ZZZ3

ZZZ3 is a dedicated nuclear subunit of the ATAC (Ada-Two-A-Containing) histone acetyltransferase complex, where it functions as a chromatin reader that directs the complex's acetyltransferase activity to target genes (PMID:16428443, PMID:30217978). First identified in Drosophila as a stable component co-purifying with the catalytic Gcn5 module and the adaptors Ada2A and Ada3 — but not with SAGA-specific subunits — ZZZ3 helped define ATAC as a HAT complex distinct from SAGA (PMID:16428443); the complex carries two acetyltransferase activities and stimulates nucleosome sliding by ISWI-, SWI-SNF-, and RSC-type remodelers without itself remodeling nucleosomes (PMID:18327268). Mechanistically, the ZZ-type zinc finger of ZZZ3 reads histone H3 by caging its N-terminal Ala1 in an acidic cavity, and loss of ZZZ3 or disruption of this ZZ–H3 contact reduces ATAC-dependent H3K9 acetylation at promoters and lowers target gene expression (PMID:30217978). The intact complex is nuclear-restricted: although core modules assemble co-translationally in the cytoplasm, assembled ATAC is detected exclusively in the nucleus (PMID:37682711). ZZZ3 contributes to disease-relevant transcriptional programs, serving as an interactor recruited by TAZ-CAMTA1 and YAP-TFE3 oncogenic fusions to hyperactivate a TEAD program in epithelioid hemangioendothelioma (PMID:33913810) and binding the CD70 super-enhancer to drive CD70 transcription in diffuse large B-cell lymphoma (PMID:39376717). In human embryonic stem cells, ZZZ3 supports ribosome biogenesis, translation, mTOR signaling, and proliferation without affecting pluripotency (PMID:38701777).

1. 2006 High

   Establishing that ZZZ3 is a bona fide subunit of a HAT complex distinct from SAGA defined its molecular context and the complex it operates within.

   Evidence Affinity purification, mass spectrometry, and reciprocal co-immunoprecipitation/fractionation in Drosophila

   PMID:16428443

   Open questions at the time

   • Did not define ZZZ3's specific molecular function within ATAC
   • Mammalian ATAC composition not addressed
   • No domain-level mechanism for ZZZ3
2. 2008 High

   Characterizing ATAC's enzymatic and chromatin activities placed ZZZ3 within a complex that both acetylates histones and stimulates ATP-dependent remodelers.

   Evidence MudPIT mass spectrometry, in vitro HAT and nucleosome-sliding assays, and in vivo mutagenesis in Drosophila embryos

   PMID:18327268

   Open questions at the time

   • Did not assign a specific function to the ZZZ3 subunit itself
   • Mechanism linking acetylation to remodeler stimulation unresolved
3. 2018 High

   Solving the ZZ domain structure and its H3 recognition mode revealed how ZZZ3 functions as a histone reader that targets ATAC acetyltransferase activity to chromatin.

   Evidence Solution NMR of the ZZ domain–H3 peptide complex with ZZZ3 knockdown, H3K9ac ChIP, and expression analysis

   PMID:30217978

   Open questions at the time

   • Genome-wide map of ZZZ3-dependent recruitment sites not defined
   • Whether other ATAC readers cooperate with the ZZ domain unaddressed
4. 2021 High

   Identifying ZZZ3/ATAC as an effector recruited by oncogenic fusion proteins connected the reader function to a disease transcriptional program.

   Evidence Co-IP/MS proteomic-genetic screen with ChIP-seq and RNA-seq in human and murine cell lines

   PMID:33913810

   Open questions at the time

   • Direct ZZZ3 contribution versus other ATAC subunits not dissected
   • Whether the ZZ–H3 reader function is required for fusion recruitment unknown
5. 2023 High

   Demonstrating nuclear-exclusive residence of assembled ATAC clarified where ZZZ3 acts and how its localization differs from the related SAGA complex.

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

   PMID:37682711

   Open questions at the time

   • Mechanism enforcing nuclear restriction not identified
   • Whether ZZZ3 specifically governs import unknown
6. 2024 Medium

   Loss-of-function in human ESCs linked ZZZ3 to ribosome biogenesis, translation, and mTOR-dependent proliferation, extending its role beyond chromatin readout.

   Evidence siRNA knockdown in human ESCs with ribosome biogenesis, translation, mTOR, proliferation, and pluripotency readouts

   PMID:38701777

   Open questions at the time

   • No pathway reconstitution or epistasis linking ATAC activity to these phenotypes
   • Single lab, no rescue with ZZ-mutant
   • Direct transcriptional targets driving the dormant-like state not defined
7. 2024 Medium

   Mapping ZZZ3 to the CD70 super-enhancer in DLBCL implicated it in regulating tumor–NK cell interactions through enhancer-driven transcription.

   Evidence H3K27ac ChIP-seq, scRNA-seq, siRNA silencing, overexpression, and NK proliferation/cytotoxicity assays in DLBCL cells

   PMID:39376717

   Open questions at the time

   • Direct ZZZ3–super-enhancer binding not structurally established
   • Whether ZZ-domain reader activity is required not tested
8. 2025 Medium

   Showing that YEATS2 O-GlcNAcylation stabilizes ATAC on chromatin and strengthens its affinity for ZZZ3 revealed a post-translational input regulating complex assembly on DNA.

   Evidence ETD mass spectrometry site mapping, Co-IP, ChIP, T604A mutagenesis, and xenograft experiments

   PMID:40541806

   Open questions at the time

   • ZZZ3 itself not directly modified; effect is via YEATS2
   • Single lab without orthogonal confirmation
   • Quantitative contribution of ZZZ3 affinity change to H3K9ac unresolved

• How the ZZ-domain reader function mechanistically couples to ATAC's downstream roles in ribosome biogenesis, mTOR signaling, and disease-specific transcriptional programs remains unresolved.
• No reconstitution linking ZZ–H3 recognition to mTOR/translation phenotypes
• No structure of the full mammalian ATAC complex bound to chromatin
• Mechanism of nuclear restriction unknown