GO:1990786 cellular response to dsDNA: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1990786 cellular response to dsDNA describes how a cell changes its state or activity after encountering double-stranded DNA (dsDNA) as a stimulus.
• The cGAS-STING axis is the best-characterized sensor pathway that converts cytosolic dsDNA into interferon and NF-kB inflammatory responses.
• dsDNA can arise from infection, radiation, replication stress, chromosome missegregation, or mitochondrial release, and not all dsDNA sources activate cGAS-STING equally.
• SARM1 is a newly defined dsDNA sensor that triggers NAD+ degradation and a distinct cell death program, expanding the response beyond classical immunity.
• Dysregulated dsDNA responses drive glaucoma, psoriasis, retinal ischemia-reperfusion injury, and neuroinflammation, making the pathway a therapeutic target.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect which genes causally control cellular response to dsDNA.
Description
GO:1990786 cellular response to dsDNA is a Gene Ontology biological process term that captures any change in a cell's state or activity, including movement, secretion, enzyme production, or gene expression, that occurs as a result of a double-stranded DNA stimulus. This term is deliberately broad: it covers immune sensing of foreign or misplaced dsDNA, DNA-damage-associated responses, and cell death programs triggered when dsDNA appears in the wrong cellular compartment. Researchers encounter this process in virology, autoimmunity, neurobiology, oncology, and genome engineering, because dsDNA is both a pathogen-associated molecular pattern and a danger-associated molecular pattern. The pathway is clinically important because excessive or chronic dsDNA sensing underlies inflammatory diseases such as psoriasis and glaucoma, while failed dsDNA responses permit pathogen escape and tumor immune evasion. Understanding the molecular players, from sensors to adaptors to effectors, is therefore a central goal in cell biology and translational medicine.
cellular response to dsDNA At A Glance
| GO ID | GO:1990786 |
|---|---|
| GO term | cellular response to dsDNA |
| Ontology | biological_process |
| Synonym | none |
| Definition | Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a double-stranded DNA stimulus. |
| Major function | Detection of double-stranded DNA and conversion into transcriptional, metabolic, or cell death responses. |
| Key sensors | cGAS, STING, SARM1, and other dsDNA-binding factors. |
| Representative stimuli | Viral dsDNA, micronuclei, radiation-induced DNA damage, replication stress, chromosome missegregation. |
| Disease relevance | Glaucoma, psoriasis, retinal ischemia-reperfusion injury, neuroinflammation, and cell death disorders. |
What Is GO:1990786?
In practical terms, GO:1990786 cellular response to dsDNA refers to the collection of cellular reactions that follow exposure to double-stranded DNA. The stimulus can be exogenous, such as viral or bacterial dsDNA, or endogenous, such as micronuclear DNA, mitochondrial DNA released into the cytosol, or dsDNA breaks generated by radiation and replication stress. The response may include transcriptional reprogramming, cytokine secretion, metabolic shifts such as NAD+ depletion, and regulated cell death. The term is not restricted to a single sensor or a single downstream pathway; it is defined by the nature of the stimulus (dsDNA) and the cellular nature of the response.
Why Is cellular response to dsDNA Important in Cell Biology?
Cellular response to dsDNA is important because it sits at the intersection of host defense, sterile inflammation, genome stability, and cell fate. When the response is appropriately triggered, it helps eliminate pathogens and damaged cells; when it is misregulated, it drives chronic inflammatory disease and tissue degeneration. The pathway also determines how cells interpret CRISPR-induced DNA breaks and how engineered DNA donors are sensed, which directly affects genome-editing outcomes. Because dsDNA is a universal danger signal, understanding GO:1990786 informs immunology, neuroscience, cancer biology, and therapeutic development.
• Defines how cells detect foreign dsDNA during viral and bacterial infection.
• Links cytosolic dsDNA to type I interferon and NF-kB inflammatory programs through cGAS-STING.
• Explains how radiation, replication stress, and chromosome missegregation generate dsDNA ligands, although not all micronuclei activate cGAS-STING.
• Introduces SARM1 as a dsDNA sensor that promotes NAD+ degradation and a distinct cell death mode.
• Underlies inflammatory eye disease, including glaucoma and retinal ischemia-reperfusion injury.
• Contributes to skin inflammation such as psoriasis through STING/NF-kB signaling.
• Influences genome-editing outcomes because DNA breaks and donor templates engage dsDNA response machinery.
• Provides therapeutic targets such as STING antagonists and cGAS-STING inhibitors.
• Connects DNA repair and G-quadruplex resolution to genome stability and dsDNA response.
• Supports development of immune-evasive DNA donors and recombinase-based writing tools.
What Happens During cellular response to dsDNA?
dsDNA recognition by cytosolic sensors
In simple terms: The cell has alarm proteins that grab loose double-stranded DNA and start a warning signal.
The initiating step of cellular response to dsDNA is recognition of dsDNA by dedicated sensors. cGAS binds double-stranded DNA and produces a cyclic dinucleotide second messenger that activates STING, leading to interferon and NF-kB responses. SARM1 has also been identified as a dsDNA sensor that promotes NAD+ degradation and cell death, demonstrating that dsDNA recognition is not limited to the cGAS-STING axis. The source of dsDNA matters: micronuclei induced by radiation, replication stress, or chromosome segregation errors do not always activate cGAS-STING, indicating that sensor accessibility and chromatin state influence the response.
Signal amplification through STING and NF-kB
In simple terms: Once the alarm is pulled, a relay system amplifies the message and turns on inflammatory genes.
After cGAS activation, STING serves as the central adaptor that recruits and activates downstream kinases, culminating in IRF3- and NF-kB-dependent transcription. Pharmacological inhibition of STING with H-151 suppresses STING/NF-kB-mediated inflammation in psoriasis models, confirming that this amplification step is a viable therapeutic node. In the retina, inhibition of the cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury, showing that the same relay operates in neuronal tissue.
Metabolic and cell death execution
In simple terms: The dsDNA alarm can also flip metabolic switches that decide whether the cell lives or dies.
Cellular response to dsDNA can terminate in regulated cell death. SARM1 senses dsDNA and triggers NAD+ degradation, depleting a critical metabolic cofactor and promoting cell death. This metabolic execution arm is distinct from transcriptional interferon output and expands the functional consequences of dsDNA sensing beyond inflammation. In glaucoma, microglial cGAS-STING signaling underlies pathogenesis, linking dsDNA-driven neuroinflammation to progressive neuronal loss.
Integration with genome stability pathways
In simple terms: The cell also uses DNA repair and genome maintenance factors to manage dsDNA stress.
dsDNA response intersects with genome stability machinery. HLTF resolves G-quadruplex structures and promotes G4-induced replication fork slowing to maintain genome stability, a process that can influence the dsDNA landscape and downstream sensing. Programmable base editing avoids double-stranded DNA cleavage, illustrating how editing strategies can be designed to minimize activation of dsDNA response pathways. Immune-evasive DNA donors and recombinases have been engineered to license kilobase-scale writing while reducing sensing of introduced DNA.
Key Genes Involved in GO:1990786 cellular response to dsDNA
The following genes and proteins are central to cellular response to dsDNA, spanning sensing, signaling, metabolic execution, and genome maintenance.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CGAS | Cytosolic dsDNA sensor producing cyclic dinucleotides | Core initiator of interferon and NF-kB responses |
| STING1 | Adaptor that relays cGAS signals to IRF3 and NF-kB | Therapeutic target; H-151 antagonist suppresses inflammation |
| SARM1 | dsDNA sensor promoting NAD+ degradation and cell death | Defines a metabolic cell death arm of dsDNA response |
| IRF3 | Transcription factor downstream of STING | Drives type I interferon gene expression |
| NFKB1 | Transcription factor downstream of STING | Drives inflammatory cytokine expression |
| TBK1 | Kinase activating IRF3 downstream of STING | Signal amplification node |
| HLTF | Helicase resolving G-quadruplexes and promoting fork slowing | Links genome stability to dsDNA stress |
| APOBEC1 | Base editor component enabling C-to-T editing without dsDNA breaks | Used to study dsDNA response avoidance in editing |
| CAS9 | Nuclease generating programmable double-strand breaks | Tool for inducing dsDNA breaks and studying response |
| RECOMBINASE | Enzyme enabling kilobase-scale DNA writing | Engineered for immune-evasive genome writing |
| MITOCHONDRIAL_DNA | Endogenous source of cytosolic dsDNA | Danger signal in sterile inflammation |
| MICRONUCLEI | Nuclear envelope-limited dsDNA structures | Source of dsDNA that may or may not activate cGAS-STING |
| RAD51 | Homologous recombination factor | Genome stability factor influencing dsDNA response |
| ATM | DNA damage kinase | Coordinates response to dsDNA breaks |
| P53 | Tumor suppressor responding to DNA damage | Links dsDNA stress to cell fate |
| CASPASE1 | Inflammatory caspase | Potential effector of dsDNA-induced inflammation |
| NAMPT | NAD+ salvage enzyme | Metabolic context for SARM1-mediated NAD+ depletion |
How Is cellular response to dsDNA Regulated?
Cellular response to dsDNA is regulated at multiple levels. Sensor availability and localization control whether cGAS encounters dsDNA, and micronuclei are not universally competent to activate cGAS-STING, indicating that nuclear envelope integrity and chromatin state gate the response. STING activity is subject to pharmacological inhibition, as shown by H-151 suppression of STING/NF-kB-mediated inflammation. Downstream, NF-kB and IRF3 transcriptional outputs are tuned by kinase cascades involving TBK1. Metabolic regulation is exemplified by SARM1, whose dsDNA-dependent NAD+ degradation determines cell death outcomes. Genome maintenance factors such as HLTF modulate replication fork progression and G-quadruplex resolution, indirectly shaping the dsDNA landscape. Finally, the choice of genome-editing strategy, such as base editing versus nuclease cleavage, determines the extent of dsDNA break formation and thus the level of pathway activation.
cellular response to dsDNA and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CGAS | Glaucoma, retinal neuroinflammation | Cgas knockout microglia or retinal explants |
| STING1 | Psoriasis, ischemia/reperfusion injury | Sting1 knockout mice or H-151-treated models |
| SARM1 | NAD+ depletion and cell death | Sarm1 knockout neurons with dsDNA challenge |
| HLTF | Genome instability and replication stress | HLTF knockout cells with G4 ligands |
| CGAS/STING1 | Micronuclei-driven inflammation | Radiation- or replication stress-induced micronuclei models |
Glaucoma and retinal neurodegeneration
Microglial cGAS-STING signaling underlies glaucoma pathogenesis, linking dsDNA sensing to progressive retinal ganglion cell loss. In retinal ischemia/reperfusion injury, inhibition of the cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death, suggesting that dsDNA response inhibitors may be neuroprotective.
Psoriasis and inflammatory skin disease
The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-kB-mediated inflammation, demonstrating that dsDNA response signaling is a driver of skin inflammation and a tractable drug target.
Cell death and metabolic disorders
SARM1 senses dsDNA to promote NAD+ degradation and cell death, connecting dsDNA response to metabolic collapse and neurodegeneration-associated cell death programs. This pathway may be relevant to conditions where NAD+ depletion contributes to pathology.
Genome instability and cancer biology
HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability, a process that influences dsDNA stress and may affect tumorigenesis. Micronuclei generated by radiation, replication stress, or chromosome segregation errors are common in cancer cells, yet they do not always activate cGAS-STING, which has implications for immunotherapy responses.
From cellular response to dsDNA-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is CGAS required for dsDNA-induced interferon? | CGAS knockout cell line |
| Does a point mutation in STING alter NF-kB activation? | STING1 point-mutation knock-in |
| Can a tagged sensor be used for imaging dsDNA response? | Tagged knock-in of CGAS or STING1 |
| Does overexpression of SARM1 enhance NAD+ depletion? | SARM1 overexpression cell model |
| Which genes control micronuclei sensing? | CRISPR library screening in radiation-treated cells |
| Can immune-evasive donors reduce dsDNA sensing? | Recombinase-mediated knock-in with modified donors |
How to Study the cellular response to dsDNA Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional changes after dsDNA stimulus | Interferon and NF-kB target profiling |
| NAD+ assay | Metabolic depletion driven by SARM1 | Cell death mechanism studies |
| Immunofluorescence | Localization of dsDNA and sensors | Micronuclei and cytosolic dsDNA imaging |
| CRISPR knockout | Loss-of-function causality | Testing CGAS, STING1, SARM1 requirement |
| Base editing | Precise point mutations without dsDNA breaks | Dissecting sensor signaling residues |
| Knock-in tagging | Protein localization and interaction | Live-cell imaging of sensors |
| Library screening | Genome-wide modifiers of dsDNA response | Identifying novel regulators |
| Recombinase-mediated writing | Large DNA insertion with reduced sensing | Immune-evasive donor design |
Transcriptional profiling of dsDNA response
RNA-seq after dsDNA stimulation or cGAS-STING activation measures interferon and NF-kB target gene induction, providing a global view of the transcriptional arm of GO:1990786. Comparing wild-type and knockout cells identifies genes that are causally dependent on specific sensors.
Metabolic and cell death assays
NAD+ quantification and cell viability assays are used to measure the SARM1-dependent metabolic arm of dsDNA response. These assays distinguish metabolic execution from transcriptional interferon output.
Imaging of dsDNA and sensor localization
Fluorescence microscopy of micronuclei, cytosolic dsDNA, and tagged sensors reveals where and when the response initiates. Tagged knock-in lines enable live-cell tracking of sensor recruitment.
Genome-editing and donor design
Base editing and immune-evasive donor strategies are used to manipulate dsDNA response genes while minimizing unintended dsDNA break formation. These methods allow precise dissection of pathway components.
How CRISPR Can Be Used to Study GO:1990786 cellular response to dsDNA
Knockout
CRISPR knockout of CGAS, STING1, or SARM1 is used to test whether these genes are required for dsDNA-induced interferon, NF-kB activation, or NAD+ depletion. Knockout models provide clean loss-of-function evidence for causal roles in GO:1990786.
Point Mutation
Point mutations introduced by base editing or homology-directed repair can dissect catalytic residues and signaling interfaces in dsDNA sensors without creating double-strand breaks. This is valuable for separating sensor DNA-binding from downstream activation.
Knock-in
Knock-in of epitope tags or fluorescent proteins at endogenous loci enables imaging and interaction studies of dsDNA response proteins. Immune-evasive DNA donors and recombinases can license kilobase-scale writing with reduced activation of dsDNA sensing.
Overexpression
Overexpression of SARM1 or STING1 can amplify dsDNA response outputs and reveal gain-of-function phenotypes such as enhanced NAD+ degradation or inflammation. Overexpression models are useful for testing inhibitors and pathway crosstalk.
How EDITGENE Supports cellular response to dsDNA Research
Researchers studying cellular response to dsDNA-related genes often need to determine whether a candidate gene is causally involved in sensing, signaling, or execution. EDITGENE provides the full spectrum of CRISPR cell models, from knockout to knock-in, to enable rigorous mechanistic and translational studies.
Contact EDITGENE today to design your custom CRISPR model for cellular response to dsDNA research.
Frequently Asked Questions About cellular response to dsDNA
What is GO:1990786 cellular response to dsDNA?
It is a Gene Ontology biological process describing any change in a cell's state or activity caused by a double-stranded DNA stimulus, including gene expression, secretion, and cell death.
What genes are involved in cellular response to dsDNA?
Key genes include CGAS, STING1, SARM1, IRF3, NFKB1, TBK1, and HLTF, among others.
How does cGAS-STING sense dsDNA?
cGAS binds dsDNA and produces a second messenger that activates STING, which then drives IRF3- and NF-kB-dependent transcription.
Does SARM1 respond to dsDNA?
Yes, SARM1 senses dsDNA to promote NAD+ degradation and cell death, defining a metabolic arm of the response.
Do micronuclei always activate cGAS-STING?
No, micronuclei induced by radiation, replication stress, or chromosome segregation errors do not always activate cGAS-STING.
What diseases involve cellular response to dsDNA?
Glaucoma, psoriasis, retinal ischemia-reperfusion injury, and neuroinflammation are linked to dsDNA response signaling.
How can I study cellular response to dsDNA in the lab?
Common methods include RNA-seq, NAD+ assays, immunofluorescence, CRISPR knockout, base editing, and library screening.
Can CRISPR knockout help identify dsDNA response genes?
Yes, knockout of CGAS, STING1, or SARM1 tests whether these genes are required for dsDNA-induced phenotypes.
What is the role of HLTF in dsDNA response?
HLTF resolves G-quadruplexes and promotes G4-induced replication fork slowing to maintain genome stability, influencing dsDNA stress.
How does genome editing avoid activating dsDNA response?
Base editing avoids double-strand breaks, and immune-evasive DNA donors with recombinases reduce sensing of introduced DNA.
Conclusion
GO:1990786 cellular response to dsDNA is a central biological process that converts dsDNA detection into transcriptional, metabolic, and cell death outcomes. Its core sensors, including cGAS, STING, and SARM1, are linked to inflammatory and neurodegenerative diseases, making the pathway a high-value therapeutic and research target. Precise CRISPR models are essential to establish causality and to design interventions that modulate dsDNA sensing without compromising genome stability.
References
- 1. Wang L et al.. 2025. SARM1 senses dsDNA to promote NAD(+) degradation and cell death.. Cell 188(25):7137-7154.e21 PMID: 41138726
- 2. Komor AC et al.. 2016. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.. Nature 533(7603):420-4 PMID: 27096365
- 3. Liu Y et al.. 2024. Microglial cGAS-STING signaling underlies glaucoma pathogenesis.. Proc Natl Acad Sci U S A 121(36):e2409493121 PMID: 39190350
- 4. Tou CJ et al.. 2026. Immune evasive DNA donors and recombinases license kilobase-scale writing.. Nature 653(8114):576-586 PMID: 41813887
- 5. Takaki T et al.. 2024. Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING.. Mol Cell 84(11):2203-2213.e5 PMID: 38749421
- 6. Bai G et al.. 2024. HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability.. Mol Cell 84(16):3044-3060.e11 PMID: 39142279
- 7. Pan Y et al.. 2021. The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.. Br J Pharmacol 178(24):4907-4922 PMID: 34460100
- 8. Wu X et al.. 2023. Inhibition of cGAS-STING pathway alleviates neuroinflammation-induced retinal ganglion cell death after ischemia/reperfusion injury.. Cell Death Dis 14(9):615 PMID: 37726272
