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

转录调节因子和 RNA 成熟因子在维持基因组稳定性中的作用

• 批准号: RGPIN-2016-05026
• 负责人: Maréchal, Alexandre
• 金额: $ 2.26万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709564
• 关键词: Roles; Transcriptional; Regulators; RNA; Maturation

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.

我们不断地暴露在压力下，这些压力会破坏我们的遗传物质，并可能导致突变。突变会导致癌症等与年龄相关的疾病。幸运的是，我们的细胞配备了蛋白质，可以检测损伤并保护我们的基因组免受降解。我们最近发现了许多识别基因组断裂区域的新型蛋白质。这些蛋白质如何保护基因组目前尚不清楚。在这些因素中，我们发现PRP19对于化疗药物和辐射的抗性特别重要，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免受突变的影响，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从细胞中去除时它们会发生什么。这将为我们带来一个非常精确和新颖的观点，即蛋白质如何保护我们的DNA，为什么基因组中的某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的位点并防止突变。 我们还将研究其他最近发现的蛋白质在基因组保护中的作用，这些蛋白质可以与基因组病变相互作用，以揭示基因组保护机制的新方面。这些新的蛋白质有一天可能被用作各种疾病的新的治疗靶点。最后，突变的一个主要来源是对细胞更新至关重要的基因复制和制造蛋白质所必需的基因转录之间的冲突。我们将研究细胞如何解决DNA复制和转录之间的冲突，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。这些信息可以指导我们制定新的策略，以提高加拿大目前抗癌治疗的效率。