GO:2000279 negative regulation of DNA biosynthetic process: Regulation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2000279 describes any process that stops, prevents or reduces the frequency, rate or extent of DNA biosynthetic process.
• Negative regulation of DNA biosynthesis is essential for genome stability, cell cycle control, and immune signaling [1,3,7].
• Key regulatory mechanisms include repressor proteins, post-translational modifications, and epigenetic silencing [1,2,5].
• Dysregulation of this process is linked to cancer, autoimmune diseases, and developmental disorders [1,3,8].
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) are powerful tools to dissect this regulatory network [1,3].
• Understanding GO:2000279 aids in identifying therapeutic targets for diseases characterized by uncontrolled DNA synthesis [7,8].
Description
The Gene Ontology term GO:2000279, negative regulation of DNA biosynthetic process, encompasses any biological process that stops, prevents, or reduces the frequency, rate, or extent of DNA biosynthesis. DNA biosynthesis is fundamental for cell proliferation, genome duplication, and repair, and its tight negative regulation ensures genomic integrity and prevents uncontrolled cell growth. This regulation is critical in both prokaryotes and eukaryotes, where repressors and checkpoint controls modulate replication initiation and elongation [5,7]. In recent years, studies have revealed that negative regulators of DNA biosynthesis also play key roles in immune responses and epigenetic inheritance [1,2,3]. For example, ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation, indirectly affecting DNA synthesis in immune cells. Similarly, RAD23A negatively regulates RIG-I/MDA5 signaling by promoting TRAF2 degradation, linking DNA biosynthetic regulation to antiviral defense. These findings underscore the broad biological significance of GO:2000279.
negative regulation of DNA biosynthetic process At A Glance
| GO ID | GO:2000279 |
|---|---|
| GO term | negative regulation of DNA biosynthetic process |
| Ontology | biological_process |
| Synonym | negative regulation of DNA anabolism; negative regulation of DNA biosynthesis; negative regulation of DNA formation; negative regulation of DNA synthesis |
| Major function | Inhibits or reduces the rate of DNA synthesis, ensuring genome stability and controlled cell proliferation |
| Related processes | DNA replication, cell cycle checkpoints, DNA repair, innate immunity |
| Key regulators | Repressor proteins, post-translational modifiers, epigenetic factors |
| Disease relevance | Cancer, autoimmune disorders, developmental abnormalities |
What Is GO:2000279?
GO:2000279 is defined as any process that stops, prevents or reduces the frequency, rate or extent of DNA biosynthetic process. In other words, it includes molecular events that inhibit the production of DNA, such as repression of replication initiation, inhibition of nucleotide synthesis, or blockade of DNA polymerase activity. This term is a biological process and is synonymous with negative regulation of DNA anabolism, biosynthesis, formation, and synthesis.
Why Is negative regulation of DNA biosynthetic process Important in Cell Biology?
Negative regulation of DNA biosynthetic process is crucial for maintaining genomic integrity and preventing aberrant proliferation. Uncontrolled DNA synthesis can lead to mutations, chromosomal instability, and tumorigenesis. Moreover, this regulation is integral to immune signaling pathways, where negative regulators such as ZDHHC18 and RAD23A modulate innate immune responses [1,3]. Understanding GO:2000279 provides insights into fundamental cell biology and offers potential therapeutic targets for diseases ranging from cancer to autoimmunity.
• Prevents unscheduled DNA replication that could cause genomic instability.
• Coordinates cell cycle progression with DNA damage checkpoints.
• Modulates innate immune responses to cytosolic DNA.
• Influences epigenetic inheritance through regulation of DNA methylation.
• Plays a role in bacterial stress responses and ectoine catabolism.
• Dysregulation is associated with cancer and autoimmune diseases [3,8].
• Provides targets for antibiotic development in bacteria [5,6].
• Essential for normal development and tissue homeostasis.
• Impacts aging and age-related diseases via DNA repair pathways.
• Offers opportunities for CRISPR-based functional genomics [1,3].
What Happens During negative regulation of DNA biosynthetic process?
Initiation of DNA Synthesis Inhibition
In simple terms: This step blocks the start of DNA copying.
Negative regulation of DNA biosynthesis often begins at the initiation stage, where repressor proteins bind to origins of replication or inhibit the assembly of the pre-replicative complex. In bacteria, the lac repressor exemplifies how DNA-binding proteins can negatively regulate gene expression, indirectly affecting DNA synthesis by controlling nucleotide metabolism. In eukaryotes, checkpoint kinases such as ATM and ATR can phosphorylate and inhibit components of the replication machinery in response to DNA damage.
Elongation and Termination Control
In simple terms: This step slows or stops DNA strand extension.
During elongation, negative regulators can act by depleting nucleotide pools, inhibiting DNA polymerase processivity, or promoting replication fork stalling. For instance, RAD23A negatively regulates RIG-I/MDA5 signaling by promoting TRAF2 polyubiquitination and degradation, which can indirectly affect DNA synthesis in immune cells. Additionally, ZDHHC18-mediated palmitoylation of cGAS negatively regulates cGAS-mediated innate immunity, impacting DNA sensing and downstream DNA biosynthetic processes.
Post-Translational Modifications
In simple terms: Chemical tags on proteins can turn off DNA synthesis.
Post-translational modifications such as phosphorylation, ubiquitination, and palmitoylation play critical roles in negative regulation. For example, ZDHHC18 palmitoylates cGAS to inhibit its activity, thereby negatively regulating cGAS-mediated innate immunity and associated DNA biosynthetic responses. Similarly, ubiquitination of TRAF2 by RAD23A leads to its degradation, dampening RIG-I/MDA5 signaling.
Epigenetic Silencing
In simple terms: DNA can be tagged to keep genes off.
Epigenetic mechanisms, including DNA methylation and histone modifications, contribute to negative regulation of DNA biosynthetic process. In plants, negative regulation of DNA methylation ensures proper gene silencing and genome stability. This epigenetic control can indirectly suppress DNA synthesis by maintaining chromatin in a repressive state.
Transcriptional Repression
In simple terms: Turning off genes that make DNA-building proteins.
Transcriptional repressors can downregulate genes encoding enzymes involved in nucleotide biosynthesis and DNA replication. For instance, negative regulation of cytokine gene transcription illustrates how transcription factors can suppress gene expression programs, including those required for DNA synthesis. The lac repressor is a classic example of transcriptional repression that indirectly limits DNA biosynthesis by controlling metabolic pathways.
Key Genes Involved in GO:2000279 negative regulation of DNA biosynthetic process
The following genes and proteins are key players in negative regulation of DNA biosynthetic process, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ZDHHC18 | Palmitoylates cGAS to negatively regulate innate immunity | Immune regulation, DNA sensing |
| RAD23A | Promotes TRAF2 polyubiquitination and degradation, negatively regulating RIG-I/MDA5 signaling | Antiviral signaling, DNA biosynthesis |
| cGAS | DNA sensor; its activity is negatively regulated by ZDHHC18 | Innate immunity, autoimmune diseases |
| TRAF2 | Signaling adaptor; degraded upon RAD23A action | NF-kB signaling, immune response |
| RIG-I | Cytosolic RNA sensor; negatively regulated by RAD23A pathway | Antiviral immunity |
| MDA5 | Cytosolic RNA sensor; negatively regulated by RAD23A pathway | Antiviral immunity |
| lac repressor | Binds operator to repress lac operon transcription | Bacterial gene regulation, DNA synthesis |
| EhuR | Regulates ectoine uptake and catabolism in Sinorhizobium meliloti | Bacterial stress response |
| IRF10 | Fish interferon regulatory factor; negatively regulates IFN | Immune regulation |
| IRF11 | Fish interferon regulatory factor; negatively regulates IFN | Immune regulation |
| DNA methyltransferases | Establish and maintain DNA methylation; negatively regulated in plants | Epigenetics |
| Cytokine transcription factors | Negatively regulate cytokine gene transcription | Immune modulation |
| ATM | Checkpoint kinase; inhibits DNA replication in response to damage | DNA damage response |
| ATR | Checkpoint kinase; inhibits DNA replication in response to damage | DNA damage response |
| p53 | Tumor suppressor; negatively regulates DNA synthesis under stress | Cancer biology |
| Rb | Retinoblastoma protein; inhibits cell cycle progression and DNA synthesis | Cancer biology |
| E2F | Transcription factor; negatively regulated by Rb | Cell cycle control |
| Cdt1 | Replication licensing factor; inhibited by geminin | DNA replication |
How Is negative regulation of DNA biosynthetic process Regulated?
Negative regulation of DNA biosynthetic process is controlled at multiple levels, including transcriptional repression, post-translational modifications, and checkpoint signaling. For example, the lac repressor binds to operator sequences to inhibit transcription of genes involved in lactose metabolism, indirectly affecting DNA synthesis. In eukaryotes, the ATM/ATR checkpoint kinases phosphorylate and inhibit key replication proteins in response to DNA damage. Additionally, ZDHHC18-mediated palmitoylation of cGAS negatively regulates innate immune signaling, which can impact DNA biosynthetic pathways. RAD23A promotes TRAF2 degradation to dampen RIG-I/MDA5 signaling, further illustrating post-translational control. Epigenetic mechanisms, such as DNA methylation, also contribute to negative regulation in plants.
negative regulation of DNA biosynthetic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ZDHHC18 | Autoimmune diseases, innate immunity | Knockout mice, cell lines |
| RAD23A | Antiviral immunity, cancer | Knockout cells, xenografts |
| cGAS | Autoinflammatory diseases, cancer | Knock-in mice, reporter cells |
| ATM | Ataxia-telangiectasia, cancer | Patient-derived cells, KO models |
| p53 | Li-Fraumeni syndrome, cancer | Knockout mice, organoids |
Cancer
Dysregulation of negative regulation of DNA biosynthetic process can lead to uncontrolled cell proliferation and cancer. Loss of checkpoint kinases such as ATM or ATR, or inactivation of tumor suppressors like p53 and Rb, results in unscheduled DNA synthesis and genomic instability. Targeting these pathways is a major therapeutic strategy in oncology.
Autoimmune and Inflammatory Diseases
Negative regulators of DNA biosynthesis play critical roles in immune signaling. ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation, and its dysregulation may contribute to autoimmune diseases characterized by chronic type I interferon production. Similarly, RAD23A negatively regulates RIG-I/MDA5 signaling, and its dysfunction could lead to excessive immune responses.
Developmental Disorders
Proper control of DNA synthesis is essential for normal development. Mutations in genes that negatively regulate DNA biosynthesis can cause developmental abnormalities due to impaired cell cycle control and genomic instability. For instance, defects in checkpoint kinases lead to growth retardation and predisposition to cancer.
Bacterial Infections
In bacteria, negative regulation of DNA biosynthesis affects stress responses and metabolic adaptation. EhuR regulates ectoine uptake and catabolism in Sinorhizobium meliloti, and its disruption alters bacterial survival under stress. Understanding these pathways can inform antibiotic development.
From negative regulation of DNA biosynthetic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ZDHHC18 negatively regulate cGAS-mediated DNA synthesis? | ZDHHC18 knockout cells + cGAS stimulation |
| How does RAD23A affect TRAF2 stability and DNA biosynthesis? | RAD23A knockout cells + ubiquitination assays |
| What is the role of ATM in inhibiting DNA synthesis after damage? | ATM point-mutant knock-in cells |
| Can overexpression of EhuR reduce ectoine catabolism? | EhuR overexpression in S. meliloti |
| Does IRF10 negatively regulate IFN and DNA synthesis? | IRF10 knockout fish models |
| How does lac repressor control DNA synthesis indirectly? | lac operator point mutations in E. coli |
How to Study the negative regulation of DNA biosynthetic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality and negative regulation | Identify novel regulators of DNA synthesis |
| RNA-seq | Transcriptional changes | Assess impact of negative regulators on gene expression |
| Proteomics | Protein interactions and modifications | Map ubiquitination/palmitoylation events |
| EdU/BrdU incorporation | DNA synthesis rate | Quantify negative regulation in cells |
| ChIP-seq | Protein-DNA binding | Identify repressor binding sites |
| Luciferase reporter | Transcriptional activity | Measure promoter repression |
| Western blot | Protein expression and degradation | Validate knockout/overexpression |
| Flow cytometry | Cell cycle and DNA content | Analyze proliferation arrest |
CRISPR-Cas9 Knockout Screening
Genome-wide CRISPR knockout screens can identify genes that negatively regulate DNA biosynthetic process. For example, knocking out ZDHHC18 or RAD23A can reveal their impact on cGAS or RIG-I/MDA5 signaling and downstream DNA synthesis [1,3].
RNA Sequencing (RNA-seq)
RNA-seq measures transcriptomic changes upon perturbation of negative regulators. It can reveal how overexpression or knockout of genes like EhuR or IRF10 affects global gene expression and DNA synthesis pathways [6,8].
Proteomics and Post-Translational Modification Analysis
Mass spectrometry-based proteomics can identify ubiquitination or palmitoylation events mediated by RAD23A or ZDHHC18, providing mechanistic insights into negative regulation [1,3].
Imaging and Flow Cytometry
Fluorescence microscopy and flow cytometry can monitor DNA synthesis using EdU or BrdU incorporation, allowing quantification of negative regulation in live cells.
How CRISPR Can Be Used to Study GO:2000279 negative regulation of DNA biosynthetic process
Knockout
CRISPR knockout of negative regulators such as ZDHHC18 or RAD23A can lead to enhanced DNA synthesis and immune activation, helping to define their roles in GO:2000279 [1,3].
Point Mutation
Introducing point mutations in catalytic residues of ZDHHC18 or in the ubiquitin-interacting domain of RAD23A can dissect their molecular mechanisms in negative regulation [1,3].
Knock-in
Knock-in of tagged versions of cGAS or TRAF2 allows real-time tracking of their regulation and degradation, providing insights into negative regulation of DNA biosynthetic process [1,3].
Overexpression
Overexpression of negative regulators like EhuR or IRF10 can suppress DNA synthesis and immune signaling, offering gain-of-function models to study GO:2000279 [6,8].
How EDITGENE Supports negative regulation of DNA biosynthetic process Research
Researchers studying negative regulation of DNA biosynthetic process-related genes often need to determine whether a candidate gene is causally involved in controlling DNA synthesis, immune signaling, or disease progression. EDITGENE provides comprehensive CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of DNA biosynthetic process research.
Frequently Asked Questions About negative regulation of DNA biosynthetic process
What is GO:2000279?
GO:2000279 is the Gene Ontology term for negative regulation of DNA biosynthetic process, defined as any process that stops, prevents or reduces the frequency, rate or extent of DNA biosynthesis.
What genes are involved in negative regulation of DNA biosynthetic process?
Key genes include ZDHHC18, RAD23A, cGAS, TRAF2, RIG-I, MDA5, lac repressor, EhuR, IRF10, and IRF11, among others [1,3,5,6,8].
How does negative regulation of DNA synthesis affect cancer?
Dysregulation can lead to uncontrolled proliferation and genomic instability, contributing to cancer development.
What are the synonyms for GO:2000279?
Synonyms include negative regulation of DNA anabolism, DNA biosynthesis, DNA formation, and DNA synthesis.
Which diseases are linked to negative regulation of DNA biosynthetic process?
Cancer, autoimmune diseases, developmental disorders, and bacterial infections are associated with dysregulation of this process [1,3,6,7].
What experimental models are used to study GO:2000279?
CRISPR knockout, point mutation, knock-in, and overexpression models in cell lines and animal models are commonly used [1,3,6,8].
How does ZDHHC18 regulate DNA biosynthesis?
ZDHHC18 palmitoylates cGAS to negatively regulate cGAS-mediated innate immunity, indirectly affecting DNA biosynthetic processes.
What is the role of RAD23A in DNA synthesis regulation?
RAD23A promotes TRAF2 polyubiquitination and degradation, negatively regulating RIG-I/MDA5 signaling and impacting DNA biosynthesis.
Can CRISPR be used to study negative regulation of DNA synthesis?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression are powerful tools to dissect this regulatory network [1,3].
What methods measure negative regulation of DNA biosynthetic process?
EdU/BrdU incorporation, RNA-seq, proteomics, ChIP-seq, and luciferase reporters are commonly used.
Conclusion
GO:2000279, negative regulation of DNA biosynthetic process, is a fundamental biological process that ensures controlled DNA synthesis and genomic stability. Its dysregulation is implicated in cancer, autoimmune diseases, and developmental disorders. Advances in CRISPR-based models and multi-omics approaches continue to unravel the complex regulatory networks involved. EDITGENE provides essential tools and services to accelerate research in this field, from knockout cell lines to CRISPR library screening.
References
- 1. Shi C et al.. 2022. ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation.. EMBO J 41(11):e109272 PMID: 35438208
- 2. Saze H et al.. 2008. Negative regulation of DNA methylation in plants.. Epigenetics 3(3):122-4 PMID: 18567943
- 3. Fang DF et al.. 2013. RAD23A negatively regulates RIG-I/MDA5 signaling through promoting TRAF2 polyubiquitination and degradation.. Biochem Biophys Res Commun 431(4):686-92 PMID: 23357418
- 4. Ye J et al.. 1997. Negative regulation of cytokine gene transcription.. FASEB J 11(11):825-33 PMID: 9285480
- 5. Lewis M. 2005. The lac repressor.. C R Biol 328(6):521-48 PMID: 15950160
- 6. Yu Q et al.. 2017. Negative Regulation of Ectoine Uptake and Catabolism in Sinorhizobium meliloti: Characterization of the EhuR Gene.. J Bacteriol 199(1) PMID: 27795315
- 7. Skarstad K et al.. 2013. Regulating DNA replication in bacteria.. Cold Spring Harb Perspect Biol 5(4):a012922 PMID: 23471435
- 8. Wang ZX et al.. 2024. Crystal Structures of DNA-bound Fish IRF10 and IRF11 Reveal the Determinants of IFN Regulation.. J Immunol 213(5):743-752 PMID: 39058321
