Friday, May 16, 2025
5/16/2025
NF-KB regulation by the DNA damage response - PROJECT SUMMARY NF-κB is a transcription factor activated in response to environmental genotoxic stress and important for driving DNA damage-induced inflammation. However, mechanisms linking DNA damage that occur in the nucleus to NF-κB activation in the cytoplasm remain poorly understood. NF-κB is rapidly activated after DNA damage through a signaling cascade regulated by the Ataxia-telangiectasia mutated (ATM) kinase, which is stimulated by DNA double-strand breaks. Once activated, ATM relocalizes to the cytoplasm to interact with the ubiquitin ligase TRAF6. In turn, TRAF6 induces the IKK complex to initiate IκBα proteasomal degradation, which sequesters the NF-κB heterodimer p65-p50 in the cytoplasm. The degradation of IκBα allows p65-p50 nuclear localization to promote specific inflammatory gene expressions. However, it is still unclear whether other signaling pathways are present in cells to rapidly activate NF-κB following DNA lesions that are not recognized by ATM. More importantly, the canonical innate immune response driven by NF-κB relies entirely on gene expression to release IFNs and other immunomodulatory proteins from the injured cells. However, DNA lesions that block RNA polymerases and thus stop transcription impede inflammatory gene expression in the injured cells, resulting in the inhibition of the innate immune response. Therefore, how cells can trigger an innate immune response in the context of DNA damage-induced transcription blockage is still unknown. Our goal is to identify a new innate immune signaling mechanism that is triggered specifically after DNA damage has blocked transcription. We hypothesize that DNA lesions that impede transcription trigger innate immune signaling by directly secreting specific factors to alert neighboring cells. In Aim 1, we propose to explain the mechanism by which environmental agents suppressing transcription trigger an innate immune response to alert neighboring cells of potential dangers and recruit immune cells without relying solely on gene expression. Then in Aim 2, we propose to determine the physiological impact of environmental agents suppressing transcription mediated by DNA damage. We aim to link genetic diseases affecting DNA repair pathways with chronic inflammation triggered by overactivated NF-κB in response to specific DNA lesions. The findings from this study will provide a foundation for future research utilizing mouse models with compromised DNA repair pathways to investigate how environmental factors influence chronic inflammation and to test NF-ⲕB inhibitors’ efficacy as a potential therapy.
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