DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation

Abstract

The transcription factors of the nuclear factor κB (NF-κB) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-κB differs from the classical canonical pathway by shuttling of the NF-κB Essential Modifier (IKKγ/NEMO) subunit through the nucleus. Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). Blockade of DNA-PK by a specific shRNA or by DNA-PKcs-deficient cells abrogated NEMO entry into the nucleus, as well. Accordingly, SUMOylation of NEMO, a prerequisite of nuclear NEMO, was abolished. Based on these observations, we propose a model in which NEMO phosphorylation by DNA-PK provides the first step in the nucleocytoplasmic trafficking of NEMO.

Genome-wide association studies for immunoglobulin concentrations in colostrum and serum in Chinese Holstein

“…NCF1 encodes a cytosolic subunit of neutrophil NADPH oxidase, an enzyme responsible for reactive oxygen species (ROS) production, which is pivotal in both host defense and the control of inflammation [ 28 , 29 ]. IKBKG encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting activation of genes involved in inflammation and immunity [ 30 , 31 ]. SORBS3 encodes an SH3 domain-containing adaptor protein that regulates cell adhesion and signal transduction.…”

GSTpi reduces DNA damage and cell death by regulating the ubiquitination and nuclear translocation of NBS1

“…When DNA damage occurred, some speci c sensor proteins including ATM, ATR, and DNA-PKcs recruit to damage sites and initiate a DDR [43,44]. ATM and ATR have similar sequences to lipid kinases of the PI3K family [45], they can selectively phosphorylate and activate the serine-threonine checkpoint effector kinases which are called Chk2 and Chk1 [46].…”

DNA-PKcs: A Targetable Protumorigenic Protein Kinase

“…Conversely, active DNA-PKcs drives anti-viral response through a secondary pathway in humans, called STING-independent DNA sensing pathway (SIDSP) (144), where DNA-PKcs also acts as a sensor. In addition, DNA-PKcs has been shown to activate IKK and NFB signaling directly (145) and indirectly (146) in the presence of bacterial CpG-DNA and DNA damage to activate innate immunity. In cancer, DNA-PKcs activates immunity signaling through the NFB signaling in response to DNA damaging agents such as N-benzyladriamycin (147) and IR (148).…”