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

Authors
  • Medunjanin, Senad1
  • Putzier, Maximilian1
  • Nöthen, Till1
  • Weinert, Sönke1
  • Kähne, Thilo1
  • Luani, Blerim1
  • Zuschratter, Werner2
  • Braun-Dullaeus, Ruediger C.1
  • 1 Magdeburg University,
  • 2 Leibniz Institute for Neurobiology,
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Jan 13, 2020
Volume
77
Issue
20
Pages
4133–4142
Identifiers
DOI: 10.1007/s00018-019-03411-y
PMID: 31932854
PMCID: PMC7532968
Source
PubMed Central
Keywords
License
Unknown

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. Electronic supplementary material The online version of this article (10.1007/s00018-019-03411-y) contains supplementary material, which is available to authorized users.

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