MDM2 promotes genome instability by ubiquitinating the transcription factor HBP1
MDM2 promotes genome instability by ubiquitinating the transcription factor HBP1
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MDM2 通过泛素化转录因子 HBP1 促进基因组不稳定
DOI：
10.1038/s41388-019-0761-2
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发表时间：
2019-06-13
期刊：
影响因子：
8
通讯作者：
Zhang, Xiaowei
中科院分区：
文献类型：
--
作者：
Cao, Zhengyi .;Xue, Junhui;Zhang, Xiaowei
基因组不稳定性是肿瘤细胞的共同特征，基因组不稳定性的持续存在是肿瘤发生的潜在机制。 E3 泛素连接酶 MDM2 与基因组不稳定密切相关，但其机制尚不清楚。我们的数据表明转录因子 HBP1 是 MDM2 的靶标。无论 p53 状态如何，MDM2 通过泛素化 HBP1 促进 HBP1 蛋白酶体降解，从而减弱 HBP1 在其靶基因（例如 DNA 甲基转移酶 DNMT1 和组蛋白甲基转移酶 EZH2）表达中的转录抑制，从而导致整体 DNA 高甲基化和组蛋白高甲基化，最终 基因组不稳定。 MDM2 对 HBP1 的抑制最终促进细胞生长和肿瘤发生。接下来，我们深入探讨了MDM2/HBP1轴在电离辐射后DNA损伤修复中的调控机制。我们的数据表明，MDM2 过表达介导的 HBP1 抑制会延迟 DNA 损伤修复，并以不依赖于 p53 的方式导致细胞死亡。该研究阐明了在p53缺失的情况下MDM2如何促进基因组不稳定并增强肿瘤发生的机制，从而为靶向MDM2作为癌症治疗提供了理论和实验基础。
Genome instability is a common feature of tumor cells, and the persistent presence of genome instability is a potential mechanism of tumorigenesis. The E3 ubiquitin ligase MDM2 is intimately involved in genome instability, but its mechanisms are unclear. Our data demonstrated that the transcription factor HBP1 is a target of MDM2. MDM2 facilitates HBP1 proteasomal degradation by ubiquitinating HBP1, regardless of p53 status, thus attenuating the transcriptional inhibition of HBP1 in the expression of its target genes, such as the DNA methyltransferase DNMT1 and histone methyltransferase EZH2, which results in global DNA hypermethylation and histone hypermethylation and ultimately genome instability. The repression of HBP1 by MDM2 finally promotes cell growth and tumorigenesis. Next, we thoroughly explored the regulatory mechanism of the MDM2/HBP1 axis in DNA damage repair following ionizing radiation. Our data indicated that MDM2 overexpression-mediated repression of HBP1 delays DNA damage repair and causes cell death in a p53-independent manner. This investigation elucidated the mechanism of how MDM2 promotes genome instability and enhances tumorigenesis in the absence of p53, thus providing a theoretical and experimental basis for targeting MDM2 as a cancer therapy.