ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs

Ku70型 Ku80型 泛素连接酶 DNA损伤 内质网相关蛋白降解 细胞生物学 DNA修复 未折叠蛋白反应 生物 泛素 内质网 化学 癌症研究 DNA 生物化学 转录因子 DNA结合蛋白 基因
作者
Zhiyuan Xiang,Guixue Hou,Shanliang Zheng,Minqiao Lu,Tianyu Li,Qingyu Lin,Hao Liu,Xingwen Wang,Tianqi Guan,Yuhan Wei,Wenxin Zhang,Yi Zhang,Chaoran Liu,Li Li,Qun‐Ying Lei,Ying Hu
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:121 (37) 被引量:1
标识
DOI:10.1073/pnas.2403038121
摘要

Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) and DNA damage repair signaling pathways, with both pathways essential for carcinogenesis and drug resistance. How these signaling pathways coordinate with each other remains unexplored. We found that ER stress specifically induces the DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend DNA damage and impede cell death. Intriguingly, sustained ER stress rapidly decreased the activity of DNA-PKcs and DNA damage accumulated, facilitating a switch from adaptation to cell death. This DNA-PKcs inactivation was caused by increased KU70/KU80 protein degradation. Unexpectedly, the ERAD ligase HRD1 was found to efficiently destabilize the classic nuclear protein HDAC1 in the cytoplasm, by catalyzing HDAC1's polyubiquitination at lysine 74, at a late stage of ER stress. By abolishing HDAC1-mediated KU70/KU80 deacetylation, HRD1 transmits ER signals to the nucleus. The resulting enhanced KU70/KU80 acetylation provides binding sites for the nuclear E3 ligase TRIM25, resulting in the promotion of polyubiquitination and the degradation of KU70/KU80 proteins. Both in vitro and in vivo cancer models showed that genetic or pharmacological inhibition of HADC1 or DNA-PKcs sensitizes colon cancer cells to ER stress inducers, including the Food and Drug Administration-approved drug celecoxib. The antitumor effects of the combined approach were also observed in patient-derived xenograft models. These findings identify a mechanistic link between ER stress (ERAD) in the cytoplasm and DNA damage (NHEJ) pathways in the nucleus, indicating that combined anticancer strategies may be developed that induce severe ER stress while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.
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