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首页> 外文期刊>Cell death and differentiation >KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress
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KMTase Set7/9 is a critical regulator of E2F1 activity upon genotoxic stress

机译：KMTase Set7 / 9是遗传毒性胁迫下E2F1活性的关键调节剂

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摘要

During the recent years lysine methyltransferase Set7/9 ((Su(var)-3-9, Enhancer-of-Zeste, Trithorax) domain containing protein 7/9) has emerged as an important regulator of different transcription factors. In this study, we report a novel function for Set7/9 as a critical co-activator of E2 promoter-binding factor 1 (E2F1)-dependent transcription in response to DNA damage. By means of various biochemical, cell biology, and bioinformatics approaches, we uncovered that cell-cycle progression through the G1/S checkpoint of tumour cells upon DNA damage is defined by the threshold of expression of both E2F1 and Set7/9. The latter affects the activity of E2F1 by indirectly modulating histone modifications in the promoters of E2F1-dependent genes. Moreover, Set7/9 differentially affects E2F1 transcription targets: it promotes cell proliferation via expression of the CCNE1 gene and represses apoptosis by inhibiting the TP73 gene. Our biochemical screening of the panel of lung tumour cell lines suggests that these two factors are critically important for transcriptional upregulation of the CCNE1 gene product and hence successful progression through cell cycle. These findings identify Set7/9 as a potential biomarker in tumour cells with overexpressed E2F1 activity.
机译：近年来，赖氨酸甲基转移酶Set7 / 9（（Su（var）-3-9，Zeste增强子，Trithorax）含有蛋白7/9的结构域）已成为不同转录因子的重要调节剂。在这项研究中，我们报告Set7 / 9作为E2启动子结合因子1（E2F1）依赖转录对DNA损伤的关键共激活因子的新功能。通过各种生化，细胞生物学和生物信息学方法，我们发现在DNA损伤时通过肿瘤细胞的G1 / S检查点的细胞周期进程由E2F1和Set7 / 9的表达阈值确定。后者通过间接调节依赖于E2F1的基因启动子中的组蛋白修饰来影响E2F1的活性。此外，Set7 / 9差异影响E2F1转录靶点：它通过CCNE1基因的表达促进细胞增殖，并通过抑制TP73基因来抑制细胞凋亡。我们对肺肿瘤细胞系的生化筛选表明，这两个因素对于CCNE1基因产物的转录上调以及因此在整个细胞周期中的成功进展至关重要。这些发现将Set7 / 9鉴定为E2F1活性过高的肿瘤细胞中的潜在生物标志物。

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