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Updated: Feb 28, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Nuclear TRADD prevents DNA damage-mediated death by facilitating non-homologous end-joining repair
Gi-Bang Koo1,2, Jae-Hoon Ji3, Hyeseong Cho1,2,3
1Department of Biochemistry, Ajou University School of Medicine, Suwon, Gyeonggi, 16499, Republic of Korea.
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.
Insights
Nuclear TRADD translocates to DNA damage sites, aiding repair and cell survival. Impaired nuclear TRADD causes cell death via JNK and ROS, highlighting its crucial role in the DNA damage response.
Area of Science:
- Cellular Biology
- Molecular Biology
- Genetics
Background:
- TNF receptor-associated death domain (TRADD) is a key signaling adaptor in TNF receptor pathways.
- TRADD shuttles between cytoplasm and nucleus, but its nuclear function remains unclear.
Purpose of the Study:
- To investigate the role of nuclear TRADD in the DNA damage response (DDR).
- To elucidate the mechanisms by which TRADD influences DNA repair and cell survival.
Main Methods:
- Studied TRADD translocation to DNA double-strand break (DSB) sites.
- Assessed the impact of TRADD deficiency and nuclear localization on DNA repair markers (γH2AX).
- Investigated TRADD's interaction with DNA repair factors (53BP1, Ku70/80) and its role in NHEJ and HR.
- Analyzed cell death pathways (JNK, ROS) in response to impaired TRADD nuclear localization.
Main Results:
- Cytoplasmic TRADD moves to DSB sites during DDR.
- TRADD deficiency or cytosolic sequestration increases γH2AX foci, reversed by nuclear TRADD.
- TRADD promotes NHEJ by recruiting 53BP1 and Ku70/80, but not HR.
- Defective nuclear TRADD localization induces cell death via sustained JNK activation and ROS accumulation.
Conclusions:
- Nuclear TRADD translocation to DSBs is vital for DNA damage repair and cell survival.
- TRADD facilitates NHEJ, contributing to genomic stability.
- Dysfunctional nuclear TRADD impairs DNA repair, leading to cell death, underscoring its critical role in maintaining cellular integrity.
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