Influence of Retrotransposition on DNA Damage and Repair in Aging Cells

该项目的近期研究目标是确定反转录转座子的潜在贡献， 一类可移动的遗传元件，导致突变和染色体频率的增加 在老化过程中发生的重新排列。更广泛的目标是在研究、培训和 在项目的指导阶段与科学界进行互动，以制定 独立研究计划，调查基因组不稳定变化对衰老的影响 以及反转录转座子如何影响基因组的不稳定性。酵母菌将被用作实验有机体 更有效地实现项目的目标。酵母和人类衰老是由相关基因控制的 并以基因损伤频率增加为特征。此外，酵母菌和 人类反转录转座子也会导致相同类型的基因变化。对酶活性的调节 内源酵母反转录转座子通过突变，利用不同的遗传背景而发生变化 将与基因系统相结合，以选择或筛选突变和染色体 衰老细胞中的重排。分子分析，包括DNA测序和DNA微阵列，将 然后被用来检查突变谱和表征染色体重排。突变株 具有缺陷的特定DNA修复过程也将被用于调查两者之间的关系 反转录转座子活跃时的寿命和特定形式的基因组不稳定性。这项工作将确定 反转录转座子是否有助于酵母衰老相关的基因组不稳定？是否 很可能成为减少人类基因突变和基因组重排的干预措施的良好靶点 衰老。这样的干预措施可能会减少组织/器官功能随年龄的丧失以及 与衰老相关的疾病。指导阶段开发的研究材料和系统，核心 赞助机构的设施和其他资源，以及导师对前一阶段的建议 该项目将为一个独特的独立研究项目的发展做出贡献。

The immediate research goal of this project is to determine the potential contribution of retrotransposons, a class of mobile genetic elements, to increases in frequencies of mutations and chromosome rearrangements that occur during aging. A broader objective is to build upon research, training, and interactions with the scientific community during the mentored phase of the project to develop an independent research program to investigate the consequences of changes in genome instability for aging and how retrotransposons influence genome instability. Yeast will be used as an experimental organism to more efficiently address the aims ofthe project. Yeast and human aging are controlled by related genetic pathways and are characterized by increases in frequencies of genetic damage. Furthermore, yeast and human retrotransposons can contribute to the same kinds of genetic changes. Modulation of the activity of endogenous yeast retrotransposons through mutations, use of different genetic backgrounds, and changes in growth media will be combined with genetic systems to select or screen for mutations and chromosome rearrangements in aging cells. Molecular analyses, including DNA sequencing and DNA microarrays, will then be used to examine mutation spectra and characterize chromosome rearrangements. Mutant strains with deficiencies in specific DNA repair processes will also be used to investigate the relationship between lifespan and particular forms of genome instability when retrotransposons are active. The work will identify whether retrotransposons contribute to aging-associated genome instability in yeast and whether they are likely to be a good target for interventions to reduce mutations and genome rearrangements during human aging. Such interventions could potentially reduce the loss of tissue/organ function with age and the risk of aging-related diseases. Research materials and systems developed during the mentored phase, core facilities and other resources at the sponsoring institution, and advice from the mentors for the prior phase of the project will all contribute to the development of a distinct independent research program.