id: Q9NY61 gene_symbol: AATF product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- AATF (Apoptosis-Antagonizing Transcription Factor, also known as Che-1) is a multifunctional nuclear/nucleolar protein that serves as a structural component of the small subunit (SSU) processome involved in ribosome biogenesis and as a transcriptional cofactor for RNA polymerase II. AATF interacts with POLR2J and Rb family members (RB1, RBL1, RBL2) to modulate E2F target gene expression, and displaces HDAC1 from SP1-bound promoters to activate p21/CDKN1A transcription. In the DNA damage response, AATF is phosphorylated by ATM/ATR, Chk2, and MK2 kinases, leading to modulation of p53-dependent transcriptional programs. AATF also interacts with SAGA/ATAC complex HAT module subunits (ADA2A, ADA2B, GCN5/KAT2A) and binds RNA. It antagonizes apoptosis induced by Dlk/ZIP kinase and PAWR/Par-4. Recent work shows AATF cooperates with NRF-1 to maintain nuclear OXPHOS gene transcription in glioblastoma. existing_annotations: - term: id: GO:0005730 label: nucleolus evidence_type: IBA original_reference_id: GO_REF:0000033 review: summary: >- IBA annotation placing AATF in the nucleolus, supported by phylogenetic inference across multiple orthologs. AATF nucleolar localization is strongly supported by nucleolar proteomics (PMID:12429849), HPA immunofluorescence (GO_REF:0000052), cryo-EM SSU processome structure (PMID:34516797), and UniProt subcellular location annotation. action: ACCEPT reason: >- Nucleolar localization is one of the best-established features of AATF. The IBA annotation is consistent with multiple lines of experimental evidence including cryo-EM structural data showing AATF as part of the nucleolar SSU processome (PMID:34516797) and nucleolar proteomics (PMID:12429849). UniProt states "Nucleus, nucleolus" as subcellular location. supported_by: - reference_id: PMID:34516797 supporting_text: "The human small subunit processome mediates early maturation of the small ribosomal subunit" - reference_id: PMID:12429849 supporting_text: "we have carried out a proteomic analysis to draw up a list of proteins present within nucleoli of HeLa cells" - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000108 review: summary: >- IEA annotation inferred from GO:0003713 (transcription coactivator activity) via inter-ontology logical links. AATF functions as a transcriptional cofactor that activates transcription of multiple target genes including p21/CDKN1A (PMID:12847090), p53/TP53 (PMID:17157788), and NRF-1 target OXPHOS genes (Sorino et al. 2026). action: ACCEPT reason: >- This is a reasonable logical inference from transcription coactivator activity. AATF clearly positively regulates transcription: it displaces HDAC1 from promoters leading to activation of p21 (PMID:12847090), promotes p53 transcription after DNA damage (PMID:17157788), and the original identification showed "a Gal4-BD-AATF fusion protein exhibited strong transactivation activity" (PMID:10580117). supported_by: - reference_id: PMID:12847090 supporting_text: "Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter" - reference_id: PMID:17157788 supporting_text: "These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters" - reference_id: PMID:10580117 supporting_text: "a Gal4-BD-AATF fusion protein exhibited strong transactivation activity" - reference_id: "file:human/AATF/AATF-deep-research-falcon.md" supporting_text: "AATF physically interacts with NRF-1 and is required for NRF-1-mediated transcription of nuclear-encoded OXPHOS genes by affecting RNA polymerase II recruitment (Sorino et al. 2026)" - term: id: GO:0003713 label: transcription coactivator activity evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- IEA annotation transferred from mouse ortholog via Ensembl Compara. AATF/Che-1 acts as a transcriptional cofactor that binds RNA polymerase II subunit POLR2J (PMID:10783144), displaces HDAC1 from promoters to activate transcription of p21 (PMID:12847090), and cooperates with NRF-1 for OXPHOS gene transcription (Sorino et al. 2026). action: ACCEPT reason: >- Transcription coactivator activity is a well-supported core function of AATF. The protein binds RNA Pol II via POLR2J, interacts with sequence-specific transcription factors (SP1, NRF-1, Rb family), and activates transcription from multiple promoters. The original Gal4-AATF fusion showed "strong transactivation activity" (PMID:10580117). supported_by: - reference_id: PMID:10783144 supporting_text: "Here we describe Che-1, a novel human protein that interacts with hRPB11" - reference_id: PMID:12847090 supporting_text: "Che-1 is a recently identified human RNA polymerase II binding protein involved in the regulation of gene transcription and cell proliferation" - term: id: GO:0005667 label: transcription regulator complex evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- IEA annotation transferred from mouse ortholog. AATF interacts with SAGA/ATAC HAT module subunits (ADA2A, ADA2B, GCN5/KAT2A) (PMID:29232376) and with Rb/E2F complexes (PMID:10783144, PMID:12450794), consistent with participation in transcription regulator complexes. action: ACCEPT reason: >- AATF is documented to interact with components of SAGA/ATAC complexes (PMID:29232376) and with Rb-containing transcriptional regulatory complexes. The term is appropriately broad to capture these associations. However, the SSU processome (GO:0032040) is the more structurally defined complex membership, covered by a separate annotation. supported_by: - reference_id: PMID:29232376 supporting_text: "Co-immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins" - reference_id: PMID:10783144 supporting_text: "these results identify a novel protein that binds Rb and the core of pol II, and suggest that Che-1 may be part of transcription regulatory complex" - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- IEA annotation transferred from mouse ortholog. Cytoplasmic localization of AATF has been shown by IDA in PMID:14627703 and PMID:15207272, and PMID:22909821 showed that AATF is sequestered in the cytoplasm by MRLC3 and released to the nucleus upon MK2 phosphorylation after genotoxic stress. action: ACCEPT reason: >- Cytoplasmic localization is supported by multiple IDA annotations from focused studies. The IEA annotation is consistent with the experimental evidence. supported_by: - reference_id: PMID:14627703 supporting_text: "AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments" - reference_id: PMID:22909821 supporting_text: "AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation" - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: >- IEA annotation transferred from mouse ortholog via Ensembl Compara. The role of AATF in the UPR is directly supported by Ishigaki et al. 2010 (PMID:19911006), which showed that AATF is induced by ER stress through the PERK-eIF2alpha pathway and acts as an antiapoptotic transcriptional cofactor that drives AKT1 expression via STAT3 in pancreatic beta-cells. Knockdown of AATF sensitizes cells to ER stress-mediated death. action: KEEP_AS_NON_CORE reason: >- The UPR/antiapoptotic role is well-supported experimentally (PMID:19911006) but is a context-specific secondary function of AATF rather than a core activity. AATF's core functions are SSU processome / 40S ribosome biogenesis (PMID:34516797) and transcription coactivator activity at TP53/CDKN1A and other promoters (PMID:12847090, PMID:17157788). The UPR contribution is downstream of the more general transcription coactivator activity acting on the AKT1 promoter via STAT3, so it is appropriately retained as non-core rather than promoted to a core function. In a proteostasis-network context, this evidence supports a stress-response regulatory role only; it does not justify annotating AATF as a chaperone, protein-folding factor, or core ER protein-quality-control component. supported_by: - reference_id: PMID:19911006 supporting_text: "AATF is induced by ER stress through the PERK-eIF2alpha pathway and transcriptionally activates the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene through signal transducer and activator of transcription 3 (Stat3), which sustains Akt1 activation and promotes cell survival" - reference_id: PMID:19911006 supporting_text: "RNAi-mediated knockdown of AATF or AKT1 renders cells sensitive to ER stress" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12847090 review: summary: >- Protein binding annotation based on interaction with SP1 (UniProtKB:P08047) from PMID:12847090. Che-1/AATF interacts with SP1 at the p21 promoter and displaces HDAC1 from SP1 binding sites. action: MODIFY reason: >- The interaction with SP1 is well-documented and functionally significant -- AATF displaces HDAC1 from SP1-bound promoter regions. However, "protein binding" is uninformative per curation guidelines. A more specific term should capture the transcription cofactor nature of this interaction. proposed_replacement_terms: - id: GO:0003713 label: transcription coactivator activity supported_by: - reference_id: PMID:12847090 supporting_text: "Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17157788 review: summary: >- Protein binding annotation covering interactions with CHEK2 (O96017), RELA (Q04206), and ATM (Q13315) from PMID:17157788. The checkpoint kinases ATM/ATR and Chk2 interact with and phosphorylate Che-1 in response to DNA damage, promoting its accumulation and recruitment to TP53 and p21 promoters. action: KEEP_AS_NON_CORE reason: >- The interactions with ATM, ATR, and CHEK2 are well-documented and functionally important for the DNA damage response. These represent kinase-substrate relationships rather than core molecular function of AATF. The interactions are real but "protein binding" does not capture the biology. These are better described by the BP annotation for DNA damage response context. Keeping as non-core since these reflect AATF being a substrate of checkpoint kinases rather than defining AATF's own molecular function. supported_by: - reference_id: PMID:17157788 supporting_text: "The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22909821 review: summary: >- Protein binding annotation based on interaction with MRLC3/Myl12a (Q6ZWQ9) from PMID:22909821. AATF is sequestered in the cytoplasm by MRLC3, and MK2-dependent phosphorylation releases AATF for nuclear translocation after genotoxic stress. action: KEEP_AS_NON_CORE reason: >- This is a genuine interaction with a cytoplasmic sequestration partner. The interaction with MRLC3 is specific and functionally characterized -- it regulates AATF nucleocytoplasmic distribution. However, this reflects regulation of AATF localization rather than a core molecular function. supported_by: - reference_id: PMID:22909821 supporting_text: "Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 review: summary: >- Protein binding annotation based on interaction with NGDN (Q8NEJ9) from the HI-II-14 proteome-scale human interactome map (PMID:25416956). NGDN (Neuroguidin/Ngd1) is a ribosome biogenesis factor. This interaction is supported by multiple independent studies (also PMID:30021884, PMID:33961781, PMID:35271311). action: KEEP_AS_NON_CORE reason: >- The AATF-NGDN interaction is notable because NGDN is also a component of the SSU processome, consistent with AATF's role in ribosome biogenesis. The interaction is reproduced across four independent high-throughput studies. However, "protein binding" is uninformative. This interaction likely reflects their co-participation in the SSU processome complex. supported_by: - reference_id: PMID:25416956 supporting_text: "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:29232376 review: summary: >- Protein binding annotations based on interactions with SAGA/ATAC HAT module subunits TADA2A (O75478), TADA3 (O75528), TADA2B (Q86TJ2), and KAT2A/GCN5 (Q92830) from PMID:29232376. The study used co-immunoprecipitation, co-localization, and yeast two-hybrid assays to demonstrate these interactions. action: KEEP_AS_NON_CORE reason: >- These interactions with SAGA/ATAC complex subunits are well-supported by multiple experimental approaches (co-IP, co-localization, Y2H). They suggest AATF participates in HAT-containing transcriptional regulatory complexes. While these support the transcription regulator complex (GO:0005667) CC annotation, the generic "protein binding" term does not add informative annotation beyond what is already captured by the MF and CC terms. supported_by: - reference_id: PMID:29232376 supporting_text: "Co-immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins in human cells" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30021884 review: summary: >- Protein binding annotation based on interaction with NGDN (Q8NEJ9) detected by crosslinking mass spectrometry in intact cell nuclei (PMID:30021884). action: KEEP_AS_NON_CORE reason: >- Duplicate interaction partner (NGDN) as PMID:25416956. This crosslinking MS study provides independent confirmation of the AATF-NGDN interaction in a nuclear context, consistent with their shared role in the SSU processome. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 review: summary: >- Protein binding annotation based on interaction with MNS1 (Q8NEH6) from a binary protein interactome reference map (PMID:32296183). MNS1 (meiosis-specific nuclear structural protein 1) is involved in cilium assembly. action: KEEP_AS_NON_CORE reason: >- This interaction is from a large-scale binary interactome study. MNS1 is a meiosis/cilia protein and the biological relevance of its interaction with nuclear AATF is unclear. Keeping as non-core since the interaction is detected in a high-quality systematic screen but may not reflect a biologically meaningful interaction in normal cellular context. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 review: summary: >- Protein binding annotations based on interactions with APP (P05067), PIK3R1 isoform 2 (P27986-2), and RAC1 (P63000) from a neurodegenerative disease-focused interactome mapping study (PMID:32814053). The AATF-APP interaction is consistent with AATF's documented role in antagonizing amyloid beta production (PMID:14627703). action: KEEP_AS_NON_CORE reason: >- The APP interaction is plausible given AATF's documented role in inhibiting aberrant Abeta production through interaction with Par-4/PAWR (PMID:14627703). The PIK3R1 and RAC1 interactions are from a neurodegenerative disease-focused screen and their biological significance for AATF function is less clear. These are non-core interactions that may reflect disease-context-specific associations. supported_by: - reference_id: PMID:14627703 supporting_text: "AATF inhibits aberrant production of amyloid beta peptide 1-42 by interacting directly with Par-4" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 review: summary: >- Protein binding annotation based on interaction with NGDN (Q8NEJ9) from dual proteome-scale networks (PMID:33961781). This is the third independent study detecting the AATF-NGDN interaction. action: KEEP_AS_NON_CORE reason: >- Another independent confirmation of the AATF-NGDN interaction, consistent with their co-participation in the SSU processome. The reproducibility across studies strongly supports this interaction but "protein binding" remains uninformative. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 review: summary: >- Protein binding annotation based on interaction with NGDN (Q8NEJ9) from OpenCell endogenous tagging study (PMID:35271311). Fourth independent detection of AATF-NGDN interaction. action: KEEP_AS_NON_CORE reason: >- Yet another confirmation of the AATF-NGDN interaction. The repeated detection across four independent high-throughput studies (PMID:25416956, PMID:30021884, PMID:33961781, PMID:35271311) strongly validates this interaction, consistent with co-participation in the SSU processome. - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- IEA annotation for nuclear localization based on combined automated methods including ortholog transfer and InterPro domain mapping. Nuclear localization of AATF is extremely well established by multiple IDA studies (PMID:10580117, PMID:14627703, PMID:15207272, PMID:12429849). action: ACCEPT reason: >- Nuclear localization is one of the most robustly supported features of AATF, confirmed by multiple independent IDA studies. The IEA annotation is correct and consistent with experimental data. - term: id: GO:0005730 label: nucleolus evidence_type: IEA original_reference_id: GO_REF:0000120 review: summary: >- IEA annotation for nucleolar localization based on combined automated methods. Nucleolar localization is well supported by proteomics (PMID:12429849), HPA immunofluorescence, and cryo-EM structure (PMID:34516797). action: ACCEPT reason: >- Correct IEA annotation consistent with multiple lines of experimental evidence. Nucleolus is a key site of AATF function as part of the SSU processome. - term: id: GO:0005730 label: nucleolus evidence_type: NAS original_reference_id: PMID:34516797 review: summary: >- NAS annotation from ComplexPortal based on the cryo-EM SSU processome paper (PMID:34516797). The structures were obtained from nucleolar particles, firmly placing AATF in the nucleolus as part of the SSU processome. action: ACCEPT reason: >- The cryo-EM structures of the human SSU processome (PMID:34516797) directly demonstrate AATF as a structural component of this nucleolar complex. The paper title itself states "Nucleolar maturation of the human small subunit processome." supported_by: - reference_id: PMID:34516797 supporting_text: "this 4.5-megadalton nucleolar assembly with the distinctive ability to mature the small ribosomal subunit from within" - term: id: GO:0030490 label: maturation of SSU-rRNA evidence_type: NAS original_reference_id: PMID:34516797 review: summary: >- NAS annotation from ComplexPortal for SSU rRNA maturation based on the SSU processome cryo-EM paper. The SSU processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to RNA cleavage and processing. action: ACCEPT reason: >- AATF is a structural component of the SSU processome, which mediates "early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps" (PMID:34516797). SSU-rRNA maturation is a core function of this complex and AATF's participation is demonstrated by the cryo-EM structure. supported_by: - reference_id: PMID:34516797 supporting_text: "The human small subunit processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps" - term: id: GO:0005730 label: nucleolus evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: >- IDA annotation from HPA based on immunofluorescence data showing AATF localizes to the nucleolus. action: ACCEPT reason: >- HPA immunofluorescence provides direct experimental evidence for nucleolar localization, consistent with all other evidence sources. - term: id: GO:0032040 label: small-subunit processome evidence_type: IDA original_reference_id: PMID:34516797 review: summary: >- IDA annotation placing AATF as part of the small-subunit processome based on cryo-EM structures at 2.7 to 3.9 angstrom resolution (PMID:34516797). AATF is directly resolved in the SSU processome particle structures. action: ACCEPT reason: >- This is one of the strongest annotations for AATF. The cryo-EM structures at high resolution directly show AATF as a structural component of the SSU processome, a 4.5-MDa nucleolar assembly. The SSU processome is listed in ComplexPortal as CPX-2511 with AATF as a component. This is a core cellular component annotation. supported_by: - reference_id: PMID:34516797 supporting_text: "We report the high-resolution cryo-electron microscopy structures of maturing human small subunit (SSU) processomes at resolutions of 2.7 to 3.9 angstroms" - term: id: GO:0032040 label: small-subunit processome evidence_type: NAS original_reference_id: PMID:34516797 review: summary: >- NAS annotation from ComplexPortal placing AATF in the small-subunit (SSU) processome (CPX-2511), citing PMID:34516797 — the same cryo-EM SSU processome paper that supports the existing IDA row for GO:0032040 on this gene. action: ACCEPT reason: >- The term and citation are correct and reinforce one of AATF's core functions. ComplexPortal curates AATF as a stoichiometric component of CPX-2511 (SSU processome). This NAS row duplicates the existing higher-strength IDA annotation for GO:0032040 from the same PMID; both are accepted because the term placement is unambiguous from the cryo-EM structures. supported_by: - reference_id: PMID:34516797 supporting_text: "The human small subunit processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps" - term: id: GO:0042274 label: ribosomal small subunit biogenesis evidence_type: IDA original_reference_id: PMID:34516797 review: summary: >- IDA annotation for ribosomal small subunit biogenesis based on the cryo-EM SSU processome structures (PMID:34516797). As a structural component of the SSU processome, AATF participates in the maturation process that generates the small ribosomal subunit. action: ACCEPT reason: >- AATF is a bona fide component of the SSU processome, which is the first precursor of the small eukaryotic ribosomal subunit. The processome mediates RNA folding, modifications, rearrangements, cleavage, and targeted degradation of pre-ribosomal RNA. This is a core biological process for AATF. supported_by: - reference_id: PMID:34516797 supporting_text: "These conserved mechanisms highlight the SSU processome's impressive structural plasticity, which endows this 4.5-megadalton nucleolar assembly with the distinctive ability to mature the small ribosomal subunit from within" - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22658674 review: summary: >- HDA annotation for RNA binding from the mRNA interactome capture study (PMID:22658674). AATF was identified among 860 mRNA-binding proteins in HeLa cells using UV crosslinking and oligo(dT) purification. action: ACCEPT reason: >- RNA binding is consistent with AATF's role as a component of the SSU processome, which processes pre-rRNA. The interactome capture identifies proteins crosslinked to poly(A) RNA, indicating mRNA binding. This is further supported by AATF's nuclear/nucleolar localization and involvement in ribosome biogenesis. The HDA evidence from a systematic mRNA interactome study is appropriate. supported_by: - reference_id: PMID:22658674 supporting_text: "We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria" - term: id: GO:0003723 label: RNA binding evidence_type: HDA original_reference_id: PMID:22681889 review: summary: >- HDA annotation for RNA binding from a second independent mRNA-bound proteome study (PMID:22681889). AATF was identified among ~800 mRNA-binding proteins using photoreactive nucleotide-enhanced UV crosslinking in HEK293 cells. action: ACCEPT reason: >- Independent confirmation of AATF RNA binding from a second systematic study using a different cell line (HEK293 vs HeLa in PMID:22658674). The convergent evidence from two independent high-throughput RNA interactome studies strengthens the RNA binding annotation. supported_by: - reference_id: PMID:22681889 supporting_text: "Application to a human embryonic kidney cell line identified close to 800 proteins" - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:10783144 review: summary: >- Protein binding annotation based on interactions with POLR2J (P52435) and RB1 (P06400) from PMID:10783144. Che-1/AATF was identified as a binding partner of hRPB11 (POLR2J) and shown to interact with Rb through two distinct domains, repressing Rb growth suppression by counteracting Rb-mediated inhibition of E2F1 transactivation. action: MODIFY reason: >- The interaction with POLR2J is the defining molecular function of Che-1/AATF and represents its core role as a transcriptional cofactor. "Protein binding" is uninformative. The POLR2J interaction is better captured by transcription coactivator activity, and the Rb interaction modulates transcriptional regulation. proposed_replacement_terms: - id: GO:0003713 label: transcription coactivator activity supported_by: - reference_id: PMID:10783144 supporting_text: "Here we describe Che-1, a novel human protein that interacts with hRPB11" - reference_id: PMID:10783144 supporting_text: "Che-1 represses the growth suppression function of Rb, counteracting the inhibitory action of Rb on the trans-activation function of E2F1" - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:10580117 review: summary: >- IDA annotation for nuclear localization from the original AATF identification paper (PMID:10580117). AATF was described as a "nuclear phosphoprotein." action: ACCEPT reason: >- The original identification of AATF described it as a nuclear phosphoprotein, and nuclear localization is one of the most well-established features of AATF across all subsequent studies. supported_by: - reference_id: PMID:10580117 supporting_text: "we identified apoptosis antagonizing transcription factor (AATF), a nuclear phosphoprotein of 523 amino acids" - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:14627703 review: summary: >- IDA annotation for nuclear localization from PMID:14627703. AATF was observed to colocalize with Par-4 in both nuclear and cytoplasmic compartments in neural cells. action: ACCEPT reason: >- Direct experimental observation of AATF in the nucleus. The colocalization with Par-4 in nuclear compartments is well documented in this study. supported_by: - reference_id: PMID:14627703 supporting_text: "AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments" - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:15207272 review: summary: >- IDA annotation for nuclear localization from PMID:15207272. AATF expression was observed in cortical neurons and PC12 cells, with nuclear localization. action: ACCEPT reason: >- Consistent with all other nuclear localization evidence for AATF. supported_by: - reference_id: PMID:15207272 supporting_text: "AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells" - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:14627703 review: summary: >- IDA annotation for cytoplasmic localization from PMID:14627703. AATF colocalizes with Par-4 in cytoplasmic compartments in neural cells. action: ACCEPT reason: >- Cytoplasmic localization is experimentally demonstrated and functionally relevant. PMID:22909821 later showed that AATF is sequestered in the cytoplasm by MRLC3 and released to the nucleus upon phosphorylation, indicating regulated nucleocytoplasmic distribution. supported_by: - reference_id: PMID:14627703 supporting_text: "AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments" - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:15207272 review: summary: >- IDA annotation for cytoplasmic localization from PMID:15207272. AATF was detected in cytoplasm in neural cell contexts. action: ACCEPT reason: >- Consistent with cytoplasmic detection in PMID:14627703 and the regulated nucleocytoplasmic shuttling mechanism described in PMID:22909821. - term: id: GO:0043522 label: leucine zipper domain binding evidence_type: IPI original_reference_id: PMID:10580117 review: summary: >- IPI annotation for leucine zipper domain binding based on interaction with Dlk/ZIP kinase (DAPK3, O43293) from PMID:10580117. AATF was identified as an interaction partner of Dlk/ZIP kinase and contains a putative leucine zipper domain. action: ACCEPT reason: >- The interaction with Dlk/ZIP kinase via the leucine zipper domain is the original basis for AATF identification. AATF "contains an extremely acidic domain and a putative leucine zipper characteristic of transcription factors" (PMID:10580117). The leucine zipper mediates the interaction with Dlk and with Par-4/PAWR. supported_by: - reference_id: PMID:10580117 supporting_text: "AATF contains an extremely acidic domain and a putative leucine zipper characteristic of transcription factors" - term: id: GO:0043522 label: leucine zipper domain binding evidence_type: IPI original_reference_id: PMID:14627703 review: summary: >- IPI annotation for leucine zipper domain binding based on interaction with Par-4/PAWR (Q96IZ0) from PMID:14627703. AATF interacts directly and selectively with Par-4 via the leucine zipper domain. action: ACCEPT reason: >- The leucine zipper-mediated interaction with Par-4 is well characterized and functionally significant -- the AATF/Par-4 complex formation is essential for AATF's inhibitory effect on aberrant Abeta secretion. supported_by: - reference_id: PMID:14627703 supporting_text: "it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells" - reference_id: PMID:14627703 supporting_text: "AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion" - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:12429849 review: summary: >- IDA annotation for nuclear localization from nucleolar proteomics study (PMID:12429849). AATF was identified among 213 nucleolar proteins in HeLa cells, which are by definition also nuclear proteins. action: ACCEPT reason: >- Nucleolar proteins are a subset of nuclear proteins. The proteomic identification of AATF in purified nucleoli confirms nuclear localization. supported_by: - reference_id: PMID:12429849 supporting_text: "we have carried out a proteomic analysis to draw up a list of proteins present within nucleoli of HeLa cells. This analysis allowed the identification of 213 different nucleolar proteins" # Additional annotations not in GOA but supported by strong literature evidence - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:12847090 review: summary: >- AATF/Che-1 regulates transcription by displacing HDAC1 from promoters (PMID:12847090), modulating E2F target gene expression via Rb interaction (PMID:10783144, PMID:12450794), and activating p53 transcription after DNA damage (PMID:17157788). This is a core biological process for AATF that is not explicitly annotated in GOA at an appropriate level. action: NEW reason: >- While GO:0045893 (positive regulation of DNA-templated transcription) is present as IEA, there is strong direct experimental evidence for AATF in regulation of transcription. AATF can both activate (p21, p53 promoters) and repress (pro-apoptotic PUMA, BAX, BAK promoters per PMID:22909821) transcription depending on context. The parent term "regulation of DNA-templated transcription" better captures the bidirectional nature of AATF transcriptional regulation. supported_by: - reference_id: PMID:12847090 supporting_text: "Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter" - reference_id: PMID:22909821 supporting_text: "AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes" - reference_id: PMID:17157788 supporting_text: "These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters" references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10580117 title: AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis. findings: - statement: >- AATF was identified as a 523-amino-acid nuclear phosphoprotein that interacts with the pro-apoptotic kinase Dlk/ZIP kinase and antagonizes Dlk-induced apoptosis. supporting_text: >- In search for interaction partners that might serve as regulators or targets of this kinase we identified apoptosis antagonizing transcription factor (AATF), a nuclear phosphoprotein of 523 amino acids. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- AATF contains an extremely acidic domain and a putative leucine zipper, and a Gal4-BD-AATF fusion protein exhibited strong transactivation activity, establishing AATF as a transcription factor. supporting_text: >- AATF contains an extremely acidic domain and a putative leucine zipper characteristic of transcription factors. Indeed, a Gal4-BD-AATF fusion protein exhibited strong transactivation activity. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- AATF interfered with Dlk-induced apoptosis, establishing its anti-apoptotic function. supporting_text: >- Interestingly, AATF interfered with Dlk-induced apoptosis. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:10783144 title: Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb. findings: - statement: >- Che-1/AATF was identified as a novel interaction partner of hRPB11 (POLR2J), a core subunit of RNA polymerase II, and possesses a domain with high homology to E. coli RNA polymerase sigma factor 70. supporting_text: >- Here we describe Che-1, a novel human protein that interacts with hRPB11. Che-1 possesses a domain of high homology with Escherichia coli RNA polymerase final sigma-factor 70 and SV40 large T antigen. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Che-1 interacts with Rb through two distinct domains and represses Rb growth suppression by counteracting the inhibitory action of Rb on E2F1 transactivation. supporting_text: >- Che-1 interacts with the retinoblastoma susceptibility gene (Rb) by two distinct domains. Functionally, we demonstrate that Che-1 represses the growth suppression function of Rb, counteracting the inhibitory action of Rb on the trans-activation function of E2F1. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Che-1 may be part of a transcription regulatory complex bridging RNA Pol II and Rb. supporting_text: >- These results identify a novel protein that binds Rb and the core of pol II, and suggest that Che-1 may be part of transcription regulatory complex. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:12429849 title: Functional proteomic analysis of human nucleolus. findings: - statement: >- AATF was identified among 213 nucleolar proteins in HeLa cells by mass spectrometry-based proteomic analysis, establishing its nucleolar localization. supporting_text: >- we have carried out a proteomic analysis to draw up a list of proteins present within nucleoli of HeLa cells. This analysis allowed the identification of 213 different nucleolar proteins. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- The nucleolar proteome functional classification supports the plurifunctional nature of nucleoli including roles in ribosome biogenesis and gene expression control. supporting_text: >- Functional classification of these proteins allowed outlining several biological processes taking place within nucleoli. Notably, a role in ribosome biogenesis was proposed for 31 proteins. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:12450794 title: Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb. findings: - statement: Che-1 interacts with Rb family members RB1, RBL1, RBL2 and is phosphorylated at G1/S transition - id: PMID:12847090 title: Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter. findings: - statement: >- Che-1/AATF is an RNA polymerase II binding protein that activates p21WAF1/Cip1 expression by displacing HDAC1 from SP1 binding sites on the p21 promoter, leading to histone H3 acetylation and growth arrest in colon carcinoma cells. supporting_text: >- Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Che-1 can be considered a general HDAC1 competitor, and Che-1-specific RNAi negatively affects p21 transactivation and increases cell proliferation. supporting_text: >- Che-1-specific RNA interference negatively affects p21WAF1/Cip1 transactivation and increases cell proliferation in HCT116 cells. Taken together, our results indicate that Che-1 can be considered a general HDAC1 competitor. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Che-1 previously demonstrated the ability to inhibit Rb growth-suppressing function by interfering with Rb-mediated HDAC1 recruitment on E2F target gene promoters. supporting_text: >- We previously demonstrated that Che-1 inhibits the Rb growth-suppressing function by interfering with Rb-mediated HDAC1 recruitment on E2F target gene promoters. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:14627703 title: AATF inhibits aberrant production of amyloid beta peptide 1-42 by interacting directly with Par-4. findings: - statement: >- AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments and interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. supporting_text: >- AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Co-expression of AATF completely blocked aberrant production and secretion of Abeta-42 induced by Par-4, and AATF/Par-4 complex formation was essential for this inhibitory effect. supporting_text: >- Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- AATF is an endogenous antagonist of Par-4 activity, functioning as an effective inhibitor of aberrant Abeta production under apoptotic conditions. supporting_text: >- These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:15207272 title: AATF protects neural cells against oxidative damage induced by amyloid beta-peptide. findings: - statement: >- AATF is expressed in cortical neurons and PC12 cells, and Abeta induces alterations in AATF expression; inhibition of AATF induction sensitizes neurons to Abeta toxicity. supporting_text: >- AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- AATF overexpression suppresses superoxide production, inhibits peroxynitrite formation and lipid peroxidation, and protects against Abeta-induced apoptosis, indicating AATF is a neuroprotective factor acting through ROS suppression. supporting_text: >- Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:17157788 title: Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint. findings: - statement: >- Che-1 contributes to the DNA damage response; checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. supporting_text: >- Che-1 contributes to DNA damage response and its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- DNA damage-induced phosphorylation of Che-1 causes its specific recruitment to the TP53 and p21 promoters, with a profound effect on basal p53 expression that is preserved following DNA damage. supporting_text: >- These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Che-1 contributes to maintenance of the G2/M checkpoint induced by DNA damage, revealing a mechanism by which checkpoint kinases regulate DNA damage responses. supporting_text: >- Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:19911006 title: AATF mediates an antiapoptotic effect of the unfolded protein response through transcriptional regulation of AKT1. findings: - statement: >- AATF is induced by ER stress through the PERK-eIF2alpha pathway and is an antiapoptotic component of the unfolded protein response. supporting_text: >- We show that AATF is induced by ER stress through the PERK-eIF2alpha pathway and transcriptionally activates the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene through signal transducer and activator of transcription 3 (Stat3), which sustains Akt1 activation and promotes cell survival. reference_section_type: ABSTRACT - statement: >- AATF acts as a transcriptional cofactor that drives AKT1 expression via STAT3, sustaining AKT1 activation to promote cell survival under ER stress. supporting_text: >- Ectopic expression of AATF or a constitutively active form of AKT1 confers on cells resistance to ER stress-mediated cell death, whereas RNAi-mediated knockdown of AATF or AKT1 renders cells sensitive to ER stress. reference_section_type: ABSTRACT - statement: >- AATF and WFS1 form a positive feedback loop in pancreatic beta-cells, and loss of either drives a self-perpetuating cycle of ER-stress-mediated cell death. supporting_text: >- We also discovered a positive crosstalk between the AATF and WFS1 signaling pathways. Thus, WFS1 deficiency or AATF deficiency mediates a self-perpetuating cycle of cell death. reference_section_type: ABSTRACT - id: PMID:22658674 title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. findings: - statement: AATF identified as mRNA-binding protein in HeLa mRNA interactome capture - id: PMID:22681889 title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. findings: - statement: AATF identified as mRNA-binding protein in HEK293 mRNA-bound proteome - id: PMID:22909821 title: AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. findings: - statement: >- AATF is phosphorylated by checkpoint kinase MK2 upon genotoxic stress, and this phosphorylation releases AATF from cytoplasmic MRLC3, enabling nuclear translocation. supporting_text: >- Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- Nuclear AATF binds to PUMA, BAX, and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes, acting as a critical regulator that shifts the p53 response from apoptosis toward cell-cycle arrest and DNA repair. supporting_text: >- where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- The p38/MK2/AATF signalling module is identified as a critical repressor of p53-driven apoptosis; AATF depletion dramatically enhances tumor response to genotoxic chemotherapy, while phospho-mimicking AATF causes adriamycin resistance in vivo. supporting_text: >- In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: AATF-NGDN interaction detected in systematic binary interactome screen - id: PMID:29232376 title: Che1/AATF interacts with subunits of the histone acetyltransferase core module of SAGA complexes. findings: - statement: >- AATF interacts with ADA2A, ADA2B, and GCN5 (but not SGF29) of the SAGA/ATAC HAT module, as demonstrated by yeast two-hybrid, co-immunoprecipitation in HEK293 cells, and fluorescence co-localization in HEK293 and U2OS cells. supporting_text: >- Co-immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins in human cells and yeast two-hybrid assays to delineate domains in the ADA2 and GCN5 proteins required for these interactions. reference_section_type: ABSTRACT full_text_unavailable: false - statement: >- ADA2B shows the strongest interaction with AATF among HAT module subunits, and ADA2B co-localizes with AATF in both nucleoplasm and nucleolus, while GCN5 is excluded from the nucleolus. supporting_text: >- ADA2B produced the strongest interaction with AATF, while ADA2A and GCN5 displayed weaker, nonetheless definite interaction. ADA2B co-localization with AATF was primarily in the nucleoplasm with an additional nucleolar co-localization. Unlike AATF, GCN5 appeared to be excluded from the nucleolus. reference_section_type: RESULTS full_text_unavailable: false - statement: >- The GCN5 acetyltransferase domain is required for interaction with AATF; for ADA2 isoforms, the region between the SANT domain and Ada1 box is critical. supporting_text: >- For hGCN5, amino or carboxy-terminal truncations that removed the acetyltransferase domain no longer manifested interaction with AATF suggesting this domain is required for the association. For both ADA2 isoforms, the region between the SANT domain and the Ada1 box also may be critical for interaction with AATF while the SWIRM domain is not required. reference_section_type: RESULTS full_text_unavailable: false - statement: >- Co-expression of ADA2A, ADA2B, or GCN5 with AATF significantly reduced AATF-mediated transcriptional activation of the MDM2 promoter, indicating HAT module subunits negatively modulate AATF transactivation function. supporting_text: >- AATF expression activates the promoter while co-expression of ADA2A, ADA2B or GCN5 with AATF, significantly reduced the activation imparted by AATF on MDM2 promoter-directed transcription (p <0.01). reference_section_type: RESULTS full_text_unavailable: false - statement: >- AATF is localized to both nucleoplasm and nucleolus, consistent with reported nuclear and nucleolar localization signals, and may participate in regulation of gene expression by modulating chromatin structure through HAT complex interactions. supporting_text: >- AATF was mostly found in the nucleoplasm. Like ADA2B, the AATF protein, was also localized in the nucleolus in addition to the nucleoplasm. Che-1/AATF could be participating in the regulation of gene expression by regulating chromatin structure. reference_section_type: DISCUSSION full_text_unavailable: false - id: PMID:30021884 title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. findings: - statement: AATF-NGDN interaction detected by crosslinking mass spectrometry in nuclei - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: - statement: AATF-MNS1 interaction detected in binary interactome reference map - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: - statement: AATF interactions with APP, PIK3R1, and RAC1 in neurodegeneration-focused interactome - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: - statement: AATF-NGDN interaction confirmed in dual proteome-scale networks - id: PMID:34516797 title: Nucleolar maturation of the human small subunit processome. findings: - statement: >- Cryo-EM structures at 2.7 to 3.9 angstrom resolution reveal AATF as a structural component of the human SSU processome, a 4.5-megadalton nucleolar assembly. supporting_text: >- We report the high-resolution cryo-electron microscopy structures of maturing human small subunit (SSU) processomes at resolutions of 2.7 to 3.9 angstroms. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- The SSU processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps, including targeted exosome-mediated RNA degradation and site-specific endonucleolytic cleavage. supporting_text: >- The human small subunit processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps. RNA folding states within these particles are communicated to and coordinated with key enzymes that drive irreversible steps such as targeted exosome-mediated RNA degradation, protein-guided site-specific endonucleolytic RNA cleavage, and tightly controlled RNA unwinding. reference_section_type: ABSTRACT full_text_unavailable: true - statement: >- The SSU processome demonstrates impressive structural plasticity through conserved mechanisms, endowing it with the ability to mature the small ribosomal subunit from within the nucleolus. supporting_text: >- These conserved mechanisms highlight the SSU processome's impressive structural plasticity, which endows this 4.5-megadalton nucleolar assembly with the distinctive ability to mature the small ribosomal subunit from within. reference_section_type: ABSTRACT full_text_unavailable: true - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: - statement: AATF-NGDN interaction detected in endogenous tagging study core_functions: # Core function 1: SSU processome structural component -- ribosome biogenesis - description: >- AATF functions as a structural component of the small subunit (SSU) processome, a 4.5-MDa nucleolar ribonucleoprotein assembly that mediates early maturation of the small ribosomal subunit. Within the SSU processome, AATF binds pre-rRNA and contributes to the coordinated RNA folding, modification, rearrangement, and cleavage steps required to generate mature 18S rRNA. Cryo-EM structures at 2.7-3.9 angstrom resolution directly resolve AATF within the processome particle, confirming it as a bona fide structural component. Available structural and GOA evidence places AATF in SSU/pre-40S maturation, not in pre-60S large-subunit precursor particles. AATF also interacts with NGDN, another SSU processome subunit, an interaction reproduced across four independent studies. molecular_function: id: GO:0003723 label: RNA binding directly_involved_in: - id: GO:0042274 label: ribosomal small subunit biogenesis - id: GO:0030490 label: maturation of SSU-rRNA locations: - id: GO:0005730 label: nucleolus in_complex: id: GO:0032040 label: small-subunit processome supported_by: - reference_id: PMID:34516797 supporting_text: "The human small subunit processome mediates early maturation of the small ribosomal subunit by coupling RNA folding to subsequent RNA cleavage and processing steps." - reference_id: PMID:25416956 supporting_text: "a systematic map of ?14,000 high-quality human binary protein-protein interactions" # Core function 2: Transcriptional cofactor -- RNA Pol II coactivator - description: >- AATF/Che-1 acts as a transcriptional coactivator for RNA polymerase II by binding the Pol II subunit POLR2J and cooperating with sequence-specific transcription factors to activate target gene expression. AATF displaces the histone deacetylase HDAC1 from SP1-bound promoters (e.g. CDKN1A/p21), leading to histone H3 acetylation and transcriptional activation. It also interacts with Rb family members (RB1, RBL1, RBL2) to counteract Rb-mediated repression of E2F target genes. AATF associates with SAGA/ATAC HAT module subunits (TADA2A, TADA2B, KAT2A/GCN5), linking it to chromatin-modifying transcriptional coactivator complexes. After DNA damage, ATM/ATR- and Chk2-dependent phosphorylation promotes AATF recruitment to TP53 and CDKN1A promoters, activating p53-dependent transcription. AATF also cooperates with NRF-1 to drive nuclear-encoded OXPHOS gene transcription. molecular_function: id: GO:0003713 label: transcription coactivator activity directly_involved_in: - id: GO:0045893 label: positive regulation of DNA-templated transcription - id: GO:0006355 label: regulation of DNA-templated transcription locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:10783144 supporting_text: "Here we describe Che-1, a novel human protein that interacts with hRPB11." - reference_id: PMID:10783144 supporting_text: "Che-1 represses the growth suppression function of Rb, counteracting the inhibitory action of Rb on the trans-activation function of E2F1." - reference_id: PMID:12847090 supporting_text: "Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites." - reference_id: PMID:17157788 supporting_text: "The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage." - reference_id: PMID:29232376 supporting_text: "Co-immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins in human cells"