MDM2通过泛素化HBP1调控染色质的稳定性

Chromatin instability is a common feature in tumor cells. The persistent presence of chromatin instability is a potential mechanism of tumorigenesis. Ubiquitin E3 ligase MDM2 is an important regulator in facilitating cell growth, survival and metastasis. It was reported that MDM2 is intimately involved in chromatin instability, but the mechanism is not clear. Our data tentatively demonstrated that HBP1 is a target of MDM2. MDM2 facilitates HBP1 proteasomal degradation through ubiquitinating HBP1, thus decreases HBP1 protein level and attenuates the transcriptional inhibition of HBP1 in the expressions of its target genes, such as DNA methyltransferase DNMT1 and histone methyltransferase EZH2, which results in DNA and histone hypermethylations and leads to chromatin instability. In this study, we will explore thoroughly the regulation mechanism of MDM2-HBP1-DNMT1/EZH2 signal pathway, as well as the role of the axis in chromatin instability, especially in reparative process after DNA damage. The investigation will demonstrate the mechanism of MDM2 regulating chromatin stability, and elucidate interrelation of chromatin instability and tumorigenesis, thus provide theorial and experimental basis for preventing, healing and screening the drug target for the tumor.

染色质不稳定是肿瘤细胞的一个普遍特征，也是肿瘤发生的重要机制之一。泛素E3连接酶MDM2是促进细胞增殖、存活及转移的重要的调控因子，与染色质的不稳定性密切相关，但其作用机制不清。我们的研究初步证实转录因子HBP1是MDM2下游的靶蛋白，MDM2通过泛素化HBP1，促进其蛋白酶体的降解，从而降低HBP1蛋白水平，降低HBP1对其下游DNA甲基转移酶DNMT1和组蛋白甲基转移酶EZH2基因的转录抑制作用，使基因组DNA和组蛋白甲基化水平升高，染色质的不稳定性增加。本研究将深入探讨MDM2-HBP1-DNMT1/EZH2信号通路的作用机制，以及这条信号通路对染色质稳定性的影响，尤其是DNA损伤修复过程中这条信号通路的作用和调控机制。此研究将揭示MDM2调控染色质稳定性的作用机制，阐明染色质不稳定性与肿瘤发生的关系，为肿瘤的预防、治疗，以及药物靶点的筛选提供理论和实验基础。

细胞染色质不稳定可诱导肿瘤的发生。泛素E3连接酶MDM2高表达促进染色质的不稳定，但其作用机制不清。我们的研究证实转录因子HBP1是MDM2下游的靶蛋白，MDM2通过泛素化HBP1，降低HBP1蛋白水平，使DNA甲基转移酶DNMT1和组蛋白甲基转移酶EZH2表达水平升高，从而提高整个基因组DNA和组蛋白甲基化水平，导致染色质的不稳定。并且，这种不稳定性在细胞因电离辐射而导致的DNA损伤修复过程中，抑制DNA的修复，从而加重染色质的不稳定性，诱导肿瘤的发生。本研究证实了MDM2-HBP1-DNMT1/EZH2信号通路在染色质稳定性及肿瘤发生中的作用，确定MDM2是肿瘤治疗的重要的药物靶点。