GO:0140674 ATP-dependent histone chaperone activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140674 ATP-dependent histone chaperone activity describes the ATP-driven binding and transfer of histones to or from nucleosomes, enabling chromatin dynamics.
• This activity is essential for nucleosome displacement during transcription, DNA repair, and replication, as it allows access to DNA.
• Key proteins include ATP-dependent chromatin remodelers such as SMARCAD1 and CSB, which cooperate with histone chaperones like NAP1.
• Dysregulation of ATP-dependent histone chaperone activity is linked to cancer, neurodegeneration, and developmental disorders.
• CRISPR-based knockout, point mutation, and knock-in models are powerful tools to dissect the function of these chaperones in disease.
• Studying this activity requires a combination of biochemical assays, genomics, and advanced imaging to track histone dynamics.
Description
ATP-dependent histone chaperone activity (GO:0140674) is a molecular function that couples ATP hydrolysis to the binding and transfer of histones, thereby loading or unloading them onto DNA to form or remodel nucleosomes. This activity is fundamental for all DNA-templated processes, including transcription, replication, and repair, because it regulates chromatin accessibility. Unlike passive histone chaperones, ATP-dependent chaperones actively disrupt histone-DNA contacts, allowing rapid and precise control of nucleosome positioning. Researchers study this activity to understand how cells maintain genomic integrity and how its dysfunction contributes to diseases such as cancer and neurodegeneration. The integration of ATP-dependent histone chaperone activity with other chromatin-modifying activities ensures proper gene expression programs and cellular responses to stress.
ATP-dependent histone chaperone activity At A Glance
| GO ID | GO:0140674 |
|---|---|
| GO term | ATP-dependent histone chaperone activity |
| Ontology | molecular_function |
| Synonym | ATP-dependent histone loader activity, ATP-dependent histone unloader activity, histone loader activity, histone loading activity, histone unloader activity, histone unloading activity, nucleosome remodeling activity |
| Major function | ATP hydrolysis-driven binding and transfer of histones to or from nucleosomes, facilitating chromatin dynamics. |
| Related processes | Transcription, DNA repair, replication, and chromatin assembly. |
| Key example | SMARCAD1, a human chromatin remodeller with subnucleosome preference. |
| Disease relevance | Implicated in cancer, neurodegeneration, and developmental disorders. |
What Is GO:0140674?
According to the Gene Ontology, ATP-dependent histone chaperone activity (GO:0140674) is defined as binding to and carrying a histone or a histone complex to unload or deposit it as a nucleosome, driven by ATP hydrolysis. This definition encompasses both histone loader and unloader activities, as well as nucleosome remodeling activity, highlighting the energy-dependent nature of the process.
Why Is ATP-dependent histone chaperone activity Important in Cell Biology?
ATP-dependent histone chaperone activity is crucial because it provides the energy needed to overcome the stable histone-DNA interactions within nucleosomes, allowing rapid changes in chromatin structure that are essential for gene regulation, DNA repair, and replication. Without this activity, cells cannot efficiently access DNA for transcription or repair, leading to genomic instability and disease. Moreover, the interplay between ATP-dependent chaperones and other chromatin modifiers ensures proper inheritance of epigenetic states.
• Enables nucleosome displacement during transcription, allowing RNA polymerase access to DNA.
• Facilitates transcription-coupled DNA repair by remodeling nucleosomes at damage sites.
• Required for efficient replication fork progression through chromatin.
• Plays a role in establishing and maintaining epigenetic marks by depositing variant histones.
• Dysfunction is associated with cancer, as altered chromatin dynamics can drive oncogenesis.
• Implicated in neurodegenerative diseases where chromatin regulation is disrupted.
• Provides a target for therapeutic intervention in diseases with chromatin dysregulation.
• Essential for stem cell pluripotency and differentiation by controlling gene expression programs.
• Cooperates with histone-modifying enzymes to fine-tune chromatin states.
• Studied using CRISPR screens to identify novel components and pathways.
Molecular Mechanism of ATP-dependent histone chaperone activity
ATP Binding and Hydrolysis
In simple terms: The chaperone uses energy from ATP to power its histone-moving function.
ATP-dependent histone chaperones contain ATPase domains that bind and hydrolyze ATP, converting chemical energy into mechanical force. This hydrolysis drives conformational changes that enable the chaperone to bind histones and disrupt their interactions with DNA. For example, the human remodeller SMARCAD1 exhibits ATP-dependent nucleosome remodeling with a preference for subnucleosomes.
Histone Binding and Transfer
In simple terms: The chaperone grabs histones and moves them on or off DNA.
Upon ATP hydrolysis, the chaperone undergoes a cycle of histone binding and release, transferring histones to or from nucleosomes. This activity can either deposit histones to form nucleosomes or remove them to create nucleosome-free regions. The specificity for particular histone variants or modifications can be regulated by associated factors.
Nucleosome Remodeling and Displacement
In simple terms: The chaperone slides or evicts nucleosomes to expose DNA.
ATP-dependent histone chaperones can slide nucleosomes along DNA, evict histones, or exchange histone variants, thereby altering chromatin structure. This remodeling is essential for processes such as transcription, where nucleosomes must be displaced to allow polymerase passage. The Cockayne syndrome protein B (CSB) cooperates with NAP1-like histone chaperones to remodel nucleosomes during transcription-coupled DNA repair.
Coordination with Other Chromatin Modifiers
In simple terms: The chaperone works with other proteins to fine-tune chromatin.
ATP-dependent histone chaperone activity is often coupled with histone-modifying enzymes, such as histone deacetylases (HDACs), to ensure proper chromatin states. For instance, human class I HDAC complexes show enhanced catalytic activity in the presence of ATP and co-immunoprecipitate with the ATP-dependent chaperone Hsp70. This coordination allows for dynamic regulation of gene expression.
Regulation by Post-translational Modifications
In simple terms: Chemical tags on the chaperone can turn its activity on or off.
The activity of ATP-dependent histone chaperones can be regulated by post-translational modifications, such as phosphorylation or acetylation, which affect their localization, ATPase activity, or interactions with partner proteins. For example, the yeast Dot1 protein regulates nucleosome dynamics through its inherent histone chaperone activity, which is modulated by cell cycle signals.
Key Genes Involved in GO:0140674 ATP-dependent histone chaperone activity
The following genes encode proteins with ATP-dependent histone chaperone activity or are closely associated with this function, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SMARCAD1 | ATP-dependent chromatin remodeller with subnucleosome preference | Studied for its role in DNA repair and transcription; knockout models show chromatin defects. |
| CSB (ERCC6) | ATP-dependent chromatin remodeling in transcription-coupled DNA repair | Mutations cause Cockayne syndrome; used to study DNA repair and neurodegeneration. |
| NAP1L1 | Histone chaperone cooperating with CSB in nucleosome remodeling | Involved in chromatin assembly and repair; potential target in cancer. |
| HSP70 (HSPA1A) | ATP-dependent chaperone co-immunoprecipitating with HDAC complexes | Links protein folding to chromatin regulation; implicated in cancer and neurodegeneration. |
| DOT1 (DOT1L) | Histone chaperone activity regulating nucleosome dynamics in yeast | Model for studying histone methylation and chromatin inheritance. |
| HDAC1 | Histone deacetylase with enhanced activity in presence of ATP and Hsp70 | Target for cancer therapy; involved in transcriptional repression. |
| HDAC2 | Histone deacetylase in complex with ATP-dependent chaperones | Implicated in cancer and neurodegenerative diseases. |
| SMARCA4 (BRG1) | ATP-dependent chromatin remodeler | Frequently mutated in cancer; studied for nucleosome sliding. |
| SMARCA2 (BRM) | ATP-dependent chromatin remodeler | Synthetic lethal with SMARCA4 mutations in cancer. |
| CHD1 | ATP-dependent chromatin remodeler | Involved in transcription and stem cell pluripotency. |
| CHD4 | ATP-dependent chromatin remodeler in NuRD complex | Role in DNA damage response and cancer. |
| INO80 | ATP-dependent chromatin remodeler | Functions in DNA repair and replication. |
| SWR1 (EP400) | ATP-dependent histone variant H2A.Z exchanger | Regulates gene expression and genome stability. |
| RSC complex | ATP-dependent nucleosome remodeler in yeast | Model for chromatin remodeling mechanisms. |
| FACT complex | Histone chaperone with ATP-dependent remodeling | Involved in transcription elongation and DNA repair. |
| TDP-43 | RNA-binding protein with chaperone-like activity | Linked to ALS; forms liquid spherical shells with HSP70. |
| HSPA8 (HSC70) | ATP-dependent chaperone | Cooperates with histone chaperones in chromatin assembly. |
| ATRX | ATP-dependent chromatin remodeler | Mutations cause ATR-X syndrome; involved in histone deposition. |
How Is ATP-dependent histone chaperone activity Regulated?
The activity of ATP-dependent histone chaperones is regulated at multiple levels. ATP availability directly influences their function, as hydrolysis is required for histone transfer. Post-translational modifications, such as phosphorylation by cell cycle kinases, can modulate their ATPase activity and interactions. Additionally, their recruitment to specific genomic loci is guided by histone modifications, DNA damage signals, and transcription factors. For example, the yeast Dot1 protein's chaperone activity is regulated during the cell cycle to control nucleosome dynamics. In human cells, the Cockayne syndrome protein B (CSB) is targeted to sites of DNA damage through interactions with NAP1-like chaperones, ensuring efficient repair. Furthermore, ATP-dependent chaperones can be regulated by their association with other chromatin-modifying complexes, such as HDACs, which enhance their catalytic activity in the presence of ATP.
ATP-dependent histone chaperone activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SMARCA4 | Cancer (e.g., lung adenocarcinoma) | Knockout in cancer cell lines; point mutations in ATPase domain. |
| CSB (ERCC6) | Cockayne syndrome | Knockout in neuronal cells; knock-in of patient mutations. |
| TDP-43 | Amyotrophic lateral sclerosis (ALS) | Overexpression of mutant TDP-43 in motor neurons; tagged knock-in. |
| ATRX | ATR-X syndrome | Knockout in neural progenitor cells; point mutation in ATPase domain. |
| NAP1L1 | Cancer (various) | Overexpression and knockout in cancer cell lines. |
Cancer
Dysregulation of ATP-dependent histone chaperone activity is frequently observed in cancer. Mutations in chromatin remodelers such as SMARCA4 and CHD4 disrupt nucleosome dynamics, leading to aberrant gene expression and genomic instability. Overexpression of histone chaperones like NAP1L1 has been linked to poor prognosis in several cancers, as it promotes proliferation and DNA repair. Targeting these activities with small molecules or CRISPR-based screens is a promising therapeutic strategy.
Neurodegeneration
In neurodegenerative diseases, impaired ATP-dependent histone chaperone activity contributes to neuronal dysfunction. For instance, mutations in CSB cause Cockayne syndrome, characterized by developmental defects and neurodegeneration, due to defective transcription-coupled DNA repair. Additionally, the RNA-binding protein TDP-43, which forms pathological aggregates in ALS, interacts with HSP70 chaperones, suggesting a link between chaperone networks and neurodegeneration.
Developmental Disorders
Germline mutations in ATP-dependent chromatin remodelers such as ATRX lead to developmental disorders like ATR-X syndrome, which features intellectual disability and facial dysmorphism. These disorders highlight the critical role of histone chaperone activity in proper development and gene regulation.
From ATP-dependent histone chaperone activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the role of SMARCAD1 in DNA repair? | Knockout of SMARCAD1 in HeLa cells followed by DNA damage assays. |
| How do CSB mutations affect transcription-coupled repair? | Point mutation knock-in of patient CSB mutations in fibroblasts. |
| Does NAP1L1 overexpression promote tumor growth? | Overexpression of NAP1L1 in cancer cell lines and xenograft models. |
| What is the function of Dot1 chaperone activity in yeast? | Knockout of DOT1 in Saccharomyces cerevisiae and nucleosome stability assays. |
| How does Hsp70 cooperate with HDAC complexes? | Tagged knock-in of Hsp70 in human cells and co-immunoprecipitation. |
| Can CRISPR screens identify novel histone chaperones? | Genome-wide knockout library screening in cells under DNA damage. |
How to Study the ATP-dependent histone chaperone activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ATPase assay | ATP hydrolysis rate | Measuring intrinsic activity of chaperones. |
| Gel shift assay | Histone-DNA binding | Assessing nucleosome assembly/disassembly. |
| MNase-seq | Nucleosome positioning | Genome-wide mapping of chromatin changes. |
| ChIP-seq | Histone modifications and variant distribution | Identifying chaperone targets. |
| Single-molecule FRET | Dynamic histone exchange | Real-time remodeling kinetics. |
| CRISPR knockout screen | Gene essentiality and synthetic lethality | Identifying novel chaperone regulators. |
| Co-immunoprecipitation | Protein-protein interactions | Detecting chaperone complexes. |
| Live-cell imaging | Subcellular localization and dynamics | Tracking chaperone recruitment to damage sites. |
Biochemical Assays for ATP-dependent Histone Chaperone Activity
In vitro assays using recombinant proteins and purified histones can measure ATP hydrolysis, histone binding, and nucleosome remodeling. For example, ATPase activity is quantified by monitoring phosphate release, while gel shift assays assess histone-DNA interactions. These methods are essential for dissecting the mechanism of action of chaperones like SMARCAD1.
Genomic Approaches to Map Nucleosome Dynamics
Techniques such as MNase-seq, ATAC-seq, and ChIP-seq provide genome-wide maps of nucleosome positioning and histone modifications upon manipulation of chaperone activity. These methods reveal how ATP-dependent chaperones influence chromatin accessibility and gene expression.
Imaging and Single-Molecule Studies
Advanced imaging, including live-cell fluorescence microscopy and single-molecule FRET, allows real-time visualization of histone exchange and nucleosome remodeling by ATP-dependent chaperones. These approaches have revealed dynamic interactions between chaperones and nucleosomes.
CRISPR Screens for Functional Genomics
Genome-wide CRISPR knockout or activation screens can identify genes that modulate ATP-dependent histone chaperone activity or that are synthetically lethal with chaperone mutations. Such screens have uncovered novel components of chromatin remodeling pathways.
How CRISPR Can Be Used to Study GO:0140674 ATP-dependent histone chaperone activity
Knockout
CRISPR knockout of genes encoding ATP-dependent histone chaperones, such as SMARCAD1 or CSB, allows researchers to study loss-of-function phenotypes, including defects in DNA repair, transcription, and cell cycle progression. These models are valuable for validating the essential roles of these proteins in chromatin dynamics.
Point Mutation
Introducing specific point mutations in the ATPase domain of chaperones (e.g., SMARCA4) via CRISPR can dissect the contribution of ATP hydrolysis to histone chaperone activity without completely abolishing protein expression. Such models mimic patient mutations and provide insights into disease mechanisms.
Knock-in
Knock-in of tagged versions of chaperones (e.g., GFP or HA tags) enables live-cell imaging and biochemical purification of endogenous complexes. This approach helps track the dynamic localization and interactions of ATP-dependent histone chaperones in real time.
Overexpression
CRISPR activation (CRISPRa) or cDNA overexpression can drive high levels of chaperone expression to study gain-of-function effects, such as oncogenic transformation or enhanced DNA repair. Overexpression models are particularly useful for studying chaperones like NAP1L1 in cancer.
How EDITGENE Supports ATP-dependent histone chaperone activity Research
Researchers studying ATP-dependent histone chaperone activity-related genes often need to determine whether a candidate gene is causally involved in chromatin regulation and disease. EDITGENE provides comprehensive CRISPR-based services to create precisely engineered cell models, enabling functional validation and drug discovery.
Contact EDITGENE today to design your custom CRISPR model for ATP-dependent histone chaperone activity research.
Frequently Asked Questions About ATP-dependent histone chaperone activity
What is ATP-dependent histone chaperone activity?
It is a molecular function defined by GO:0140674, where ATP hydrolysis drives the binding and transfer of histones to or from nucleosomes, facilitating chromatin dynamics.
What genes are involved in ATP-dependent histone chaperone activity?
Key genes include SMARCAD1, CSB (ERCC6), NAP1L1, HSP70 (HSPA1A), DOT1L, and various chromatin remodelers like SMARCA4 and CHD4.
How does ATP-dependent histone chaperone activity work?
The chaperone binds ATP, hydrolyzes it to ADP and phosphate, and uses the released energy to alter histone-DNA interactions, leading to nucleosome sliding, eviction, or exchange.
Why is ATP-dependent histone chaperone activity important?
It is essential for transcription, DNA repair, replication, and epigenetic inheritance; its dysfunction is linked to cancer and neurodegeneration.
What diseases are associated with ATP-dependent histone chaperone activity?
Mutations in chaperone genes cause Cockayne syndrome, ATR-X syndrome, and various cancers, while dysregulation contributes to ALS and other neurodegenerative diseases.
How can I study ATP-dependent histone chaperone activity?
Use biochemical assays (ATPase, gel shift), genomic methods (MNase-seq, ChIP-seq), imaging, and CRISPR screens to dissect its function.
What are the synonyms for ATP-dependent histone chaperone activity?
Synonyms include ATP-dependent histone loader activity, ATP-dependent histone unloader activity, histone loader activity, histone loading activity, histone unloader activity, histone unloading activity, and nucleosome remodeling activity.
Which CRISPR model is best for studying ATP-dependent histone chaperone activity?
Knockout models are ideal for loss-of-function studies, while point mutations and knock-ins help dissect specific domains and track endogenous proteins.
Can EDITGENE help create custom models for histone chaperone research?
Yes, EDITGENE provides knockout, point mutation, knock-in, overexpression, and library screening services tailored to chromatin research.
What is the GO ID for ATP-dependent histone chaperone activity?
The GO ID is GO:0140674.
Conclusion
ATP-dependent histone chaperone activity (GO:0140674) is a fundamental molecular function that powers chromatin dynamics, enabling essential processes such as transcription, DNA repair, and replication. Its dysregulation is implicated in a range of human diseases, making it a critical area of research. By leveraging CRISPR-based models and advanced biochemical assays, researchers can uncover the precise mechanisms and therapeutic potential of these chaperones. EDITGENE stands ready to support these efforts with custom cell models and screening services.
References
- 1. Hu P et al.. 2025. Subnucleosome preference of human chromatin remodeller SMARCAD1.. Nature 644(8077):818-826 PMID: 40468067
- 2. Yu H et al.. 2021. HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells.. Science 371(6529) PMID: 33335017
- 3. Johnson CA et al.. 2002. Human class I histone deacetylase complexes show enhanced catalytic activity in the presence of ATP and co-immunoprecipitate with the ATP-dependent chaperone protein Hsp70.. J Biol Chem 277(11):9590-7 PMID: 11777905
- 4. Lee S et al.. 2018. Dot1 regulates nucleosome dynamics by its inherent histone chaperone activity in yeast.. Nat Commun 9(1):240 PMID: 29339748
- 5. Workman JL. 2006. Nucleosome displacement in transcription.. Genes Dev 20(15):2009-17 PMID: 16882978
- 6. Madhani HD. 2025. Mechanisms of Inheritance of Chromatin States: From Yeast to Human.. Annu Rev Biophys 54(1):59-79 PMID: 39715046
- 7. Cho I et al.. 2013. ATP-dependent chromatin remodeling by Cockayne syndrome protein B and NAP1-like histone chaperones is required for efficient transcription-coupled DNA repair.. PLoS Genet 9(4):e1003407 PMID: 23637612
