Dual Mechanisms of NF-κB Activation in DNA Damage Responses: Bridging Transcriptional Stress and Inflammation

Significance 

The integrity of cellular DNA is vital for maintaining genomic stability and proper cellular function. However, DNA is frequently subjected to damage from endogenous sources, such as metabolic byproducts, and exogenous insults, like radiation and chemicals. This damage, if unrepaired, can lead to mutations, genomic instability, and severe consequences, including cancer, age-related diseases, and chronic inflammation. A crucial aspect of the cellular response to DNA damage is the activation of the DNA damage response (DDR), a coordinated signaling network that not only orchestrates DNA repair but also modulates cell cycle arrest and initiates inflammatory responses. Among these responses, the activation of the transcription factor NF-κB is critical for promoting inflammation and regulating immune responses. Despite its importance, NF-κB activation in the context of DNA damage remains poorly understood, particularly when transcription is impaired due to severe lesions. Canonically, NF-κB activation relies on the degradation of IκB proteins, allowing NF-κB to translocate into the nucleus and regulate target genes. However, this canonical pathway presupposes ongoing transcription, raising a pivotal question: how do cells initiate an NF-κB-driven immune response when transcription is blocked by DNA damage, such as lesions that stall RNA polymerases?

This conundrum highlights a significant challenge in understanding genotoxic stress responses. On one hand, DNA damage promotes inflammation necessary for tissue repair and immune surveillance. On the other hand, lesions that hinder transcription can paradoxically suppress the cell’s ability to mount this response. This duality represents a major gap in the current understanding of the relationship between DNA damage and immune signaling. Motivated by this challenge, new research paper published in Nature Structural & Molecular Biology and conducted by Dr. Elodie Bournique, Ambrocio Sanchez, Sunwoo Oh, Daniel Ghazarian, Alisa L. Mahieu, Lavanya Manjunath, Eirene Ednacot, Pedro Ortega, Selma Masri, Professor Ivan Marazzi & Professor Rémi Buisson from the University of California, Irvine investigated the mechanisms by which cells activate NF-κB in situations where transcriptional capacity is compromised. This study specifically aimed to identify alternative pathways that cells might use to bypass the requirement for transcriptional activity. By investigating the distinct roles of ATM kinase and IRAK1 in NF-κB activation, the team explored how different types of DNA damage—ranging from double-strand breaks to transcription-blocking lesions—elicit inflammatory responses.

The researchers began with the observation that DNA lesions induce rapid NF-κB activation, even in conditions where transcription is inhibited. Using a quantitative image-based cytometry (QIBC) approach, they visualized and measured the localization of the NF-κB subunit p65 within cells. This enabled them to monitor how specific types of DNA damage influence NF-κB activity. They found that different DNA lesions triggered distinct pathways, each tailored to the nature of the damage. One set of experiments focused on understanding the role of ataxia-telangiectasia mutated (ATM) kinase in response to DNA double-strand breaks (DSBs). The team treated cells with camptothecin (CPT), a topoisomerase inhibitor that causes replication stress and DSBs. They observed that ATM played a pivotal role in activating NF-κB by phosphorylating TRAF6, a key signaling molecule. Cells lacking ATM or treated with ATM inhibitors showed significantly reduced NF-κB activity, highlighting its critical function in responding to DSBs. Moreover, they demonstrated that this pathway was most active in cells undergoing replication, as the formation of DSBs is closely tied to replication fork collapse.

In parallel, the authors investigated how cells activate NF-κB when transcription is impaired by DNA lesions that do not produce DSBs. They exposed cells to ultraviolet (UV) radiation and actinomycin D (ActD), both of which cause transcriptional stress. Unlike the ATM-dependent pathway, they found that NF-κB activation in these contexts relied on IRAK1 kinase. By using IRAK1 knockout cells and pharmacological inhibitors, they confirmed that IRAK1 mediated this alternative pathway. Interestingly, IRAK1 activation was driven by the secretion of interleukin-1α (IL-1α) from damaged cells, which signaled neighboring cells through the IL-1 receptor. This mechanism provided a means for transcriptionally impaired cells to still participate in inflammatory signaling by relying on extracellular communication. The experiments further revealed that TRAF6 served as a common mediator, linking both ATM-dependent and IRAK1-dependent pathways to NF-κB activation. Whether triggered by DSBs or transcriptional stress, TRAF6 coordinated downstream signaling events that ultimately led to the nuclear translocation of NF-κB. This dual functionality of TRAF6 highlight its central role in integrating different types of stress signals into a unified inflammatory response. Lastly, the team explored the dynamics of these pathways across the cell cycle. They discovered that the ATM pathway predominantly acted in replicating cells, while the IRAK1-dependent mechanism functioned across all cell-cycle phases. This finding demonstrated how the cell tailors its response to DNA damage based on its replication status, ensuring that appropriate inflammatory signals are generated under diverse conditions.

In conclusion, the research work of Professor Rémi Buisson and colleagues is significant because it lies in its transformative understanding of how cells manage to initiate immune responses in the face of DNA damage, even when transcription is blocked. By uncovering two distinct mechanisms—one mediated by ATM and the other by IRAK1—the researchers have revealed a nuanced and adaptable cellular strategy for inflammatory signaling. This discovery not only fills a critical gap in molecular biology but also redefines the interplay between DNA repair processes and innate immunity. One of the most impactful findings is the identification of an IRAK1-dependent pathway that enables cells with transcriptional stress to still communicate inflammatory signals. The reliance on IL-1α secretion and extracellular signaling highlights a clever evolutionary adaptation, allowing damaged cells to enlist neighboring cells in the immune response even when their own transcriptional capacity is impaired. This provides an alternative mechanism that ensures tissue-wide coordination during injury or stress, a process critical for maintaining homeostasis in multicellular organisms.

The implications of these findings are wide-ranging, particularly in cancer biology, aging, and immunology. In cancer, the discovery of these pathways offers new therapeutic targets. For instance, ATM inhibitors, already under development as cancer treatments, could be optimized to suppress NF-κB-driven inflammation in tumor cells, potentially reducing their growth and resistance to therapy. Conversely, modulating IRAK1 or IL-1α signaling could help mitigate chronic inflammation in autoimmune diseases or fibrosis, where unchecked immune responses contribute to disease progression. Moreover, the study sheds light on the delicate balance between cell survival and inflammation. While ATM-mediated NF-κB activation supports cell survival by promoting DNA repair, excessive or inappropriate activation can lead to chronic inflammation and tissue damage. Understanding how these pathways are regulated could pave the way for interventions that fine-tune immune responses, preventing both under-activation, which compromises repair, and over-activation, which drives inflammation-related diseases. The study also opens new research directions. The interplay between these two pathways and their impact on different cell types and tissues remain to be explored. The role of these mechanisms in aging and age-related inflammation, often referred to as “inflammaging,” could provide valuable insights into strategies for promoting healthy aging. In summary, this work has far-reaching implications for basic science and clinical applications, offering a deeper understanding of how cells orchestrate immune responses under duress and presenting new opportunities for therapeutic innovation. It underscores the versatility of cellular signaling networks and their ability to adapt to complex challenges, advancing our grasp of the fundamental processes that maintain health and respond to disease.

Dual Mechanisms of NF-κB Activation in DNA Damage Responses: Bridging Transcriptional Stress and Inflammation - Medicine Innovates

About the author

Rémi Buisson

Associate Professor, Biological Chemistry
School of Medicine
University of California, Irvine

Research Interests: Genomic instability is a hallmark of cancer. On one hand, genomic instability of cancer cells promotes loss of tumor suppressors and activation of oncogenes. On the other hand, genomic instability renders cancer cells susceptible to radiation and chemotherapy. The laboratory focus on dissecting mechanisms that result in compromised genomic integrity and study DNA repair pathways to understand how cells fix their genome. The long-term goal of our research is developing new strategies to eliminate cancer cells with high genomic instability to provide needed insight into potential novel targeted therapies.

About the author

Professor Ivan Marazzi

School of Medicine
University of California, Irvine

The Marazzi lab studies epigenetic- and chromatin- mediated control of gene expression in the context of cellular response to pathogens or cellular differentiation. We are interested in proteins and non-coding RNA that play a role in controlling cell response and cell fate. We use biochemistry and next generation sequencing technique to understand molecular mechanisms and genome-wide effects of known and novel candidate genes.

Reference 

Bournique E, Sanchez A, Oh S, Ghazarian D, Mahieu AL, Manjunath L, Ednacot E, Ortega P, Masri S, Marazzi I, Buisson R. ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damageNat Struct Mol Biol (2025). https://doi.org/10.1038/s41594-024-01417-0.

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