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

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...

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Autores principales: Medunjanin, Senad, Putzier, Maximilian, Nöthen, Till, Weinert, Sönke, Kähne, Thilo, Luani, Blerim, Zuschratter, Werner, Braun-Dullaeus, Ruediger C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532968/
https://www.ncbi.nlm.nih.gov/pubmed/31932854
http://dx.doi.org/10.1007/s00018-019-03411-y
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author Medunjanin, Senad
Putzier, Maximilian
Nöthen, Till
Weinert, Sönke
Kähne, Thilo
Luani, Blerim
Zuschratter, Werner
Braun-Dullaeus, Ruediger C.
author_facet Medunjanin, Senad
Putzier, Maximilian
Nöthen, Till
Weinert, Sönke
Kähne, Thilo
Luani, Blerim
Zuschratter, Werner
Braun-Dullaeus, Ruediger C.
author_sort Medunjanin, Senad
collection PubMed
description 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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spelling pubmed-75329682020-10-19 DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation Medunjanin, Senad Putzier, Maximilian Nöthen, Till Weinert, Sönke Kähne, Thilo Luani, Blerim Zuschratter, Werner Braun-Dullaeus, Ruediger C. Cell Mol Life Sci Original Article 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. Springer International Publishing 2020-01-13 2020 /pmc/articles/PMC7532968/ /pubmed/31932854 http://dx.doi.org/10.1007/s00018-019-03411-y Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Medunjanin, Senad
Putzier, Maximilian
Nöthen, Till
Weinert, Sönke
Kähne, Thilo
Luani, Blerim
Zuschratter, Werner
Braun-Dullaeus, Ruediger C.
DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title_full DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title_fullStr DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title_full_unstemmed DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title_short DNA-PK: gatekeeper for IKKγ/NEMO nucleocytoplasmic shuttling in genotoxic stress-induced NF-kappaB activation
title_sort dna-pk: gatekeeper for ikkγ/nemo nucleocytoplasmic shuttling in genotoxic stress-induced nf-kappab activation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532968/
https://www.ncbi.nlm.nih.gov/pubmed/31932854
http://dx.doi.org/10.1007/s00018-019-03411-y
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