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

我们不断地暴露在压力之下，这些压力会破坏我们的遗传物质，并可能导致突变。突变会导致与年龄有关的疾病，如癌症。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降解的蛋白质。我们最近发现了许多新的蛋白质，它们可以识别基因组的断裂区域。目前还不清楚这些蛋白质是如何保护基因组的。在这些因素中，我们发现PRP19对化疗药物和照射的耐药性特别重要，从而帮助细胞修复其DNA。为了弄清楚PRP19如何保护我们的基因组不受突变的影响，我们将确定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。这将给我们带来一个非常精确和新颖的观点，关于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，以及如何稳定这些脆弱的位点并防止突变。

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.