Lezina Larissa, Aksenova Vasilisa, Fedorova Olga, Malikova Daria, Shuvalov Oleg, Antonov Alexey V, Tentler Dmitri, Garabadgiu Alexander V, Melino Gerry, Barlev Nikolai A
Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
MRC Toxicology Unit, Leicester, LE1 9HN, UK.
Oncotarget. 2015 Sep 22;6(28):25843-55. doi: 10.18632/oncotarget.4584.
Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins. Signal transduction pathways, besides DDR itself, also control expression of genes whose products cause cell cycle arrest and/or apoptosis thus ultimately affecting the sensitivity of cells to genotoxic stress. In this study, using a number of experimental approaches we provide evidence that lysine-specific methyltransferase (KMT) Set7/9 affects DDR and DNA repair, at least in part, by regulating the expression of an E3 ubiquitin ligase, Mdm2. Furthermore, we show that Set7/9 physically interacts with Mdm2. Several cancer cell lines with inverse expression of Set7/9 and Mdm2 displayed diminished survival in response to genotoxic stress. These findings are signified by our bioinformatics studies suggesting that the unleashed expression of Mdm2 in cancer patients with diminished expression of Set7/9 is associated with poor survival outcome.
抗癌药物造成的基因毒性应激会导致DNA断裂和基因组不稳定。辐射或拓扑异构酶II的药理学抑制所诱导的DNA双链断裂会激活共济失调毛细血管扩张突变（ATM）激酶信号通路，进而触发细胞周期停滞和DNA修复。组蛋白H2Ax的ATM依赖性γ磷酸化以及包括泛素化在内的其他组蛋白修饰，会促进组蛋白的交换以及DNA损伤反应（DDR）和修复蛋白的募集。除了DDR自身外，信号转导通路还控制其产物会导致细胞周期停滞和/或凋亡的基因的表达，从而最终影响细胞对基因毒性应激的敏感性。在本研究中，我们使用多种实验方法提供了证据，表明赖氨酸特异性甲基转移酶（KMT）Set7/9至少部分地通过调节E3泛素连接酶Mdm2的表达来影响DDR和DNA修复。此外，我们表明Set7/9与Mdm2存在物理相互作用。Set7/9和Mdm2表达呈反向关系的几种癌细胞系在面对基因毒性应激时存活率降低。我们的生物信息学研究表明Set7/9表达降低的癌症患者中Mdm2的过度表达与不良生存结果相关，这些发现具有重要意义。
