ZZZ3

ZZZ3 is a dedicated nuclear subunit of the ATAC histone acetyltransferase complex, a ~700 kDa assembly biochemically distinct from SAGA that harbors dual HAT activities (GCN5/KAT2 and ATAC2/KAT14) and stimulates nucleosome remodeling by ISWI and SWI/SNF-family complexes (PMID:16428443, PMID:18327268). Its ZZ-type zinc finger domain directly recognizes the N-terminal alanine of histone H3 through an acidic cavity, thereby recruiting the ATAC complex to chromatin to promote H3K9 acetylation at promoters and activate target gene expression (PMID:30217978). O-GlcNAcylation of the ATAC subunit YEATS2 strengthens ZZZ3–YEATS2 interaction on chromatin, stabilizing ATAC complex occupancy and sustaining H3K9 acetylation (PMID:40541806). ZZZ3 also engages oncogenic fusion transcription factors (TAZ-CAMTA1, YAP-TFE3) and super-enhancer elements to drive context-specific transcriptional programs, and is required for ribosome biogenesis, mTOR signaling, and proliferation in human embryonic stem cells (PMID:33913810, PMID:39376717, PMID:38701777).

1. 2006 High

   Identification of ZZZ3 (Atac1) as a core subunit of a novel ~700 kDa HAT complex (ATAC) biochemically distinct from SAGA resolved whether all GCN5-containing complexes were equivalent and established an independent chromatin-modifying entity.

   Evidence Affinity purification, mass spectrometry, and co-immunoprecipitation of Drosophila dAda2A-containing complex

   PMID:16428443

   Open questions at the time

   • Catalytic activities of ATAC beyond GCN5 were not yet defined
   • Whether ZZZ3 itself contributes to histone recognition was unknown
   • Mammalian ATAC composition had not been confirmed
2. 2008 High

   Demonstration that ATAC contains a second HAT (Atac2/KAT14) and stimulates nucleosome sliding by remodeling complexes established the dual enzymatic architecture of the complex and its broader chromatin function beyond acetylation.

   Evidence MudPIT mass spectrometry, recombinant Atac2 HAT assays, nucleosome-remodeling assays, and Drosophila Atac2 mutant analysis

   PMID:18327268

   Open questions at the time

   • The specific contribution of ZZZ3 versus other subunits to ATAC recruitment was not addressed
   • Whether ATAC stimulation of remodeling is direct or indirect was unresolved
3. 2018 High

   Structural resolution of the ZZZ3 ZZ domain bound to H3 revealed a direct histone-reading mechanism — recognition of H3 N-terminal Ala1 via an acidic cavity — answering how ZZZ3 recruits ATAC to specific chromatin loci for H3K9 acetylation and gene activation.

   Evidence Solution NMR structure of ZZ–H3 peptide complex, mutagenesis disrupting binding, ZZZ3 knockdown with ChIP for H3K9ac

   PMID:30217978

   Open questions at the time

   • How ZZ domain reading integrates with YEATS2 histone recognition within the same complex was unclear
   • Whether modifications on H3 modulate ZZ domain binding was not tested
4. 2021 High

   Discovery that oncogenic fusion transcription factors TAZ-CAMTA1 and YAP-TFE3 co-opt ZZZ3/ATAC revealed a disease-relevant mechanism by which aberrant transcription factors hijack the ATAC complex to establish tumor-specific gene programs in epithelioid hemangioendothelioma.

   Evidence Reciprocal co-IP/MS and integrative ChIP-seq/RNA-seq in human and murine cell lines

   PMID:33913810

   Open questions at the time

   • Whether ZZZ3 is the direct interaction surface for the fusion proteins or another ATAC subunit mediates binding was not resolved
   • Therapeutic vulnerability of this interaction was not tested
5. 2023 Medium

   Demonstrating that ATAC subunits including ZZZ3 assemble co-translationally and function exclusively in the nucleus clarified that, unlike SAGA, ATAC has no cytoplasmic pool, constraining models of its biogenesis and regulation.

   Evidence Subcellular fractionation, co-translational assembly assays, endogenous tagging, and immunofluorescence in mammalian cells

   PMID:37682711

   Open questions at the time

   • The order of subunit assembly and rate-limiting steps in ATAC biogenesis were not defined
   • Whether co-translational assembly is essential for ATAC function was not tested
6. 2024 Medium

   Linking ZZZ3 to ribosome biogenesis, translation, and mTOR signaling in human ESCs demonstrated a cell-type-specific proliferative function beyond generic chromatin modification, showing that ZZZ3 is required for proliferation homeostasis without affecting pluripotency.

   Evidence siRNA knockdown of ZZZ3 with proliferation assays, ribosome biogenesis, and mTOR pathway analysis in human embryonic stem cells

   PMID:38701777

   Open questions at the time

   • Direct transcriptional targets linking ZZZ3/ATAC to ribosome biogenesis genes were not mapped
   • Whether this phenotype depends on ZZ domain histone reading was not tested
7. 2024 Medium

   Identification of ZZZ3 binding at the CD70 super-enhancer in DLBCL cells and its role in upregulating CD70 to suppress NK cell-mediated cytotoxicity established a mechanism for ZZZ3-dependent immune evasion in lymphoma.

   Evidence ChIP-seq for H3K27ac, siRNA silencing, ZZZ3 overexpression rescue, and NK cell co-culture assays

   PMID:39376717

   Open questions at the time

   • Whether ZZZ3 binding at the CD70 super-enhancer requires the ZZ–H3 interaction was not examined
   • In vivo tumor immune evasion phenotype was not tested
8. 2025 Medium

   Revealing that O-GlcNAcylation of YEATS2 strengthens its interaction with ZZZ3 on chromatin and stabilizes ATAC complex occupancy identified a nutrient-sensitive post-translational modification that tunes ATAC-dependent H3K9 acetylation.

   Evidence Co-IP, ETD mass spectrometry mapping of O-GlcNAc site, YEATS2 T604A mutant, ChIP for H3K9ac

   PMID:40541806

   Open questions at the time

   • Whether O-GlcNAcylation affects ZZZ3 ZZ domain–histone interaction or only YEATS2–ZZZ3 binding was not distinguished
   • Upstream signals regulating YEATS2 O-GlcNAcylation were not identified

• A full structural model of the intact ATAC complex, the interplay between ZZZ3 ZZ domain and YEATS2 histone reading in target selection, and the mechanism by which ZZZ3 regulates ribosome biogenesis genes remain open questions.
• No cryo-EM or crystal structure of the full ATAC complex exists
• How ZZ and YEATS domain histone recognition cooperate within the same complex is not known
• Direct target genes linking ZZZ3 to ribosome biogenesis and mTOR signaling are not mapped