Format

Send to

Choose Destination
Sci Rep. 2017 Jun 13;7(1):3332. doi: 10.1038/s41598-017-03211-z.

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

Koo GB1,2, Ji JH3, Cho H1,2,3, Morgan MJ4, Kim YS5,6.

Author information

1
Department of Biochemistry, Ajou University School of Medicine, Suwon, Gyeonggi, 16499, Republic of Korea.
2
Department of Biomedical Sciences, graduate School, Ajou University, Suwon, Gyeonggi, 16499, Republic of Korea.
3
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Gyeonggi, 16499, Republic of Korea.
4
Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, 80045, USA.
5
Department of Biochemistry, Ajou University School of Medicine, Suwon, Gyeonggi, 16499, Republic of Korea. yousunkim@ajou.ac.kr.
6
Department of Biomedical Sciences, graduate School, Ajou University, Suwon, Gyeonggi, 16499, Republic of Korea. yousunkim@ajou.ac.kr.

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.

PMID:
28611389
PMCID:
PMC5469829
DOI:
10.1038/s41598-017-03211-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center