Heritable protein aggregation affecting genome preservation and RNA regulation

描述(申请人提供)：Prion蛋白质是表观遗传元件，能够采用可遗传的自我永续构象，从而产生基于蛋白质结构的特征，而不是基于核酸的基因。虽然已知一些Prion可以形成病理性的纤维聚集体，但越来越多的证据表明，在真核生物中广泛存在的Prion在正常的生物过程中具有不同的作用，并暗示它们是进化变化的重要驱动力。在这项提案中，我将研究新发现的通常调节核酸的普里恩蛋白在普里恩状态下如何影响细胞生理学。酵母是这些研究的首选模型系统，因为它的遗传易感性和真核生物之间蛋白质聚集机制的高度相似性。首先，我将通过遗传和分子分析来研究DNA修复酶的类病毒行为如何直接影响基因组的完整性。我选择的例子也清楚地定义了与人类癌症的联系。该提案的其余部分将通过全基因组分析和分子分析相结合的方式，将重点放在调节mRNA稳定性和翻译的普恩蛋白上。我预计这项工作的影响和我周密的培训计划都将使我在未来建立自己的研究小组。

DESCRIPTION (provided by applicant): Prion proteins are epigenetic elements capable of adopting self-perpetuating conformations that are heritable, thereby producing traits based on protein structure rather than nucleic acid-based genes. While some prions are known to form pathological fibrous aggregates, increasing evidence suggests that prions-which are widespread in eukaryotes-have diverse roles in normal biological processes, and implicates them as important drivers of evolutionary change. In this proposal I will investigate how newly discovered prion proteins that normally regulate nucleic acid impact cell physiology when in the prion state. Yeast is the chosen model system for these studies, due to its genetic tractability and the high degree of similarity of protein aggregation mechanisms among eukaryotes. First, I will investigate how the prion-like behavior of a DNA repair enzyme may directly influence genomic integrity, through genetic and molecular analyses. My chosen example also has clearly defined links to human cancers. The remainder of the proposal will focus on prion proteins that regulate mRNA stability and translation, through a combination of genome-wide assays and molecular analyses. I expect that the impact of this work and my thorough training plan will both position me well to establish my own research group in the future.