CNRS-UMR6061 Genetic and Development Institute of Rennes, RTO Team, Rennes, France.
PLoS Genet. 2012 Jan;8(1):e1002470. doi: 10.1371/journal.pgen.1002470. Epub 2012 Jan 26.
An important function of all organisms is to ensure that their genetic material remains intact and unaltered through generations. This is an extremely challenging task since the cell's DNA is constantly under assault by endogenous and environmental agents. To protect against this, cells have evolved effective mechanisms to recognize DNA damage, signal its presence, and mediate its repair. While these responses are expected to be highly regulated because they are critical to avoid human diseases, very little is known about the regulation of the expression of genes involved in mediating their effects. The Nucleotide Excision Repair (NER) is the major DNA-repair process involved in the recognition and removal of UV-mediated DNA damage. Here we use a combination of in vitro and in vivo assays with an intermittent UV-irradiation protocol to investigate the regulation of key players in the DNA-damage recognition step of NER sub-pathways (TCR and GGR). We show an up-regulation in gene expression of CSA and HR23A, which are involved in TCR and GGR, respectively. Importantly, we show that this occurs through a p53 independent mechanism and that it is coordinated by the stress-responsive transcription factor USF-1. Furthermore, using a mouse model we show that the loss of USF-1 compromises DNA repair, which suggests that USF-1 plays an important role in maintaining genomic stability.
所有生物体的一个重要功能是确保其遗传物质在世代之间保持完整和不变。这是一项极具挑战性的任务，因为细胞的 DNA 不断受到内源性和环境因素的攻击。为了防止这种情况，细胞已经进化出有效的机制来识别 DNA 损伤，发出其存在的信号，并介导其修复。虽然这些反应预计会受到高度调节，因为它们对于避免人类疾病至关重要，但对于参与介导其作用的基因表达的调节却知之甚少。核苷酸切除修复（NER）是涉及识别和去除 UV 介导的 DNA 损伤的主要 DNA 修复过程。在这里，我们使用间歇 UV 辐射方案的体外和体内测定组合来研究 NER 亚途径（TCR 和 GGR）中 DNA 损伤识别步骤的关键参与者的调节。我们显示 CSA 和 HR23A 的基因表达上调，它们分别参与 TCR 和 GGR。重要的是，我们表明这是通过一种不依赖 p53 的机制发生的，并且由应激反应转录因子 USF-1 协调。此外，使用小鼠模型，我们表明 USF-1 的缺失会损害 DNA 修复，这表明 USF-1 在维持基因组稳定性方面发挥着重要作用。
