Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair

Abstract TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, th...

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Autores principales:	Gi-Bang Koo, Jae-Hoon Ji, Hyeseong Cho, Michael J. Morgan, You-Sun Kim
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fa536b64c371498fb7f67f41989edcd6
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spelling	oai:doaj.org-article:fa536b64c371498fb7f67f41989edcd62021-12-02T11:40:58ZNuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair10.1038/s41598-017-03211-z2045-2322https://doaj.org/article/fa536b64c371498fb7f67f41989edcd62017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03211-zhttps://doaj.org/toc/2045-2322Abstract TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression. TRADD facilitates non-homologous end-joining (NHEJ) by recruiting NHEJ repair factors 53BP1 and Ku70/80 complex, whereas TRADD is dispensable for homologous recombination (HR) repair. Finally, an impaired nuclear localization of TRADD triggers cell death through the persistent activation of JNK and accumulation of reactive oxygen species (ROS). Thus, our findings suggest that translocation of TRADD to DSBs into the nucleus contributes to cell survival in response to DNA damage through an activation of DNA damage repair.Gi-Bang KooJae-Hoon JiHyeseong ChoMichael J. MorganYou-Sun KimNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gi-Bang Koo Jae-Hoon Ji Hyeseong Cho Michael J. Morgan You-Sun Kim Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
description	Abstract TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression. TRADD facilitates non-homologous end-joining (NHEJ) by recruiting NHEJ repair factors 53BP1 and Ku70/80 complex, whereas TRADD is dispensable for homologous recombination (HR) repair. Finally, an impaired nuclear localization of TRADD triggers cell death through the persistent activation of JNK and accumulation of reactive oxygen species (ROS). Thus, our findings suggest that translocation of TRADD to DSBs into the nucleus contributes to cell survival in response to DNA damage through an activation of DNA damage repair.
format	article
author	Gi-Bang Koo Jae-Hoon Ji Hyeseong Cho Michael J. Morgan You-Sun Kim
author_facet	Gi-Bang Koo Jae-Hoon Ji Hyeseong Cho Michael J. Morgan You-Sun Kim
author_sort	Gi-Bang Koo
title	Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
title_short	Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
title_full	Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
title_fullStr	Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
title_full_unstemmed	Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
title_sort	nuclear tradd prevents dna damage-mediated death by facilitating non-homologous end-joining repair
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/fa536b64c371498fb7f67f41989edcd6
work_keys_str_mv	AT gibangkoo nucleartraddpreventsdnadamagemediateddeathbyfacilitatingnonhomologousendjoiningrepair AT jaehoonji nucleartraddpreventsdnadamagemediateddeathbyfacilitatingnonhomologousendjoiningrepair AT hyeseongcho nucleartraddpreventsdnadamagemediateddeathbyfacilitatingnonhomologousendjoiningrepair AT michaeljmorgan nucleartraddpreventsdnadamagemediateddeathbyfacilitatingnonhomologousendjoiningrepair AT yousunkim nucleartraddpreventsdnadamagemediateddeathbyfacilitatingnonhomologousendjoiningrepair
_version_	1718395497312419840

Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair

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