REGULATION OF TELOMERE LENGTH

端粒是稳定和完整所需的核蛋白。 染色体复制结束。端粒DNA由串联阵列组成 富含甘油三酯的序列：人类TTAGGG为10-20kb，TTAGGG为250-400bp TG1-3在萌芽酵母中，其中富含TG的链形成TG1-3的3‘端 染色体。在人类中，这些重复序列的长度几乎是恒定的 生殖细胞和酵母，可能是通过调节 通过端粒酶延长和缩短的过程，这是由于 不完全复制或核酸酶作用。这两个过程是怎样的 调节以提供恒定的端粒长度是未知的。在人类中 体细胞，TTAGGG束的长度随着细胞分裂而减少， 当端粒变得太短时，会导致细胞衰老。多么 端粒长度信息被传输到细胞周期机器 是未知的。我们的长期目标是使用酵母作为模型系统来 了解这些流程。酵母菌通过计数测量端粒长度 主要端粒结合蛋白Rap1p的分子数； 然而，Rap1p分子是如何计算的还不清楚。我们开发了一种 基于我们构建的端粒长度调节的工作模型 酵母合成端粒和我们的工作与端粒长度 调整器，TEL2。我们认为酵母端粒形成一个折叠的 带有Rap1p和2个调节蛋白Rif1p和Rif2p的结构，TO 计算Rap1p分子数并阻止延伸。短的端粒也有 形成这种结构的Rap1p分子很少，所以它们被拉长了。 结构形成可能与端粒特异的Rap1p相连 我们检测到的修改。TEL2蛋白对酵母的调控作用 体内端粒长度，体外与端粒TG1-3结合。TEL2是 在与TEL1相同的遗传途径中，TEL1是哺乳动物激酶的同源物 DNA-PKcs与酵母细胞DNA损伤检查点调节因子 循环，Mec1。缺乏TEL2的细胞的形态表明它们阻止了 在细胞周期的特定阶段。因此，TEL2可用于 以某种方式将端粒与细胞周期控制联系起来。我们的具体目标是 验证我们的假设，即1)端粒长度是通过形成 我们提出的折叠结构；2)端粒特异性修饰 Rap1p参与端粒长度控制；3)Tel2p与 体内的端粒，并将端粒与细胞周期机制联系起来。我们的 这些结果将为细胞如何测量端粒长度提供一个模型。

Telomeres are the nucleoprotein required for the stability and complete replication of chromosome ends. Telomere DNA consists of tandem arrays of TG-rich sequences: 10-20 kb of TTAGGG in humans and 250-400 bp of TG1-3 in budding yeast, where the TG-rich strand forms the 3' end of the chromosome. The length of these repeats is nearly constant in human germ cells and yeast, and is probably maintained by regulating the processes of lengthening, via telomerase, and shortening, due to incomplete replication or nuclease action. How these two processes are regulated to give a constant telomere length is unknown. In human somatic cells, the length of the TTAGGG tract decreases as cells divide, leading to cell senescence when telomeres become too short. How telomere length information is transmitted to the cell cycle machinery is unknown. Our long term goal is to use yeast as a model system to understand these processes. Yeast measure telomere length by counting the number of molecules of the major telomere binding protein Rap1p; however, how Rap1p molecules are counted is unknown. We developed a working model for telomere length regulation based on our construction of yeast synthetic telomeres and on our work with a telomere length regulator, TEL2. We propose that yeast telomeres form a folded structure with Rap1p and 2 regulatory proteins, Rif1p and Rif2p, to count Rap1p molecules and block elongation. Short telomeres have too few Rap1p molecules to form this structure, so they are elongated. Structure formation may be linked to a telomere-specific Rap1p modification that we have detected. TEL2 protein regulates yeast telomere length in vivo and binds to telomeric TG1-3 in vitro. TEL2 is in the same genetic pathway as TEL1, a homolog of the mammalian kinase DNA-PKcs and the yeast DNA damage checkpoint regulator of the cell cycle, MEC1. The morphology of cells lacking TEL2 suggests they arrest in a specific phase of the cell cycle. Thus, TEL2 may function to somehow link telomeres to cell cycle control. Our specific aims are to test our hypotheses that 1) telomere length is regulated by forming the folded structure we propose; 2) the telomere-specific modification of Rap1p is involved in telomere length control; and 3) Tel2p binds to telomeres in vivo and links telomeres to the cell cycle machinery. Our results will provide a model for how cells measure telomere length.