Influence of Retrotransposition on DNA Damage and Repair in Aging Cells

该项目的直接研究目标是确定反转录转座子的潜在贡献， 一类移动的遗传元件，突变和染色体的频率增加 在老化过程中发生的重排。一个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， 一项独立的研究计划，调查基因组不稳定性变化对衰老的影响 以及反转录转座子如何影响基因组的不稳定性。酵母将被用作实验生物， 更有效地实现项目的目标。酵母与人类衰老是由相关的遗传控制的 途径，其特征是遗传损伤频率增加。此外，酵母和 人类的反转录转座子也能引起同样的基因变化。活性的调节 内源性酵母逆转录转座子通过突变，使用不同的遗传背景， 将与遗传系统相结合，以选择或筛选突变和染色体 衰老细胞中的重组分子分析，包括DNA测序和DNA微阵列，将 然后用于检查突变谱和表征染色体重排。突变株 在特定的DNA修复过程中的缺陷也将被用来调查之间的关系， 寿命和特定形式的基因组不稳定性时，反转录转座子是活跃的。这项工作将确定 逆转录转座子是否有助于酵母中与衰老相关的基因组不稳定性，以及它们是否 这可能是一个很好的干预目标，以减少突变和基因组重排在人类 衰老这种干预可能会减少组织/器官功能随年龄的丧失， 与衰老有关的疾病。在辅导阶段开发的研究材料和系统，核心 办学机构的设施及其他资源，以及导师就上一阶段的 该项目将有助于发展一个独特的独立研究方案。

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.