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"