Roles of Transcriptional Regulators and RNA Maturation Factors in the Maintenance of Genomic Stability

我们经常暴露在破坏我们的遗传物质并可能导致突变的压力下。基因突变会导致癌症等与年龄相关的疾病。幸运的是，我们的细胞配备了可以检测损伤并保护我们的基因组免受退化的蛋白质。我们最近发现了许多识别基因组断裂区域的新蛋白质。这些蛋白质是如何保护基因组的，目前尚不清楚。在这些因素中，我们发现PRP19对化疗药物和辐射的耐药性特别重要，从而帮助细胞修复他们的DNA。为了弄清楚PRP19是如何保护我们的基因组免受突变的，我们将确定我们DNA中受PRP19保护的特定区域。我们将研究这些区域的特征以及当PRP19从细胞中移除时它们会发生什么。这将为我们带来一个极其精确和新颖的观点，即蛋白质如何保护我们的DNA，为什么基因组中的一些地方比其他地方更频繁地断裂，以及可以做些什么来稳定这些脆弱部位并防止突变。 我们还将研究其他最近发现的可以与基因组损伤相互作用的蛋白质在基因组保护中的作用，以揭示基因组保护机制的新方面。这些新蛋白质有朝一日可能会被用作多种疾病的新治疗靶点。最后，突变的一个主要来源是基因复制和基因转录之间的冲突，基因复制对细胞更新至关重要，基因转录是制造蛋白质所必需的。我们将研究细胞解决DNA复制和转录之间的冲突的方式，以了解如何防止突变。因此，我们的研究计划将增加我们对允许细胞复制DNA并产生生命所必需的蛋白质的基本机制的理解。这些信息可能会指导我们制定新的策略，从而提高加拿大目前抗癌治疗的效率。

We are constantly exposed to stresses that damage our genetic material and may cause mutations. Mutations lead to age-related diseases such as cancer. Fortunately, our cells are equipped with proteins that can detect damage and protect our genome from degradation. We have recently identified many novel proteins that recognize broken regions of the genome. What these proteins do to protect the genome is currently unknown. Among these factors, we found that PRP19 is particularly important for the resistance to chemotherapeutic drugs and irradiation and thus helps cells repair their DNA. To figure out how PRP19 shields our genome against mutations, we will identify the specific regions of our DNA that are protected by PRP19. We will study the characteristics of these regions and what happens to them when PRP19 is removed from cells. This will bring us an extremely precise and novel point of view on how proteins safeguard our DNA, why some places in the genome break more frequently than others and what could be done to stabilize these fragiles sites and prevent mutations. We will also study the roles in genome preservation of the other recently identified proteins that can interact with genome lesions to uncover novel facets of the genome protection machinery. These new proteins may one day be used as novel therapeutic targets for a variety of diseases. Finally, a major source of mutations are the clashes between gene replication which is crucial for cell renewal and gene transcription which is necessary for making proteins. We will examine the ways cells resolve the conflicts between DNA replication and transcription to understand how mutations are prevented. Our research program will thus increase our understanding of the fundamental mechanisms that allow cells to replicate their DNA and produce the proteins that are necessary for life. This information may guide us in the elaboration of novel strategies that could improve the efficiency of current anti-cancer treatments in Canada.