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.
| 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 |
Loading supporting content…
Download this section (compressed HTML)Q: 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?
Suggested experts: Mosammaparast N, Soll JM
Q: 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?
Suggested experts: Mosammaparast N
Q: 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?
Suggested experts: Mosammaparast N
Q: 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?
Suggested experts: Tainer JA, Tsutakawa SE, Mosammaparast N
Q: 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?
Suggested experts: Tainer JA, Silverman RH
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
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)