TADA1

TADA1 is a non-enzymatic structural subunit of the SAGA complex CORE module that maintains the integrity of the complex and the stability of its catalytic histone acetyltransferase subunit KAT2A (GCN5) (PMID:42009663). In the absence of TADA1, SAGA integrity is disrupted and non-chromatin-bound KAT2A is degraded by the proteasome through the E3 ligase UBR5 and the deubiquitinase OTUD5, lowering H3K9 acetylation; an intact TADA1-containing CORE module is likewise required for the stability of numerous other SAGA components (PMID:42009663). This SAGA-scaffolding role is conserved in fungi, where the ortholog Hfi1 is required for complex structural integrity and normal histone acetylation/deubiquitination and influences transcription of other SAGA subunit genes (PMID:38132798). Beyond chromatin regulation, yeast ortholog studies link this function to genome maintenance, including X-ray-induced DNA damage repair (PMID:15371366), DNA damage checkpoint control at G1/S and S phases (PMID:19507699), and mitochondrial genome and chromosome stability (PMID:12898711).

1. 2003 Low

   Established the first functional readout for the gene by showing the yeast ortholog mediates regulatory protein interactions and is required for mitochondrial and chromosome stability, framing it as a maintenance factor beyond transcription.

   Evidence Yeast genetic analysis of hfi1-srm mutants with rho(-) mutagenesis, chromosome and plasmid loss assays

   PMID:12898711

   Open questions at the time

   • Genetic phenotypes only; no molecular mechanism linking the protein to genome stability
   • No connection drawn to SAGA at this stage
   • Single lab, single study
2. 2004 Medium

   Tested whether the ortholog contributes to DNA damage responses and showed its loss confers selective X-ray sensitivity, implicating it specifically in ionizing-radiation damage repair rather than UV repair.

   Evidence Genome-wide Saccharomyces deletion screen with survival-vs-dose X-ray assays and co-segregation analysis

   PMID:15371366

   Open questions at the time

   • Does not define the molecular pathway through which it acts in repair
   • Radiation-sensitivity phenotype not mechanistically connected to chromatin acetylation
3. 2009 Medium

   Refined the genome-maintenance role by showing the ortholog participates in DNA damage checkpoint control, with mutants shortening cell-cycle arrest at G1/S and S phases.

   Evidence Genetic analysis and cell-cycle arrest assays with DNA-damaging agents in S. cerevisiae

   PMID:19507699

   Open questions at the time

   • Mechanism connecting checkpoint control to SAGA function not established
   • Single method (genetic/arrest assay)
4. 2018 Low

   Addressed regulation of the human gene by identifying miR-7702 as a direct repressor of TADA1 mRNA, linking TADA1 levels to colorectal cancer cell migration and invasion.

   Evidence Dual luciferase reporter assay, overexpression/knockdown, migration/invasion assays in human vs mouse cells

   PMID:30210694

   Open questions at the time

   • Reporter confirms miRNA targeting but does not characterize TADA1 protein function
   • Mechanistic basis for the migration/invasion phenotype unresolved
   • Single lab
5. 2023 Medium

   Placed the ortholog firmly within the SAGA CORE module, showing it is required for complex structural integrity and for normal histone acetylation/deubiquitination and SAGA subunit gene expression.

   Evidence hfi1Δ deletion in Cryptococcus neoformans with histone modification analysis, transcriptional profiling, and murine virulence assay

   PMID:38132798

   Open questions at the time

   • Fungal ortholog rather than direct human protein study
   • Does not resolve how the subunit confers structural stability mechanistically
6. 2026 High

   Defined the human protein's molecular role: a non-enzymatic CORE module subunit that stabilizes KAT2A and the broader SAGA complex, with its loss triggering UBR5/OTUD5-mediated proteasomal degradation of unassembled KAT2A and loss of H3K9 acetylation.

   Evidence Fluorescence-based KAT2A stability reporter, systematic CRISPR knockout, proteomics, and focused ubiquitin-proteasome CRISPR screen in human cells

   PMID:42009663

   Open questions at the time

   • No structural model of how TADA1 contacts and protects KAT2A within CORE
   • Connection between SAGA-scaffolding role and the genome-maintenance phenotypes seen in orthologs untested in human cells

• Whether the human SAGA-stabilizing function of TADA1 mechanistically underlies the DNA damage checkpoint, radiation-resistance, and mitochondrial genome-stability phenotypes observed in orthologs remains unresolved.
• No human study links TADA1/SAGA integrity to DNA repair or checkpoint control
• Structural basis of CORE module stabilization undetermined