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.