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.

Grant Number: 1R21ES036190-01A1
NIH Institute/Center: NIH
Principal Investigator: Remi Buisson