KAT2A

KAT2A is a histone acetyltransferase whose activity is governed by its assembly into the SAGA co-activator complex: its protein stability depends on the integrity of the SAGA CORE module subunits TADA1, TAF5L, and TAF6L, and loss of these subunits releases KAT2A from chromatin and triggers its proteasomal degradation with consequent loss of H3K9 acetylation, a process regulated by the E3 ligase UBR5 and the deubiquitinase OTUD5 [PMID:bio_10.1101_2025.07.24.666361]. An independent degradation route operates through the CUL4A-DDB1 ligase, which directs K63-linked ubiquitination and p62-mediated autophagic turnover of KAT2A; the cancer-specific protein MAGE-A10 stabilizes KAT2A by antagonizing this interaction and thereby raising histone acetylation [PMID:bio_10.1101_2025.03.05.641767]. Beyond canonical H3K9 acetylation, KAT2A acts as a histone lactyl-transferase that promotes chromatin accessibility at the HIV-1 promoter under hypoxic/hyperglycemic conditions [PMID:bio_10.1101_2025.09.14.676169], and it is recruited to specific gene promoters such as CD59 within transcriptionally active, Chk1-remodeled Sp1 complexes following DNA damage [PMID:bio_10.1101_2025.02.17.638751].

1. 2025 Medium

   Established that KAT2A's stability and chromatin association are coupled to SAGA CORE assembly, explaining how the cell links co-activator integrity to histone acetylation output.

   Evidence Fluorescence-based stability reporter, genetic perturbation of SAGA subunits, proteomics, and a focused CRISPR screen of ubiquitin-proteasome genes

   PMID:bio_10.1101_2025.07.24.666361

   Open questions at the time

   • Direct substrate engagement by UBR5 and reversal by OTUD5 not reconstituted in vitro
   • Preprint not yet peer-reviewed
   • Whether SAGA-independent KAT2A pools exist is not resolved
2. 2025 Medium

   Defined a second, autophagy-linked degradation axis for KAT2A and its antagonism by MAGE-A10, showing how cancer-specific factors can elevate histone acetylation by blocking turnover.

   Evidence Co-immunoprecipitation, ubiquitination assays, autophagy pathway analysis, and overexpression/knockdown in a single lab

   PMID:bio_10.1101_2025.03.05.641767

   Open questions at the time

   • Direct CUL4A-DDB1 ubiquitination site on KAT2A not mapped
   • Relationship between the UBR5/proteasomal and CUL4A/autophagic routes not integrated
   • Preprint not yet peer-reviewed
3. 2025 Low

   Extended KAT2A's catalytic repertoire beyond acetylation to histone lactylation, linking it to metabolic state and chromatin accessibility at the HIV-1 promoter.

   Evidence Pharmacological inhibition, metabolomic profiling, and chromatin accessibility assays in a latency-reversal model

   PMID:bio_10.1101_2025.09.14.676169

   Open questions at the time

   • Direct enzymatic characterization of KAT2A lactyl-transferase activity not demonstrated in a reconstituted system
   • Single lab, single study, preprint
   • Substrate residues for lactylation not defined
4. 2025 Low

   Placed KAT2A in a DNA-damage-responsive promoter-recruitment circuit, showing it is brought to the CD59 promoter within a Chk1-remodeled Sp1 complex to enhance transcription.

   Evidence Co-immunoprecipitation mass spectrometry, kinase inhibitor screen, and transcriptional assays

   PMID:bio_10.1101_2025.02.17.638751

   Open questions at the time

   • KAT2A recruitment inferred from complex membership without direct enzymatic validation at CD59
   • Mechanism of Chk1-dependent recruitment not defined
   • Single lab, preprint

• How the distinct KAT2A degradation routes, its acetyl- versus lactyl-transferase activities, and its promoter-specific recruitment are integrated into a unified regulatory logic remains unresolved.
• No structural model linking SAGA assembly state to degron exposure
• Relative contributions of proteasomal versus autophagic turnover in physiological contexts unknown
• Genome-wide map of KAT2A-dependent acetylation versus lactylation targets not established