DNA damage-dependent NF-κB activation: NEMO turns nuclear signaling inside out

Abstract

The dimeric transcription factor nuclear factor κB (NF-κB) functions broadly in coordinating cellular responses during inflammation and immune reactions, and its importance in the pathogenesis of cancer is increasingly recognized. Many of the signal transduction pathways that trigger activation of cytoplasmic NF-κB in response to a broad array of immune and inflammatory stimuli have been elaborated in great detail. NF-κB can also be activated by DNA damage, though relatively less is known about the signal transduction mechanisms that link DNA damage in the nucleus with activation of NF-κB in the cytoplasm. Here, we focus on the conserved signaling pathway that has emerged that promotes NF-κB activation following DNA damage. Post-translational modification of NF-κB essential modulator (NEMO) plays a central role in linking the cellular DNA damage response to NF-κB via the ataxia telangiectasia mutated (ATM) kinase. Accumulating evidence suggests that DNA damage-dependent NF-κB activation may play significant biological roles, particularly during lymphocyte differentiation and progression of human malignancies.

Fig. 1. Proposed schematic model for DNA damage dependent NF-κB activation

Following DNA damage, nuclear events trigger activation of ATM and post-translational modification of NEMO and RIP1. These nuclear events are transduced to cytoplasmic signaling complexes that mediate the activation of TAK1 and ultimately IKK. Depending on the severity of genotoxic stress (and cell type), multiple signal transduction mechanisms may be engaged to promote NF-κB activation. Several cellular fates can result to encourage cell survival. In the event of overwhelming damage, additional mechanisms— both dependent and independent of NF-κB—may be employed to promote programmed cell death (e.g. Ripoptosome assembly).