REGULATION OF TELOMERE LENGTH

端粒是核蛋白所需的稳定性和完整的 染色体末端的复制。 端粒DNA由串联阵列组成 富含TG的序列：人类中10-20 kb的TTAGGG和250-400 bp的 芽殖酵母中的TG 1 -3，其中富含TG的链形成了芽殖酵母的3'末端。 染色体 这些重复序列的长度在人类中几乎是恒定的 生殖细胞和酵母，并可能通过调节 通过端粒酶延长和缩短的过程， 不完全复制或核酸酶作用。 这两个过程是如何 调节以给出恒定的端粒长度是未知的。 人 在体细胞中，TTAGGG束的长度随着细胞分裂而减小， 当端粒变得太短时导致细胞衰老。 如何 端粒长度信息被传递到细胞周期机制 不明 我们的长期目标是使用酵母作为模型系统， 了解这些过程。酵母通过计数测量端粒长度 主要端粒结合蛋白Rap 1 p的分子数量; 然而，Rap 1 p分子如何计数是未知的。 我们开发了一个 基于我们构建的端粒长度调控工作模型 酵母合成端粒和我们的端粒长度研究 调节器，TEL 2。 我们认为酵母端粒形成一个折叠的 与Rap 1 p和2个调节蛋白Rif 1 p和Rif 2 p结构， 计数Rap 1 p分子并阻断延伸。 短端粒也有 很少的Rap 1 p分子形成这种结构，所以它们是细长的。 结构形成可能与端粒特异性Rap 1 p有关 我们发现的变化。TEL 2蛋白调节酵母 端粒长度在体内，并结合到端粒TG 1 -3在体外。 TEL 2是 与哺乳动物激酶的同源物TEL 1在相同的遗传途径中 DNA-PKcs与酵母细胞DNA损伤检查点调节因子 循环，MEC 1。 缺乏TEL 2的细胞的形态表明它们在细胞周期中 在细胞周期的特定阶段。 因此，TEL 2可以用于 将端粒与细胞周期控制联系起来我们的具体目标是 测试我们的假设，1）端粒长度是通过形成 折叠结构，我们提出; 2）端粒特异性修饰的 Rap 1 p参与端粒长度控制; 3）Tel 2 p结合 端粒在体内和连接端粒的细胞周期机制。 我们 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.