tra-1

id: Q17308
gene_symbol: tra-1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:6238
  label: Caenorhabditis briggsae
description: >-
  Cbr-TRA-1 is the Caenorhabditis briggsae ortholog of the GLI/Ci-family C2H2
  zinc-finger transcription factor TRA-1, the terminal global regulator of the
  nematode sex-determination pathway. The protein contains five tandem C2H2 zinc
  fingers (fingers 3-5 mediating sequence-specific DNA binding) and recognizes
  GLI-type cis-regulatory elements at target promoters. TRA-1 acts predominantly
  as a sequence-specific transcriptional repressor that promotes female (and
  hermaphrodite somatic) development by silencing male-fate genes; characterized
  targets include ceh-30 (whose repression eliminates CEM male sensory neurons),
  dmd-3 (controlling male tail-tip morphogenesis), and genes governing male
  somatic and neuronal differentiation. TRA-1 also has a context-dependent
  activating role; together with the Tip60/TRR-1 histone-acetyltransferase complex
  it activates fog-3 to specify the sperm/oocyte decision. TRA-1 is principally
  nuclear but also cytoplasmic, and its activity is modulated by regulated
  CRM1-dependent nuclear export coupled to binding of the tra-2 mRNA; it also
  physically interacts with the intracellular MX domain of the TRA-2 membrane
  protein. Two splice isoforms are produced, of which only the longer (isoform a,
  Tra-1L) is thought to bind DNA. As an evolutionary comparator to C. elegans
  TRA-1, the gene is notable for the unusually high sequence divergence of tra-1
  between Caenorhabditis species.
alternative_products:
- name: a (Tra-1L)
  id: Q17308-1
- name: b (Tra-1S)
  id: Q17308-2
  sequence_note: VSP_011646
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      TRA-1 is a transcription factor that acts in the nucleus, consistent with the
      GLI/Ci family phylogenetic inference and with experimental evidence that TRA-1
      is nuclear (and that its nuclear level is sex-specifically regulated by export).
      Correct and core to its function as a DNA-binding TF.
    action: ACCEPT
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the core molecular function of TRA-1, a GLI/Ci-family C2H2 zinc-finger
      transcription factor that binds sequence-specific cis-regulatory elements to
      regulate RNA polymerase II transcription of sex-determination target genes.
      Well supported by the family-wide IBA inference and by C. elegans experimental
      data on direct target regulation.
    action: ACCEPT
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      TRA-1 acts predominantly as a transcriptional repressor of male-fate genes
      (e.g. ceh-30, dmd-3) to promote female/hermaphrodite development. This repressor
      role is the central regulatory activity of TRA-1 and is consistent with the
      GLI/Ci family. Accepted as a core process.
    action: ACCEPT
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      TRA-1 also has a context-dependent activating role, notably activating fog-3
      together with the TRR-1/Tip60 HAT complex to control the sperm/oocyte decision
      (PubMed:24098152). Activation is a genuine but secondary aspect of TRA-1
      function relative to its dominant repressor role; the term is valid.
    action: ACCEPT
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      TRA-1 binds sequence-specific GLI-type cis-regulatory DNA elements via its C2H2
      zinc fingers (fingers 3-5), e.g. at the fog-3 promoter and an intronic regulatory
      site in ceh-30. This sequence-specific DNA-binding activity is core and well
      supported by the family inference.
    action: ACCEPT
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA
      binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro-based electronic annotation of sequence-specific regulatory DNA binding,
      consistent with the GLI/Ci zinc-finger architecture and with the curated IBA
      DNA-binding terms. Correct; this is a slightly more general sibling of the IBA
      cis-regulatory binding term and is retained.
    action: ACCEPT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization is correct for this transcription factor and is supported
      experimentally and by the IBA assignment. Redundant with the IBA nucleus
      annotation but valid.
    action: ACCEPT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization is documented; TRA-1 partitions between nucleus and
      cytoplasm and is subject to regulated CRM1-dependent nuclear export coupled to
      tra-2 mRNA binding, which lowers nuclear (transcriptional) activity. Valid as a
      non-core localization that is mechanistically relevant to regulation rather than
      to the core DNA-binding TF function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0019099
    label: female germ-line sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      TRA-1 is the terminal regulator of the sex-determination pathway and controls
      germline sexual fate (including the sperm/oocyte decision via fog-3). Female
      germ-line sex determination is a genuine downstream process role. Retained as a
      non-core developmental-process annotation distinct from the core molecular
      DNA-binding/TF activity.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0019101
    label: female somatic sex determination
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      TRA-1 promotes female somatic development by repressing male-fate genes in the
      soma (e.g. ceh-30, dmd-3, male neuronal/morphological programs). This is a
      central biological role of TRA-1. Retained as a (non-core relative to the
      molecular function) developmental-process annotation.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization inferred by sequence similarity from C. elegans TRA-1
      (UniProtKB:P34708). Correct for this transcription factor; redundant with the
      IBA/IEA nucleus annotations.
    action: ACCEPT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization inferred by similarity from C. elegans TRA-1. Consistent
      with the documented nucleocytoplasmic partitioning and regulated nuclear export.
      Non-core localization.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: PMID:11703944
  qualifier: located_in
  review:
    summary: >-
      Nuclear localization inferred by similarity, supported by the cited study on
      RNA-regulated TRA-1 nuclear export, which reports nuclear TRA-1 (higher in
      hermaphrodites; increased in males upon export inhibition). Correct and core.
    action: ACCEPT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: PMID:11703944
  qualifier: located_in
  review:
    summary: >-
      Cytoplasmic localization inferred by similarity, consistent with the cited study
      showing CRM1-dependent nuclear export of TRA-1 (coexport of a TRA-1/tra-2 mRNA
      complex reduces nuclear activity), which implies a cytoplasmic pool. Valid
      non-core localization mechanistically linked to regulation.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11250902
  qualifier: enables
  review:
    summary: >-
      Experimental IPI annotation supported by demonstration that TRA-1 binds the
      intracellular MX regulatory domain of the TRA-2 membrane protein (interaction
      conserved in C. briggsae, with WITH/FROM UniProtKB:Q17307 = Cbr TRA-2). The
      interaction is real and functionally important, but the bare 'protein binding'
      term is uninformative as a core molecular function. Retained as a valid but
      non-core annotation; the specific interacting partner is TRA-2.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0019099
    label: female germ-line sex determination
  evidence_type: TAS
  original_reference_id: PMID:11250902
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (TAS) role of TRA-1 in promoting female germline fate; the cited
      paper places tra-1 as the terminal regulator promoting female fates and shows
      its TRA-2 interaction regulating spermatogenesis. Genuine developmental-process
      role, retained as non-core relative to the molecular function.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0019101
    label: female somatic sex determination
  evidence_type: TAS
  original_reference_id: PMID:11250902
  qualifier: involved_in
  review:
    summary: >-
      Author-stated (TAS) role of TRA-1 in promoting female somatic fates, consistent
      with its position as terminal regulator of the sex-determination pathway. Genuine
      but non-core developmental-process annotation.
    action: KEEP_AS_NON_CORE
core_functions:
- description: >-
    Sequence-specific DNA-binding transcription factor (GLI/Ci-family C2H2
    zinc-finger) that binds GLI-type cis-regulatory elements to control RNA
    polymerase II transcription of sex-determination target genes, acting principally
    as a repressor of male-fate genes (e.g. ceh-30, dmd-3) and context-dependently as
    an activator (e.g. fog-3 with the TRR-1/Tip60 complex).
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  supported_by:
  - reference_id: PMID:11250902
    supporting_text: The tra-1 and tra-2 sex-determining genes promote female fates
      in Caenorhabditis elegans.
  directly_involved_in:
  - id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
- description: >-
    Sequence-specific binding of RNA polymerase II cis-regulatory DNA elements via
    tandem C2H2 zinc fingers (fingers 3-5 mediate site selection), the DNA-recognition
    activity underlying TRA-1 target-gene regulation.
  molecular_function:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  locations:
  - id: GO:0005634
    label: nucleus
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11250902
  title: The TRA-1 transcription factor binds TRA-2 to regulate sexual fates in Caenorhabditis
    elegans.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Establishes tra-1 as terminal regulator promoting female
      fates and reports the conserved MX-dependent TRA-1/TRA-2 physical interaction in
      both C. elegans and C. briggsae; directly supports the sex-determination and
      protein-interaction annotations for Cbr-tra-1.
- id: PMID:11703944
  title: RNA-Regulated TRA-1 nuclear export controls sexual fate.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only cache. Shows TRA-1 is a GLI-family TF required for female
      development with sex-specific nuclear distribution and CRM1-dependent nuclear
      export coupled to tra-2 3'UTR binding; supports the nucleus/cytoplasm
      localization annotations and the regulated-export mechanism.
- id: PMID:24098152
  title: Evolutionary change within a bipotential switch shaped the sperm/oocyte
    decision in hermaphroditic nematodes.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: >-
      Cited in the GO:0045944 annotation review as the source for TRA-1's
      context-dependent activating role on fog-3 (with the TRR-1/Tip60 HAT complex)
      in the sperm/oocyte decision. Added to references for traceability; full-text
      verification pending.