Phospho-Ser
| Autor: | Cuige, Zhu, Anna, Rogers, Karama, Asleh, Jennifer, Won, Dongxia, Gao, Samuel, Leung, Shan, Li, Kiran R, Vij, Jian, Zhu, Jason M, Held, Zhongsheng, You, Torsten O, Nielsen, Jieya, Shao |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions. We describe a DNA-damage-induced phosphorylation event (Ser784), which selectively enhances chromatin-associated protein degradation mediated by VCP and is required for DNA repair, signaling, and cell survival. These functional effects of Ser784 phosphorylation on DDR correlate with a decrease in VCP association with chromatin, cofactors NPL4/UFD1, and polyubiquitinated substrates. Clinically, high phospho-Ser784-VCP levels are significantly associated with poor outcome among chemotherapy-treated breast cancer patients. Thus, Ser784 phosphorylation is a DDR-specific enhancer of VCP function and a potential predictive biomarker for chemotherapy treatments. Graphical Abstract Highlights • DNA damage-induced p-Ser784-VCP enhances chromatin-associated protein degradation • p-Ser784-VCP has reduced interaction with NPL4/UFD1 and polyubiquitinated substrates • VCP phosphorylation on Ser784 is important for DNA damage response and cell survival • p-Ser784-VCP correlates with poor survival of chemotherapy-treated cancer patients Zhu et al. show that DNA-damage-induced, PIKK-mediated Ser784 phosphorylation is a specific enhancer of VCP function in chromatin-associated protein degradation. Phospho-Ser784-VCP is required for DNA repair, checkpoint signaling, and cell survival in response to a broad range of genotoxins and correlates with poor outcome among chemotherapy-treated breast cancer patients. |
| Databáze: | OpenAIRE |
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