Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
Open accessAbstract
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.
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Deficiency of TRADD results in the accumulation of double-strand break foci.
“deficiency of TRADD has been shown to result in the accumulation of DSB foci [75].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [75]
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- Authors
- Koo, G.-B., Ji, J.-H., Cho, H., Morgan, M. J., & Kim, Y.-S.
- Affiliations
- Ajou University (KR)
- University of Colorado Anschutz (US)
- Corresponding author
- Kim, You-Sun
- Venue
- Scientific Reports
- Published
- 2017-06-13
- Volume
- 7
- Issue
- 1
- Pages
- 3332-3332
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5469829
- OpenAlex
- W2624590586
- Cited by
- 7
- References
- 27
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 1
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation
- Korea Health Industry Development Institute (HI15C0554)
- National Research Foundation of Korea (2011-0030043)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- TRADD, nuclear translocation, DNA double-strand break repair, non-homologous end joining, homologous recombination, DNA damage response, 53BP1, JNK activation, reactive oxygen species, cell death, TNF receptor signaling, γH2AX foci
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, Ku Autoantigen, Animals, Cell Line, Cell Nucleus, HeLa Cells, Humans, Cell Death, Reactive Oxygen Species, Active Transport, Cell Nucleus, MAP Kinase Kinase 4, Mice, TNF Receptor-Associated Death Domain Protein, DNA End-Joining Repair
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