        Human activating signal cointegrator 1 (hASC-1) was originally isolated
        as a transcriptional coactivator of nuclear receptors.
    - reference_id: PMID:12077347
      supporting_text: >-
        Here we report that ASC-1 exists as a steady-state complex associated
        with three polypeptides, P200, P100, and P50, in HeLa nuclei
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      ASCC1 is an ASC-1 complex subunit required for efficient activation of
      multiple transcription-factor outputs.
    action: ACCEPT
    reason: >-
      Microinjection/complex-disruption experiments in the original paper
      support the conclusion that the endogenous hASC-1 complex is needed for
      AP-1, SRF, and NF-kappaB transactivation.
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        neutralization of endogenous P50 by single-cell microinjection of a P50
        antibody inhibits AP-1 transactivation
    - reference_id: PMID:12077347
      supporting_text: >-
        these results suggest that the endogenous hASC-1 complex appears to play
        an essential role in AP-1, SRF, and NF-kappaB transactivation
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:29997253
  qualifier: enables
  review:
    summary: >-
      Proposed new molecular-function annotation for ASCC1's accessory role in
      coordinating ASCC complex recruitment during alkylation damage.
    action: NEW
    reason: >-
      ASCC1 interacts with ASCC3 and regulates proper ASCC complex recruitment
      during alkylation damage. The available evidence does not support ASCC1 as
      the catalytic helicase or dealkylase, so molecular adaptor activity is the
      most conservative molecular-function representation for this complex
      coordination role.
    additional_reference_ids:
    - PMID:29144457
    supported_by:
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit.
    - reference_id: PMID:29997253
      supporting_text: >-
        ASCC1 coordinates the proper recruitment of the ASCC complex during
        alkylation
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:12077347
  qualifier: contributes_to
  review:
    summary: >-
      Proposed new molecular-function annotation for ASCC1/p50 contributing to
      the ASC-1 transcription coactivator complex.
    action: NEW
    reason: >-
      The original ASC-1 complex paper identifies the complex containing
      ASCC1/p50 as a transcriptional coactivator that enhances AP-1, SRF, and
      NF-kappaB transactivation. A contributes_to qualifier is more precise than
      asserting ASCC1 independently enables this complex-level activity, and is
      more informative than generic protein binding.
    additional_reference_ids:
    - PMID:19074642
    supported_by:
    - reference_id: PMID:12077347
      supporting_text: >-
        Human activating signal cointegrator 1 (hASC-1) was originally isolated
        as a transcriptional coactivator of nuclear receptors.
    - reference_id: PMID:12077347
      supporting_text: >-
        these results suggest that the endogenous hASC-1 complex appears to play
        an essential role in AP-1, SRF, and NF-kappaB transactivation
core_functions:
- description: >-
    ASCC1 is an accessory/regulatory subunit of the ASCC alkylation-damage
    response. Through association with ASCC3 and the ASCC complex, ASCC1 helps
    coordinate proper ASCC complex recruitment and assembly in the ALKBH3-linked
    repair pathway for alkylated nucleotides.
  molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  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:29997253
    supporting_text: >-
      ASCC1 coordinates the proper recruitment of the ASCC complex during
      alkylation
  - reference_id: PMID:29997253
    supporting_text: >-
      ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation
      damage sensitivity in a manner epistatic with ASCC3.
  - reference_id: PMID:29144457
    supporting_text: >-
      Together, our work reveals a previously unrecognized
      ubiquitin-dependent pathway induced specifically to repair alkylation
      damage
- description: >-
    ASCC1/p50 is a subunit of the nuclear ASC-1 transcription coactivator
    complex. The complex enhances transcriptional activation by AP-1, SRF, and
    NF-kappaB and participates in signal-dependent gene-expression responses,
    including gastrin/IL-8-induced SERPINB2/PAI-2 expression.
  contributes_to_molecular_function:
    id: GO:0003713
    label: transcription coactivator activity
  directly_involved_in:
  - id: GO:0006355
    label: regulation of DNA-templated transcription
  locations:
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0005667
    label: transcription regulator complex
  supported_by:
  - reference_id: PMID:12077347
    supporting_text: >-
      these results suggest that the endogenous hASC-1 complex appears to play
      an essential role in AP-1, SRF, and NF-kappaB transactivation
  - reference_id: PMID:19074642
    supporting_text: >-
      Silencing at least two subunits of ASC-1, p50 and p65, inhibited
      gastrin-stimulated PAI-2 expression, indicating that ASC-1 acts as a
      transcription activator complex to regulate transcription.
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:
  - statement: >-
      Identified ASCC1/p50 as part of a nuclear ASC-1 complex required for AP-1,
      SRF, and NF-kappaB transactivation.
    supporting_text: >-
      these results suggest that the endogenous hASC-1 complex appears to play
      an essential role in AP-1, SRF, and NF-kappaB transactivation
- id: PMID:19074642
  title: Gastrin activates paracrine networks leading to induction of PAI-2 via
    MAZ and ASC-1.
  findings:
  - statement: >-
      Supports a context-specific transcriptional role for ASC-1/p50 in
      gastrin-triggered PAI-2/SERPINB2 induction.
    supporting_text: >-
      Silencing at least two subunits of ASC-1, p50 and p65, inhibited
      gastrin-stimulated PAI-2 expression, indicating that ASC-1 acts as a
      transcription activator complex to regulate transcription.
- id: PMID:22055184
  title: DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA
    alkylation repair and cancer cell proliferation.
  findings:
  - statement: >-
      Establishes the ASCC complex as an ALKBH3-associated alkylation repair
      complex.
    supporting_text: >-
      Our data provide a molecular mechanism by which ALKBH3 collaborates with
      ASCC to maintain genomic integrity in a cell-type specific manner.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings:
  - statement: >-
      High-throughput interactome resource; useful for PPI context but not
      sufficient to define ASCC1 core molecular function.
    supporting_text: >-
      Here, we describe a systematic map of ?14,000 high-quality human binary
      protein-protein interactions.
- 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:
  - statement: >-
      Human ASCC1 loss-of-function variants disrupt neuromuscular development
      and support ASCC1 as a nuclear ASC-1 complex subunit.
    supporting_text: >-
      We report on recessive loss-of-function mutations in two genes (TRIP4 and
      ASCC1) that encode subunits of the nuclear activating signal cointegrator
      1 (ASC-1) complex.
- id: PMID:29144457
  title: A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA
    dealkylation repair.
  findings:
  - statement: >-
      Defines a ubiquitin-dependent ASCC alkylation-damage pathway and places
      ASCC1 in the ASCC2/ASCC3-associated repair complex.
    supporting_text: >-
      Mass spectrometric analysis of ASCC2-associated proteins revealed the
      constitutive association of ASCC3 and ASCC1
- 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:
  - statement: >-
      ASCC1 interacts with ASCC3, regulates ASCC complex recruitment during
      alkylation damage, and is required for resistance to alkylation damage.
    supporting_text: >-
      ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation
      damage sensitivity in a manner epistatic with ASCC3.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: >-
      BioPlex AP-MS is useful large-scale interaction context but should not
      drive a generic protein-binding core annotation.
    supporting_text: >-
      Through affinity-purification mass spectrometry, we have created two
      proteome-scale, cell-line-specific interaction networks.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings:
  - statement: >-
      U2OS multimodal cell-map evidence is broad interaction/localization
      context rather than ASCC1-specific mechanistic evidence.
    supporting_text: >-
      Here we construct a global map of human subcellular architecture through
      joint measurement of biophysical interactions and immunofluorescence
      images for over 5,100 proteins in U2OS osteosarcoma cells.
- id: PMID:37092320
  title: The ASC-1 complex promotes translation initiation by scanning ribosomes.
  full_text_unavailable: true
  findings:
  - statement: >-
      The ASC-1/ASCC complex (including ASCC1) associates with scanning
      ribosomes and promotes translation initiation on a subset of transcripts;
      the experimentally emphasized motor activity is ASCC3-dependent.
- id: PMID:37455927
  title: Investigating the role of ASCC1 in the causation of bone fragility.
  full_text_unavailable: true
  findings:
  - statement: >-
      In a SMABF2 patient and in hMSCs, loss/knockdown of ASCC1 suppresses
      osteoblast differentiation and increases adipogenesis, with reduced
      RUNX2/SERPINF1 expression and TGF-beta/SMAD3 signaling, identifying ASCC1
      as a pro-osteoblastogenic and anti-adipogenic regulator.
- 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 a reconstituted system, ASCC-mediated disassembly of ubiquitinated
      ribosomal complexes does not strictly require ribosomal collision; ASCC1
      is dispensable for the cytoplasmic ribosome-splitting step while remaining
      required for the nuclear ASCC DNA-repair function.
- id: PMID:38750793
  title: >-
      ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix
      RNA-binding motif linked to a two-histidine phosphodiesterase.
  full_text_unavailable: true
  findings:
  - statement: >-
      Crystal and SAXS structures define ASCC1 as a coupled KH-like
      (helix-clasp-helix) RNA-binding domain and a two-histidine
      phosphodiesterase domain; ASCC1 binds sequence-selectively to
      CGCG-containing RNA in a manner dependent on the KH GXXG motif.
  - statement: >-
      No phosphodiesterase activity was detected on a tested 2-5A substrate, and
      an atypical active-site histidine rotamer implies a noncanonical
      substrate, so a specific catalytic reaction for ASCC1 cannot be asserted.
- id: Reactome:R-HSA-112123
  title: Oxidative demethylation of 1-meA damaged DNA By ALKBH3
  findings:
  - statement: >-
      Reactome event for ALKBH3/ASCC-dependent oxidative demethylation of
      1-meA damaged DNA.
    supporting_text: >-
      The reversal of alkylating damage of dsDNA by ALKBH3 requires the
      presence of DNA helicase ASCC3, a component of the activating signal
      co-integrator complex
- id: Reactome:R-HSA-112124
  title: Oxidative demethylation of 3-meC damaged DNA By ALKBH3
  findings:
  - statement: >-
      Reactome event for ALKBH3/ASCC-dependent oxidative demethylation of
      3-meC damaged DNA.
    supporting_text: >-
      The reversal of alkylating damage of dsDNA by ALKBH3 requires the
      presence of DNA helicase ASCC3, a component of the activating signal
      co-integrator complex
- id: Reactome:R-HSA-112125
  title: Oxidative dealkylation of 1-EtA damaged DNA by ABH3
  findings:
  - statement: >-
      Reactome event for ALKBH3/ASCC-dependent oxidative dealkylation of
      1-etA damaged DNA.
    supporting_text: >-
      The reversal of alkylating damage of dsDNA by ALKBH3 requires the
      presence of DNA helicase ASCC3, a component of the activating signal
      co-activator complex
- id: Reactome:R-HSA-5657617
  title: ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing
    3-meC
  findings:
  - statement: >-
      Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on
      3-meC-containing alkylated DNA.
    supporting_text: >-
      ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator
      complex, which unwinds dsDNA, providing an appropriate substrate for
      ALKBH3
- id: Reactome:R-HSA-5657637
  title: ALKBH3 associated with ASCC1:ASCC2:ASCC3 binds alkylated dsDNA containing
    1-meA
  findings:
  - statement: >-
      Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on
      1-meA-containing alkylated DNA.
    supporting_text: >-
      ASCC3 is a part of ASCC1:ASCC2:ASCC3 activating signal co-integrator
      complex, which unwinds dsDNA, providing an appropriate substrate for
      ALKBH3
- id: Reactome:R-HSA-5657642
  title: ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing
    1-etA
  findings:
  - statement: >-
      Reactome complex event placing ASCC1:ASCC2:ASCC3 with ALKBH3 on
      1-etA-containing alkylated DNA.
    supporting_text: >-
      ALKBH3 in complex with ASCC1:ASCC2:ASCC3 binds alkylated DNA containing
      1-etA
proposed_new_terms: []
suggested_questions:
- question: >-
    Does ASCC1 directly bind RNA in cells, or is the ASCC1 RNA-ligase-like/KH
    region primarily a structural/regulatory module for ASCC complex assembly?
  experts:
  - Mosammaparast N
  - Soll JM
- question: >-
    Is there ASCC1-specific evidence for ribosome-associated quality control or
    stalled cytosolic ribosome rescue, or is the PN ribosomal-rescue projection a
    workbook propagation artifact from ASCC-family membership?
  experts:
  - Mosammaparast N
- question: >-
    Should ASCC1 be curated to a more specific adaptor/cofactor molecular
    function for ASCC alkylation-damage recruitment once GO has a term that
    captures accessory repair-complex assembly without implying catalytic
    helicase or dealkylase activity?
  experts:
  - Mosammaparast N
- question: >-
    Given the direct demonstration of sequence-selective CGCG RNA binding by
    ASCC1 (KH/helix-clasp-helix motif), what are the endogenous physiological RNA
    targets, and does this binding direct ASCC complex function in transcription,
    splicing-associated speckles, or alkylation-damage repair?
  experts:
  - Tainer JA
  - Tsutakawa SE
  - Mosammaparast N
- question: >-
    Does the ASCC1 two-histidine phosphodiesterase domain possess catalytic
    activity on a physiological substrate, and is the predicted noncanonical
    active-site geometry regulatory rather than catalytic?
  experts:
  - Tainer JA
  - Silverman RH
suggested_experiments:
- experiment_type: RNA-binding assay
  hypothesis: >-
    ASCC1 directly binds RNA through its C-terminal RNA-ligase-like/KH region and
    this binding contributes to ASCC recruitment during alkylation damage.
  description: >-
    Perform ASCC1 CLIP-seq or purified-protein RNA-binding assays with wild-type
    ASCC1 and mutations in the C-terminal motif, coupled to rescue of ASCC2/ASCC3
    foci formation after MMS treatment.
- experiment_type: ribosome-stalling reporter assay
  hypothesis: >-
    ASCC1 does not directly participate in cytosolic ribosome rescue despite the
    PN projection to ribosome-associated QC.
  description: >-
    Compare ASCC1 knockout/rescue cells with known RQC factors in reporters for
    nonstop, no-go, and collided-ribosome substrates, while controlling for
    indirect DNA-damage and transcriptional stress effects.
- experiment_type: in-cell RNA crosslinking and target identification
  hypothesis: >-
    The sequence-selective CGCG RNA binding shown for ASCC1 in vitro reflects
    binding to specific endogenous transcripts that target ASCC complex activity
    to particular RNA contexts.
  description: >-
    Perform ASCC1 eCLIP/PAR-CLIP in cells with and without alkylation damage,
    using KH GXXG-motif mutants as binding-dead controls, to define endogenous
    RNA targets and test whether RNA binding is required for ASCC speckle
    localization and damage-response recruitment.

ASCC1

Gene Description

Existing Annotations Review

Core Functions

ASCC1 is an accessory/regulatory subunit of the ASCC alkylation-damage response. Through association with ASCC3 and the ASCC complex, ASCC1 helps coordinate proper ASCC complex recruitment and assembly in the ALKBH3-linked repair pathway for alkylated nucleotides.

ASCC1/p50 is a subunit of the nuclear ASC-1 transcription coactivator complex. The complex enhances transcriptional activation by AP-1, SRF, and NF-kappaB and participates in signal-dependent gene-expression responses, including gastrin/IL-8-induced SERPINB2/PAI-2 expression.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human ASCC1 (UniProt Q8N9N2) functional annotation

1. Target verification (gene/protein identity)

2. Key concepts and definitions (current understanding)

2.1 The ASC-1/ASCC complex

2.2 ASCC1 domain architecture and terminology

3. Molecular function: what ASCC1 does (best-supported)

3.1 Molecular activity 1 (validated): sequence-selective RNA binding

3.2 Molecular activity 2 (structurally plausible but not yet substrate-validated): 2H phosphodiesterase-like chemistry

3.3 Key interaction partner: ASCC3 as a scaffold linking ASCC1 to ASCC2

4. Cellular localization and functional pathways

4.1 Nuclear speckles and alkylation damage response (ALKBH3–ASCC axis)

4.2 Transcriptional coactivation (historical “primary” function of ASC-1 complex)

4.3 Ribosome quality control (RQC) and translation initiation (recent expansion of function)

5. Recent developments (prioritizing 2023–2024)

5.1 2024: ASCC1 structural and biochemical mechanism (RNA-binding motif + 2H-PDE active site)

5.2 2024: ASCC-mediated RQC does not require collision (and ASCC1 is dispensable for ribosome splitting)

5.3 2023: ASCC1 in human bone biology and SMABF2 mechanism

6. Human genetics, disease associations, and real-world implementation

6.1 SMABF2 diagnosis and variant interpretation

6.2 Cancer expression and prognosis (exploratory/biomarker-level)

7. Expert synthesis and open questions

7.1 Primary function (most defensible functional phrasing)

7.2 Enzymology caution

8. Visual evidence from recent primary literature

9. Evidence map (quick reference)

Key sources (URLs; publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

ASCC1 review notes

Deep research status

Summary

Proteostasis PN projection

Annotation decisions

Falcon deep research findings (2026-06-07)

Pn Notes

ASCC1 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

Projected GO annotations (2)

Note

📄 View Raw YAML