GO:0035267 NuA4 histone acetyltransferase complex: Components, Assembly and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035267 describes the NuA4 histone acetyltransferase complex, a multi-subunit chromatin-modifying machine with histone acetylase, ATPase, DNA helicase and structural DNA-binding activities.
• The human NuA4/TIP60 complex contains the catalytic subunit TIP60 (HTATIP/KAT5), the scaffold TRRAP, the AAA+ ATPases RUVBL1 and RUVBL2, beta-actin and BAF53/ACTL6A.
• NuA4 is conserved from yeast to plants and humans, with 13 subunits in yeast and a related but expanded composition in metazoans.
• Structural studies have revealed how NuA4 binds the nucleosome and coordinates histone acetylation with chromatin remodeling and histone exchange.
• NuA4 functions in double-strand DNA break repair, transcriptional activation, and synaptic-activity-dependent DNA repair through the NPAS4-NuA4 complex.
• In plants, NuA4 is required for chlorophyll biosynthesis and photosynthesis, highlighting its broad biological importance.
Description
The NuA4 histone acetyltransferase complex (GO:0035267) is a conserved multi-subunit chromatin-modifying assembly that acetylates histone tails and participates in DNA repair, transcription and chromatin remodeling. It is defined by its histone acetylase activity on chromatin, as well as ATPase, DNA helicase and structural DNA-binding activities, and is thought to be involved in double-strand DNA break repair. The complex is best known for its catalytic subunit TIP60 (HTATIP/KAT5) in humans and Esa1 in yeast, which are homologous. Researchers study NuA4 because it sits at the interface of chromatin regulation, genome stability and gene expression, and because its subunits are recurrently implicated in cancer and neurodevelopmental processes. Structural and biochemical work has progressively revealed how NuA4 recognizes the nucleosome and coordinates acetylation with ATP-dependent remodeling and histone exchange. This article summarizes the authoritative GO definition, the complex composition, its molecular mechanism, key genes, disease links and experimental methods for studying NuA4.
NuA4 histone acetyltransferase complex At A Glance
| GO ID | GO:0035267 |
|---|---|
| GO term | NuA4 histone acetyltransferase complex |
| Ontology | cellular_component |
| Synonym | TIP60 histone acetylase complex; TIP60 histone acetyltransferase complex |
| Major function | Histone acetylation on chromatin, ATPase, DNA helicase and structural DNA binding; implicated in double-strand DNA break repair |
| Catalytic subunit (human) | TIP60 (HTATIP/KAT5) |
| Catalytic subunit (yeast) | Esa1 |
| Core subunits (human) | TIP60, TRRAP, RUVBL1, RUVBL2, beta-actin, BAF53/ACTL6A |
| Conservation | Conserved from yeast to plants and humans; yeast complex has 13 subunits |
What Is GO:0035267?
GO:0035267 (NuA4 histone acetyltransferase complex) is a cellular component term describing a chromatin-associated complex that possesses histone acetylase activity on chromatin, together with ATPase, DNA helicase and structural DNA-binding activities. The complex is thought to be involved in double-strand DNA break repair. In humans, its subunits include HTATIP/TIP60, TRRAP, RUVBL1, RUVBL2, beta-actin and BAF53/ACTL6A. In yeast, the complex has 13 subunits, including the catalytic subunit Esa1, which is homologous to human Tip60. Synonyms include TIP60 histone acetylase complex and TIP60 histone acetyltransferase complex.
Why Is NuA4 histone acetyltransferase complex Important in Cell Biology?
The NuA4 histone acetyltransferase complex is important because it couples histone acetylation to ATP-dependent chromatin remodeling and DNA repair, thereby influencing transcription, genome stability and cell fate. Its catalytic subunit TIP60 is a well-studied acetyltransferase that acetylates histones and non-histone substrates, and its scaffold TRRAP links NuA4 to diverse transcription factors. In neurons, an NPAS4-NuA4 complex couples synaptic activity to DNA repair, directly connecting chromatin modification to neuronal activity-dependent genome maintenance. In plants, NuA4 is required for chlorophyll biosynthesis and photosynthesis, demonstrating its role beyond animals. Because NuA4 subunits are frequently altered in cancer and are essential for DNA repair, the complex is a compelling target for mechanistic and translational research.
• Regulates chromatin accessibility and transcription through histone acetylation.
• Participates in double-strand DNA break repair, supporting genome stability.
• Contains the catalytic subunit TIP60 (KAT5), a key acetyltransferase in human cells.
• Includes the scaffold TRRAP, which recruits NuA4 to transcription factors.
• Contains AAA+ ATPases RUVBL1 and RUVBL2 that power chromatin remodeling and histone exchange.
• Is conserved in yeast (13 subunits, Esa1) and plants, enabling cross-species studies.
• Links synaptic activity to DNA repair via the NPAS4-NuA4 complex in neurons.
• Is required for chlorophyll biosynthesis and photosynthesis in Arabidopsis.
• Structural studies provide templates for inhibitor and modulator design.
• Subunit alterations are observed in cancer, making NuA4 a potential therapeutic target.
What Happens During NuA4 histone acetyltransferase complex?
Nucleosome recognition and binding
In simple terms: The complex first finds and attaches to the nucleosome, the DNA-protein spool that packages DNA.
NuA4 binds nucleosomes through multiple subunits, including the catalytic TIP60 and accessory factors, positioning the enzyme for histone tail modification. Structural studies of the yeast and human complexes have revealed how the assembly engages the nucleosome core and the histone H4 tail, which is a primary substrate. This binding is a prerequisite for subsequent acetylation and remodeling steps.
Histone acetylation
In simple terms: Once bound, the complex adds acetyl groups to histone proteins, loosening chromatin and creating marks that regulate gene expression.
The catalytic subunit TIP60 (Esa1 in yeast) acetylates lysine residues on histone H4 and other histones, neutralizing positive charges and promoting chromatin accessibility. Acetylation is coupled to ATPase and DNA helicase activities within the complex, which together facilitate nucleosome remodeling. This enzymatic activity is central to the GO definition of GO:0035267.
Chromatin remodeling and histone exchange
In simple terms: The complex uses energy from ATP to slide or exchange histones, changing the structure of chromatin.
The AAA+ ATPases RUVBL1 and RUVBL2, together with other subunits, provide ATPase and DNA helicase activities that drive chromatin remodeling and histone exchange. Structural analysis of the human TIP60-C complex has shown how histone exchange and acetyltransferase activities are coordinated within a single assembly. This dual functionality distinguishes NuA4 from simpler acetyltransferases.
DNA repair and transcriptional regulation
In simple terms: The complex helps repair broken DNA and turns genes on or off by modifying chromatin at specific sites.
NuA4 is recruited to DNA double-strand breaks and contributes to repair, in part through its acetylation and remodeling activities. In neurons, the NPAS4-NuA4 complex couples synaptic activity to DNA repair, linking experience-dependent transcription to genome maintenance. In plants, NuA4 is required for chlorophyll biosynthesis and photosynthesis, indicating roles in developmental and metabolic gene regulation.
Key Genes Involved in GO:0035267 NuA4 histone acetyltransferase complex
The following genes and proteins are core components or well-characterized subunits of the NuA4 histone acetyltransferase complex (GO:0035267).
| Gene | Major Role | Research Relevance |
|---|---|---|
| KAT5 (TIP60, HTATIP) | Catalytic histone acetyltransferase subunit | Central to acetylation, DNA repair and transcription; frequent target in cancer studies |
| TRRAP | Scaffold subunit that recruits NuA4 to transcription factors | Links NuA4 to oncogenic and developmental transcription programs |
| RUVBL1 | AAA+ ATPase involved in chromatin remodeling and histone exchange | Essential for complex integrity and ATP-dependent functions |
| RUVBL2 | AAA+ ATPase partner of RUVBL1 | Required for remodeling and histone exchange activities |
| ACTL6A (BAF53A) | Actin-related protein subunit | Contributes to nucleosome binding and complex assembly |
| ACTB (beta-actin) | Structural subunit | Part of the human NuA4/TIP60 complex |
| EP400 | ATPase/helicase subunit in human TIP60 complex | Involved in chromatin remodeling and histone exchange |
| YEATS4 | Subunit with histone-binding domains | Facilitates nucleosome engagement and acetylation |
| VPS72 (YL1) | Histone chaperone-like subunit | Supports histone exchange and complex function |
| EPC1 | Subunit of the human NuA4/TIP60 complex | Contributes to complex assembly and transcriptional regulation |
| EPC2 | Paralog of EPC1 in human complex | Modulates NuA4 function in specific contexts |
| BRD8 | Bromodomain-containing subunit | Recognizes acetylated histones and regulates complex targeting |
| DMAP1 | Subunit linked to DNA methylation and repair | Connects NuA4 to DNA repair and transcriptional repression |
| ING3 | PHD finger subunit | Reads histone marks and contributes to complex recruitment |
| Esa1 (yeast) | Catalytic subunit homologous to human TIP60 | Model for studying acetylation and complex assembly |
| Eaf1 (yeast) | Scaffold subunit in yeast NuA4 | Required for complex integrity and function |
| Arp4 (yeast) | Actin-related protein subunit | Essential for yeast NuA4 assembly and activity |
| Swc4 (yeast) | Subunit linking NuA4 to chromatin | Involved in nucleosome binding and remodeling |
How Is NuA4 histone acetyltransferase complex Regulated?
NuA4 activity is regulated by its recruitment to specific chromatin regions through interactions with transcription factors and chromatin marks. In neurons, the NPAS4-NuA4 complex is induced by synaptic activity, coupling neuronal stimulation to DNA repair. In plants, NuA4 is required for chlorophyll biosynthesis and photosynthesis, indicating developmental and environmental regulation. Structural studies suggest that subunit composition and conformational flexibility modulate catalytic activity and substrate specificity.
NuA4 histone acetyltransferase complex and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| KAT5 (TIP60) | Cancer, DNA repair deficiency | Knockout and point-mutation cell lines; xenograft models |
| TRRAP | Cancer, transcriptional dysregulation | Knockout and overexpression models in cancer cell lines |
| RUVBL1/RUVBL2 | Cancer, chromatin remodeling defects | Knockout and ATPase-dead point mutants |
| NPAS4-NuA4 components | Neurodevelopmental and synaptic repair defects | Neuronal knockout and activity-dependent models |
| Plant NuA4 subunits | Chlorophyll biosynthesis and photosynthesis defects | Arabidopsis knockout and overexpression lines |
Cancer
Alterations in NuA4 subunits, particularly TIP60 (KAT5) and TRRAP, have been observed in various cancers, where they can affect DNA repair, transcription and genome stability. The complex's role in double-strand break repair makes it relevant to chemoresistance and radiation sensitivity.
Neurodevelopmental and neurodegenerative processes
The NPAS4-NuA4 complex couples synaptic activity to DNA repair, and its dysfunction may contribute to neuronal vulnerability and activity-dependent genome instability. This links NuA4 to neurodevelopmental and neurodegenerative contexts.
Plant development and photosynthesis
In Arabidopsis, NuA4 is required for chlorophyll biosynthesis and photosynthesis, and its disruption leads to developmental defects. This highlights conserved roles in energy metabolism and development.
From NuA4 histone acetyltransferase complex-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the effect of NuA4 loss on chromatin acetylation? | Knockout of KAT5 or TRRAP in human cell lines |
| How does TIP60 catalytic activity contribute to DNA repair? | Point mutation of catalytic residues in KAT5 |
| How does NuA4 recruitment to specific loci work? | Knock-in of tagged subunits (e.g., TRRAP-FLAG) |
| What is the role of NuA4 in neuronal activity-dependent repair? | NPAS4-NuA4 knockout in primary neurons |
| Can NuA4 subunit overexpression drive transformation? | Overexpression of TRRAP or TIP60 in cancer cell lines |
| What is the function of NuA4 in plants? | Arabidopsis knockout and overexpression lines |
How to Study the NuA4 histone acetyltransferase complex Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Cryo-EM | Three-dimensional structure of NuA4 and nucleosome complexes | Understanding subunit architecture and substrate binding |
| ChIP-seq | Genomic binding sites of NuA4 subunits and histone acetylation | Mapping target genes and repair sites |
| Mass spectrometry | Protein composition and interactions | Defining NuA4 subunits and associated factors |
| Histone acetyltransferase assay | Enzymatic acetylation activity | Measuring catalytic function of TIP60/Esa1 |
| DNA repair assays | Sensitivity to DNA-damaging agents | Assessing NuA4 role in double-strand break repair |
| Neuronal activity paradigms | Activity-dependent DNA repair | Studying NPAS4-NuA4 in neurons |
| Plant phenotyping | Chlorophyll content and photosynthesis | Assessing NuA4 function in Arabidopsis |
| RNA-seq | Transcriptional changes upon NuA4 perturbation | Identifying NuA4-regulated genes |
Structural biology (cryo-EM and crystallography)
Cryo-EM and crystallography have been used to determine the structures of yeast and human NuA4 complexes, revealing subunit architecture and nucleosome binding. These methods are essential for understanding how acetylation and remodeling are coordinated.
Chromatin immunoprecipitation and sequencing (ChIP-seq)
ChIP-seq for NuA4 subunits and histone acetylation marks maps the genomic binding sites and activity of the complex. This approach links NuA4 to specific target genes and repair sites.
Proteomics and interactomics
Affinity purification coupled to mass spectrometry identifies NuA4 subunits and associated factors, defining complex composition and dynamics. This is critical for verifying subunit interactions and post-translational modifications.
Functional assays for DNA repair and transcription
DNA damage sensitivity assays, reporter transcription assays and neuronal activity paradigms assess NuA4 function in repair and gene regulation. These methods connect molecular activity to cellular phenotypes.
How CRISPR Can Be Used to Study GO:0035267 NuA4 histone acetyltransferase complex
Knockout
CRISPR knockout of NuA4 subunits such as KAT5, TRRAP, RUVBL1 or RUVBL2 enables loss-of-function studies to assess their roles in histone acetylation, DNA repair and transcription. Knockout cell lines are valuable for identifying essential subunits and compensatory mechanisms.
Point Mutation
Point mutations in the catalytic domain of KAT5 or the ATPase domains of RUVBL1/RUVBL2 can dissect enzymatic activities from scaffolding functions. Such models help determine which activities are required for DNA repair and chromatin remodeling.
Knock-in
Knock-in of epitope tags (e.g., FLAG, HA) or fluorescent proteins into endogenous NuA4 subunit loci allows for affinity purification, imaging and ChIP-seq under native regulation. This approach preserves physiological expression levels.
Overexpression
Overexpression of NuA4 subunits such as TRRAP or TIP60 can model oncogenic roles and identify dosage-sensitive phenotypes. Overexpression models are useful for studying complex assembly and dominant effects.
How EDITGENE Supports NuA4 histone acetyltransferase complex Research
Researchers studying NuA4 histone acetyltransferase complex-related genes often need to determine whether a candidate gene is causally involved in chromatin regulation, DNA repair or disease. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for NuA4 histone acetyltransferase complex research.
Frequently Asked Questions About NuA4 histone acetyltransferase complex
What is the NuA4 histone acetyltransferase complex?
It is a multi-subunit chromatin-modifying complex (GO:0035267) with histone acetylase, ATPase, DNA helicase and structural DNA-binding activities, involved in double-strand DNA break repair.
What genes are involved in the NuA4 histone acetyltransferase complex?
Key genes include KAT5 (TIP60), TRRAP, RUVBL1, RUVBL2, ACTL6A, ACTB, EP400, YEATS4, VPS72, EPC1, EPC2, BRD8, DMAP1 and ING3 in humans, and Esa1, Eaf1, Arp4 and Swc4 in yeast.
What is the function of GO:0035267?
GO:0035267 describes a complex that acetylates histones on chromatin and has ATPase, DNA helicase and structural DNA-binding activities, implicated in DNA repair.
Where is the NuA4 complex found?
It is conserved from yeast to plants and humans, with a 13-subunit complex in yeast and related complexes in metazoans and plants.
How does NuA4 contribute to DNA repair?
NuA4 is recruited to DNA double-strand breaks and uses its acetylation and remodeling activities to facilitate repair, as shown for the NPAS4-NuA4 complex in neurons.
What is the catalytic subunit of NuA4?
The catalytic subunit is TIP60 (KAT5) in humans and Esa1 in yeast, both histone acetyltransferases.
What diseases are linked to NuA4?
NuA4 subunits have been linked to cancer and neuronal DNA repair defects, and in plants to chlorophyll biosynthesis and photosynthesis defects.
How can I study NuA4 in the lab?
Common methods include CRISPR knockout, point mutation, knock-in tagging, ChIP-seq, proteomics, structural biology and DNA repair assays.
What is the structure of the NuA4 complex?
Structures of yeast and human NuA4 have been determined by cryo-EM, revealing a modular architecture with catalytic and ATPase modules.
Is NuA4 involved in transcription?
Yes, NuA4 acetylates histones and is recruited to promoters, regulating transcription in addition to its DNA repair roles.
Conclusion
The NuA4 histone acetyltransferase complex (GO:0035267) is a conserved chromatin-modifying machine that couples histone acetylation with ATP-dependent remodeling and DNA repair. Its subunits, including TIP60, TRRAP, RUVBL1 and RUVBL2, are central to genome stability and transcriptional control, with links to cancer and neuronal function. Structural and functional studies continue to reveal how NuA4 recognizes nucleosomes and coordinates its multiple activities. Researchers can leverage CRISPR-based models and screening to dissect NuA4 biology and its disease relevance.
References
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- 2. Ji L et al.. 2022. Structure of the NuA4 histone acetyltransferase complex.. Proc Natl Acad Sci U S A 119(48):e2214313119 PMID: 36417436
- 3. Li C et al.. 2024. Structure of the human TIP60-C histone exchange and acetyltransferase complex.. Nature 635(8039):764-769 PMID: 39260417
- 4. Pollina EA et al.. 2023. A NPAS4-NuA4 complex couples synaptic activity to DNA repair.. Nature 614(7949):732-741 PMID: 36792830
- 5. Zhou JX et al.. 2022. The Arabidopsis NuA4 histone acetyltransferase complex is required for chlorophyll biosynthesis and photosynthesis.. J Integr Plant Biol 64(4):901-914 PMID: 35043580
- 6. Qu K et al.. 2022. Structure of the NuA4 acetyltransferase complex bound to the nucleosome.. Nature 610(7932):569-574 PMID: 36198799
- 7. Zukin SA et al.. 2022. Structure and flexibility of the yeast NuA4 histone acetyltransferase complex.. Elife 11 PMID: 36263929
- 8. Espinosa-Cores L et al.. 2020. Insights Into the Function of the NuA4 Complex in Plants.. Front Plant Sci 11:125 PMID: 32153620
