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

Zhiyuan Xiang,

Guixue Hou, Shanliang Zheng

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(37)

Опубликована: Сен. 3, 2024

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

Язык: Английский

Association of Cytomegalovirus Serostatus with ELOVL2 Methylation: Implications for Lipid Metabolism, Inflammation, DNA Damage, and Repair Capacity in the MARK-AGE Study Population DOI
Robertina Giacconi, Chiara Pirazzini, Maria Giulia Bacalini

и другие.

Mechanisms of Ageing and Development, Год журнала: 2025, Номер unknown, С. 112043 - 112043

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
E3 ubiquitin ligase SYVN1 as a promising therapeutic target for diverse human diseases DOI Creative Commons
Li Zhu, Yongping Liu,

YuanWang

и другие.

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107603 - 107603

Опубликована: Янв. 1, 2025

Numerous studies conducted in recent years indicate that mammalian E3 ubiquitin ligases serve as key regulators the maintenance of cellular homeostasis by targeting ubiquitination substrate proteins and activating downstream signaling pathways. SYVN1, an ligase, is characterized its significant functions regulating various biological processes, including molecular mechanisms related to gene expression, pathways, cell death, among others. Consequently, SYVN1 plays a crucial role both normal human physiology pathogenesis diseases, such oncogenesis, cardiovascular disorders, immune regulation, skeletal anomalies, neurological diseases. This review synthesizes findings regarding physiological pathophysiological roles offering new insights into potential strategies for prevention treatment well suggesting avenues future drug development. In this Review, we summarize latest elucidating which can regulate progression diseases humans. These important provide further investigation protein, prevent treat directions

Язык: Английский

Процитировано

0
ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs DOI

Zhiyuan Xiang,

Guixue Hou, Shanliang Zheng

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(37)

Опубликована: Сен. 3, 2024

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

Язык: Английский

Процитировано

3