A eukaryotic SOS response

SOS反应最初是在细菌中发现的，作为耐受环境辐射和遗传毒性化学物质的一种手段。在真核生物中还没有观察到类似的现象;然而，全基因组分析已经确定了大量的酵母基因，它们的表达会对DNA损伤做出反应。我的实验室的目的是了解以酵母为模型的DNA损伤的转录反应的分子机制。在NSERC的支持下，我们发现几个酵母基因受到一个共同途径的调控，其特征让人想起细菌SOS系统。然而，与细菌SOS不同，酵母细胞似乎利用泛素化和磷酸化系统来修饰参与感知DNA损伤和传递信号的靶蛋白。我们最近在导致转录反应和细胞周期控制的信号转导方面取得了非常重要的发现，并令人信服地证明了类似于细菌SOS反应的调节机制。通过我们的研究也清楚地表明，并非所有的DNA损伤诱导基因都具有相同的启动子元件，它们可能属于几个不同的组（调节子）。在这里，我们提出了两个全基因组的屏幕和详细的分子分析选定的基因，旨在了解数百个基因是如何协调调节在转录水平上的DNA损伤。阐明这些信号转导级联有三个重要的意义。首先，它帮助我们揭示基因调控和发育的基本生物过程，这是生命的关键过程。其次，DNA损伤是包括癌症在内的人类遗传性疾病的主要原因，绝大多数（>90%）的化学致癌物是DNA损伤剂。我们利用上述知识开发了一种能够检测和评估环境致癌物的遗传毒性试验。最后，我们发现，所有的调控基因在这项拟议的研究是高度保守的真核生物，从酵母到人类。因此，我们提出的研究可以应用于多细胞生物，并有助于农业，环境和公共卫生。

The SOS response was first discovered in bacteria as a means of tolerating environmental radiation and genotoxic chemicals. No similar phenomenon has yet been observed in eukaryotes; however, genome-wide analyses have identified a large number of yeast genes whose expression increases in response to DNA damage. My laboratory aims to understand molecular mechanisms of transcriptional response to DNA damage using yeast as a model. Supported by NSERC, we found that several yeast genes are regulated by a common pathway with features reminiscent of the bacterial SOS system. However, unlike bacterial SOS, yeast cells appear to utilize ubiquitination and phosphorylation systems to modify target proteins involved in sensing DNA damage and relaying signals. We recently made a highly significant discovery regarding the signal transduction leading to transcriptional response and cell cycle control, and convincingly demonstrated a regulatory mechanism similar to the bacterial SOS response. It also becomes clear through our study that not all DNA damage inducible genes share the same promoter elements and that they probably belong to several distinct groups (regulons). Here we propose both genome-wide screens and detailed molecular analyses of selected genes aiming at understanding how several hundred genes are coordinately regulated in response to DNA damage at the transcriptional level. Elucidation of these signal transduction cascades has three important implications. First, it helps us to uncover fundamental biological processes of gene regulation and development, a key process of life. Second, DNA damage is the leading cause of human genetic diseases including cancer, and the vast majority (>90%) of chemical carcinogens are DNA damaging agents. We have utilized the above knowledge to develop a genotoxicity test capable of detecting and assessing environmental carcinogens. Finally, we have found that all the regulatory genes in this proposed study are highly conserved within eukaryotes, from yeast to human. Hence, our proposed studies can be applied to multicellular organisms, and contribute to agriculture, the environment and public health.