Dan Yarosh
MENDING LIFE:
WHY AND HOW CELLS PROTECT THEIR DNA
Essays on Genome Stability, Disease, Aging and Therapy
2. How DNA Damage Triggers Inflammation: ATM and Chronic Disease
Inflammation is usually portrayed as the body’s response to infection or injury. When bacteria invade or tissues are wounded, immune cells rush to the scene and release chemical signals that promote healing and defense. But what if inflammation begins without any wound at all?
It happens all the time. Persistent DNA damage activates those powerful DDR signaling pathways we covered in Essay 1 even without infection or injury, by setting off internal stress pathways that resemble immune responses. This “sterile inflammation” over time contributes to aging, cancer, cardiovascular disease, and neurodegeneration.
At the center of this connection lies the DNA damage signaling protein - ATM. Once viewed only as a genomic caretaker, ATM is now recognized as a major regulator of inflammatory signaling. It links damaged DNA to systemic disease.
The Big Picture: DNA Damage as a Source of Inflammatory Stress
Every tissue in the body experiences continuous DNA damage. Most of it is repaired efficiently. But when damage accumulates—due to aging of the repair machinery, pervasive toxins, metabolic stress, or genetic defects—cells begin to behave differently. Instead of returning to normal, they enter a state of chronic stress characterized by:
- Persistent DNA damage signaling
- Altered metabolism
- Secretion of inflammatory molecules
- Impaired tissue regeneration
A major insight is that this state is common in aging tissues and in many chronic diseases. Unrelenting DNA damage plays havoc with the immune system.
How ATM Responds to Persistent DNA Damage
ATM is best known as a sensor of DNA double-strand breaks. When they occur, ATM becomes activated and coordinates repair. In the first moments after damage ATM modifies and stabilizes signaling proteins downstream in the pathway. These secondary signaling proteins go on to stop DNA replication and cell division. After an hour or two, the p53 protein (known as “The Guardian of the Genome”) is modified to activate it in order to step up transcription of many cell defense genes, including DNA repair. Its activity peaks at about 6 hours and then declines as the damage is reversed, ATM is deactivated, and cells return to normal. (We’ll discuss this shut-down process in the next post).
Sustained Stress and Activation of Inflammatory Pathways
When DNA damage is frequent or unresolved, ATM signaling does not shut off. Instead, it becomes chronically active. One of ATM’s unexpected roles is its interaction with inflammatory transcription factors, particularly NF-κB. ATM signaling destroys the inhibitor of NF-κB complexes and unleashes transcription of a storm of genes leading to increased expression of cytokines, chemokines, adhesion molecules, and stress-response genes. In extreme cases, this is called a cytokine storm. Together, these attract immune cells and amplify local inflammation, setting off oxidizing molecules in cellular combat with a phantom invader.
Immune Recruitment
Inflammatory signals produced by damaged cells recruit macrophages, T cells, and other immune cells. Initially, this promotes clearance of defective cells. But with age or repeated stress, immune surveillance weakens, allowing damaged cells to accumulate. The result is low-grade, chronic inflammation. Chronic activation of ATM means chronic inflammation.
Mitochondrial and Metabolic Effects
Often overlooked is the impact of DNA damage on mitochondria, the source of energy for cells. ATM monitors the oxidative status of mitochondria. While some oxidation during energy production is inevitable, excessive oxidation produced by chronic inflammation damages mitochondrial DNA, activates ATM, and is a sign of something gone terribly wrong. Damaged mitochondria generate more oxidative stress, which in turn causes more DNA damage—a self-reinforcing cycle.
Cellular Senescence: An Identity Shift
When DNA damage is rapidly repaired, ATM helps restore normal function. When damage is persistent, cells undergo a deeper transformation. Many such broken cells enter a phase termed senescence, a permanent growth-arrested state. Senescent cells remain metabolically active but secrete inflammatory factors, known collectively as the senescence-associated secretory phenotype (SASP). This includes interleukins, growth factors, proteases, and pro-inflammatory lipids. ATM signaling is a major driver of SASP development. SASP suppresses local stem cells, keeping them from renewing healthy tissue. This is a major limitation on tissue and organ longevity.
When ATM Goes Wrong: Inflammation-Driven Disease
Defective ATM signaling illustrates how DNA damage and inflammation are intertwined. This connection is manifested in disease.
Ataxia telangiectasia
Individuals with inherited ATM deficiency develop ataxia-telangiectasia, a disorder marked by immune dysfunction and neurodegeneration (a consequence of persistent DNA damage we will discuss in later essays). They also suffer from systemic inflammation and cancer predisposition. These patients demonstrate what happens when DNA damage signaling fails to regulate immune responses properly.
Cancer
In tumors, chronic DNA damage results by uncontrolled and recklesscell division, which promotes inflammatory microenvironments. ATM dysfunction contributes to genomic instability, cytokine production, and immune cell infiltration. At first, this reaction may hold the cancer in check. But over time the inflammation creates selective pressure that encourage cells to evade the immune system, and the genomic instability generates many candidate cells for this evasion. Tumors may initially regress, but return with a vengeance, armed with immune-evading capabilities.
But herein lies an opportunity: some of these tumors are composed of ATM-mutated cells, and it is critical to identify them early in tumor growth. A recent clinical study in prostate cancer showed that these tumors were significantly more responsive to radiation treatment than ATM-normal tumors. Here the DNA repair defect is a vulnerability that can be exploited in therapy.
Aging and Degeneration
As we age, DNA repair efficiency declines, and damage persists longer. Chronic ATM activity leads to accumulation of senescent cells, and chronic tissue inflammation. Tissue repair is not perfect, stem cells are exhausted, and too much extracellular matrix (scar tissue) is made, leading to fibrosis. Fibrosis is a characteristic of nearly all chronic inflammatory diseases, from lungs and heart to kidney and liver disease. This process, often called “inflammaging,” is now considered a central driver of biological aging.
What Can We Do? Therapeutic Approaches
ATM and ATR inhibitors are targeted cancer therapies that block the enzymes in the pathway for DNA repair, causing fast dividing cancer cells to accumulate lethal DNA errors, especially under high replication stress. These inhibitors, such as Berzosertib, Elimusertib and Gartisertib for ATR, and M3541 for ATM, are often used to enhance the effects of chemotherapy and radiation.
A whole new field of senolytics and senomorphics looks for molecules to target and either control or eliminate senescent cells. Scientists are also exploring metabolic interventions to reduce DNA-driven inflammation. These approaches aim to restore balance between DNA repair and immune signaling.
Key Takeaways
- Persistent DNA damage promotes chronic, sterile inflammation
- ATM links genomic stress to immune signaling
- Prolonged ATM activation causes senescence and SASP
- DNA damage drives inflammation leading to cancer and aging
- Targeting DNA repair–immune crosstalk is a growing therapeutic strategy
The next essay will describe how DNA damage turns down a runaway immune response.
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References & Further Reading
1.Shiloh, Y., & Ziv, Y. (2013). The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol, 14, 197-210.
In-depth review of ATM biology.
2. Phan L.M., & Rezaeian, A.H. (2021) ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development. Genes, 12, 845-856.
ATM signaling and genome protection.
3. Rodier, F., & Campisi, J. (2011). Four faces of cellular senescence. J Cell Biol, 192, 547-556.
Senescence, inflammation, and aging.
4. Hinz, M., & Scheidereit, C. (2014). The IκB kinase complex in NF-κB regulation. EMBO Reports, 15, 46–61.
Mechanisms linking DNA damage to inflammatory signaling.
5. Franceschi, C., et al. (2018). Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrin, 14, 576-590.
DNA damage and aging-related inflammation.
6. Gorgoulis V., et al. (2019) Cellular Senescence: Defining a Path Forward. Cell, 179, 813-827.
Senescence and inflammatory phenotypes.
7.Goldstein, M., & Kastan, M. B. (2015). The DNA damage response: Implications for tumor responses to radiation and chemotherapy. Annu Rev Med 66, 129-143.
Clinical implications of repair–immune interactions.
8. D’Adda di Fagagna, F. (2008). Living on a break: Cellular senescence as a DNA-damage response. Nature Rev Cancer, 8, 512–522.
DNA damage and senescence.