Heritable protein aggregation affecting genome preservation and RNA regulation

描述（由申请人提供）：朊病毒蛋白是能够采用可遗传的自我永存构象的表观遗传元件，从而产生基于蛋白质结构而非基于核酸的基因的性状。虽然已知一些朊病毒会形成病理性纤维聚集体，但越来越多的证据表明，朊病毒在真核生物中广泛存在，在正常的生物过程中具有多种作用，并暗示它们是进化变化的重要驱动力。在这篇论文中，我将研究新发现的朊病毒蛋白在朊病毒状态下如何正常调节核酸对细胞生理学的影响。酵母是这些研究中选择的模型系统，因为它的遗传易处理性和真核生物中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研究DNA修复酶的朊病毒样行为如何直接影响基因组的完整性。我选择的例子也与人类癌症有明确的联系。该提案的其余部分将集中在朊病毒蛋白，通过全基因组测定和分子分析相结合，调节mRNA的稳定性和翻译。我希望这份工作的影响和我全面的培训计划都能让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.