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

The transcription factors of the nuclear factor ?B (NF-?B) family play a pivotal role in the cellular response to DNA damage. Genotoxic stress-induced activation of NF-?B differs from the classical canonical pathway by shuttling of the NF-?B Essential Modifier (IKK?/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-?B 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-?B 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.
Mesh Terms:
Alanine, Animals, Cell Nucleus, Cytoplasm, DNA Damage, DNA-Activated Protein Kinase, DNA-Binding Proteins, HEK293 Cells, Humans, I-kappa B Kinase, Intracellular Signaling Peptides and Proteins, Mice, NF-kappa B, NIH 3T3 Cells, Phosphorylation, Serine, Signal Transduction
Cell Mol Life Sci
Date: Oct. 01, 2020
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