Departamento de Genética, Universidad de Sevilla, Sevilla, 41080, Spain; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, 41092, Spain.
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, 41092, Spain.
DNA Repair (Amst). 2020 Oct;94:102902. doi: 10.1016/j.dnarep.2020.102902. Epub 2020 Jun 27.
Cell fitness and survival upon exposure to DNA damage depends on the repair of DNA lesions. Interestingly, cellular identity does affect and finetunes such response, although the molecular basis of such differences between tissues and cell types is not well understood. Thus, a possibility is that DNA repair itself is controlled by the mechanisms that govern cell identity. Here we show that the KLF4, involved in cellular homeostasis, proliferation, cell reprogramming and cancer development, directly regulates resection and homologous recombination proficiency. Indeed, resection efficiency follows KLF4 protein levels, i.e. decreases upon KLF4 downregulation and increases when is overexpressed. Moreover, KLF4 role in resection requires its methylation by the methyl-transferase PRMT5. Thus, PRMT5 depletion not only mimics KLF4 downregulation, but also showed an epistatic genetic relationship. Our data support a model in which the methylation of KLF4 by PRMT5 is a priming event required to license DNA resection and homologous recombination.
细胞在暴露于 DNA 损伤时的适应性和存活取决于 DNA 损伤的修复。有趣的是，细胞身份确实会影响和微调这种反应，尽管组织和细胞类型之间这种差异的分子基础还不是很清楚。因此，一种可能性是 DNA 修复本身受到控制细胞身份的机制的控制。在这里，我们表明，参与细胞内稳态、增殖、细胞重编程和癌症发展的 KLF4 直接调节切除和同源重组效率。事实上，切除效率与 KLF4 蛋白水平相关，即 KLF4 下调时会降低，过表达时会增加。此外，KLF4 在切除中的作用需要其被甲基转移酶 PRMT5 甲基化。因此，PRMT5 的消耗不仅模拟了 KLF4 的下调，而且还显示出了上位遗传关系。我们的数据支持这样一种模型，即 PRMT5 对 KLF4 的甲基化是启动 DNA 切除和同源重组所必需的。
