KU COMPLEX AND TELOMERE END PROTECTION

作为一名儿科肿瘤学家，我对新靶点有着浓厚的兴趣 用于癌症相关治疗。我对端粒生物学的兴趣来自于 一项重要的研究表明端粒是 对永生化和肿瘤发生过程的重要性。 在酵母中的实验，以及最近在人类细胞系中的实验， 建立了端粒长度和寿命之间的因果关系。 此外，大多数肿瘤表现出端粒酶的活化， 这就提出了一个问题，即端粒酶是否可以作为一种 化疗靶点然而，最近的其他研究表明， 端粒酶阴性肿瘤能够形成肿瘤，且肿瘤细胞 系可以利用端粒不依赖的途径 维护，从而突出了一个彻底的 了解端粒动力学，如果考虑引入 抗端粒酶剂进入临床竞技场。这项建议的目的是 是通过以下方法来推进我们对端粒生物学的理解： Ku复合物和蛋白质两种活性的表征 Cdc 13 p似乎在介导端粒功能中起作用， 保护染色体末端这些研究将在 酵母，这已被证明是一个有价值的模型系统，为快速 鉴定和评估可以外推到 研究人类端粒生物学。Ku异二聚体，以前 其特征在于其在双标准DNA断裂修复和V（D）J中的作用 在哺乳动物细胞中的重组，也被证明在 酵母端粒维持和染色质结构。古典 遗传学将被用来识别和分析突变的Ku 具有端粒解偶联和DNA修复功能的复合物。这些 然后利用突变体来鉴定潜在的新蛋白质， 在端粒维持中与Ku异二聚体相互作用。顾，新 将进一步分析鉴定的Ku相关蛋白和Cdc 13 p 它们在体内与端粒染色质的结合以及它们如何与端粒染色质结合， 关联性受不同遗传背景的影响。 此外，这些蛋白质在调节终末 端粒结构，G-尾，将被研究。这些研究，在 除了解决端粒末端保护中的重要问题之外， 将为我提供一个坚实的基础，在古典遗传学和现代 分子生物学，在此基础上建立分子肿瘤学职业生涯。博士 分子和人类遗传学系的伦德布拉德实验室 贝勒医学院提供了一个良好的环境， 来发展我的科学技能

As a pediatric oncologist, I have an intense interest in novel targets for cancer-related therapy. My interest in telomere biology arises from a significant body of work that indicates telomeres are of central importance to the processes of immortalization and tumorigenesis. Experiments in yeast, and recently in human cell lines, have firmly established a causal link between telomere length and lifespan. Furthermore, a majority of tumors exhibit activation of telomerase, raising the question whether telomerase can be exploited as a chemotherapeutic target. Other recent studies, however, have shown that telomerase-negative mise are capable of forming tumors, and tumor cell lines can utilize telomerase-independent pathways for telomere maintenance, thereby highlighting the importance of a thorough understanding of telomere dynamics if considering the introduction of anti-telomerase agents into the clinical arena. The aim of this proposal is to advance our understanding of telomere biology by the characterization of two activities, the Ku complex and the protein Cdc13p, which appear to play a role in mediating the telomere function of protecting chromosomal ends. These studies will be performed in yeast, which has proven to be a valuable model system for the rapid identification and evaluation of genes which can be extrapolated to the study telomere biology in humans. The Ku heterodimer, previously characterized for its role in double-standard DNA break repair and V(D)J recombination in mammalian cells, has also been shown to play a role in telomere maintenance and chromatin structure in yeast. Classical genetics will be utilized to identify and analyze mutants in the Ku complex which have uncoupled telomere and DNA repair function. These mutants will then be exploited to identify potential new proteins which interact with the Ku heterodimer in telomere maintenance. Ku, the newly identified Ku-associated proteins and Cdc13p will be further analyzed for their in vivo association with telomeric chromatin and how their associations are affected by different genetic backgrounds. Additionally, the role of these proteins in the regulation the terminal telomere structure, the G-tail, will be investigated. These studies, in addition tp addressing important questions in telomere end protection, will provide me with a firm foundation in classical genetics and modern molecular biology on which to build a career in molecular oncology. Dr. Lundblad's laboratory in the Department of Molecular and Human Genetics at the Baylor College of Medicine provides an excellent environment in which to develop my scientific skills.