抑癌基因p53通过响应各种应激信号，在抑制癌症的发生和进展中发挥着重要作用。此外，p53可以通过调节能量代谢和氧化磷酸化来调节癌细胞的代谢途径。在这里，我们提出了 p53 和 ZNF568 之间相互作用的机制。最初，我们使用X射线晶体学来确定ZNF568 KRAB结构域的不规则环结构；该环在 p53 和 ZNF568 之间的相互作用中发挥重要作用。此外，Cryo-EM 用于检查 p53 DBD 和 ZNF568 KRAB 结构域如何结合在一起。通过测量葡萄糖消耗和乳酸产生证实了 ZNF568 对 p53 介导的线粒体呼吸的功能。这些发现表明，ZNF568 可以通过与 p53 结合并抑制 SCO2 的转录来降低 p53 介导的线粒体呼吸活性。意义：ZNF568 可以直接结合 p53 DBD 并转录调节 SCO2 基因。通过 ZNF568 和 p53 之间的相互作用进行 SCO2 转录调控可能会调节线粒体呼吸和糖酵解之间的平衡。版权所有 © 2024。由 Elsevier B.V. 出版。

The tumor suppressor p53 plays important roles in suppressing the development and progression of cancer by responding to various stress signals. In addition, p53 can regulate the metabolic pathways of cancer cells by regulating energy metabolism and oxidative phosphorylation. Here, we present a mechanism for the interaction between p53 and ZNF568. Initially, we used X-ray crystallography to determine the irregular loop structure of the ZNF568 KRAB domain; this loop plays an important role in the interaction between p53 and ZNF568. In addition, Cryo-EM was used to examine how the p53 DBD and ZNF568 KRAB domains bind together. The function of ZNF568 on p53-mediated mitochondrial respiration was confirmed by measuring glucose consumption and lactate production. These findings show that ZNF568 can reduce p53-mediated mitochondrial respiratory activity by binding to p53 and inhibiting the transcription of SCO2. SIGNIFICANCE: ZNF568 can directly bind to the p53 DBD and transcriptionally regulate the SCO2 gene. SCO2 transcriptional regulation by interaction between ZNF568 and p53 may regulate the balance between mitochondrial respiration and glycolysis.Copyright © 2024. Published by Elsevier B.V.