Guangdong Key Laboratory of Fermentation and Enzyme Engineering, School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong Province 510006, PR China.
Ministry of Agriculture Key Laboratory of Animal Biochemistry and Nutrition, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan Province 450002, PR China.
Biochim Biophys Acta Gene Regul Mech. 2022 May;1865(4):194827. doi: 10.1016/j.bbagrm.2022.194827. Epub 2022 May 23.
Human p53 is a transcription factor regulating the transcription of a variety of target genes. Under various stresses, its tumor suppressor function was activated by the phosphorylation of p53. In this study, we found that full-length wild-type p53 could form phase-separated condensates with the aggregation tendency in vitro and in vivo. The LLPS of p53 was regulated by multiple functional domains. Specific DNA could promote the formation of p53 condensates. Fluorescence recovery data after photobleaching revealed that the Ser392 phosphorylation enhanced the fluidity of p53 condensates. Fluorescence analysis suggested that Ser392 phosphorylation increased the p53 concentration in condensates involved in transcription initiation and the stability of p53-mediated transcriptional condensates. The experiments in cells showed that p53 was evenly dispersed in the nucleus, it formed the dynamic condensates under the UV radiation-induced DNA damage, and the Ser392 nonphosphorylatable mutant S392A p53 formed condensates with significantly reduced number and size. These findings revealed that p53 phosphorylation modified its LLPS behavior, and suggested a mechanism that phosphorylation regulated condensate preference.
人类 p53 是一种转录因子，可调节多种靶基因的转录。在各种应激下，其肿瘤抑制功能可通过 p53 的磷酸化而被激活。在本研究中，我们发现全长野生型 p53 可在体外和体内形成具有聚集倾向的相分离凝聚物。p53 的相分离受多个功能域调节。特定的 DNA 可促进 p53 凝聚物的形成。光漂白后荧光恢复数据显示，Ser392 磷酸化增强了 p53 凝聚物的流动性。荧光分析表明，Ser392 磷酸化增加了参与转录起始的凝聚物中 p53 的浓度和 p53 介导的转录凝聚物的稳定性。细胞实验表明，p53 在核内均匀分布，在 UV 辐射诱导的 DNA 损伤下形成动态凝聚物，且 Ser392 不可磷酸化突变体 S392A p53 形成的凝聚物数量和大小明显减少。这些发现揭示了 p53 磷酸化修饰其相分离行为，并提出了一种磷酸化调节凝聚物偏好的机制。
