Telomere length control by shelterin

端粒长度通过庇护蛋白控制

基本信息

批准号：
7541401
负责人：
Titia de Lange
金额：
$ 38.6万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-15 至 2012-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): One of the key steps in human carcinogenesis is the activation of a telomere maintenance system that allows the continued proliferation of transformed cells. The telomeres of primary human cells shorten with each cell division and this attrition eventually induces cell cycle arrest, thus limiting the proliferative capacity of emerging tumorigenic clones. Malignant cells are known to overcome this barrier through the activation of telomerase, the RNP reverse transcriptase that synthesizes telomeric DNA onto chromosome ends. In the preceding funding period, we have described a regulatory pathway in cancer cells that controls the action of telomerase at individual chromosome ends. This telomere length regulation depends on the telomere specific protein complex, shelterin, which acts in cis to inhibit telomerase. Shelterin's accumulation at telomeres is proportional to the length of the telomeric repeat array, resulting in a greater inhibition of telomerase at longer telomeres. In the next funding period, we will further define the mechanism of telomerase inhibition by shelterin (AIM 1). The work in AIM 2 will focus on the positive regulation of telomerase-mediated telomere extension in human tumor cell lines. Whereas the expression of telomerase components and the biogenesis of the enzyme has been analyzed in detail, little is known about how telomerase is recruited to chromosome ends, how this recruitment is regulated, and whether telomerase requires additional activation steps. Our preliminary data has revealed putative positive regulators of telomerase-mediated telomere elongation and we propose to define these pathways and others like it further. In a second new direction, we will focus on the mechanism and regulation of telomere shortening (AIM 3), which is poorly understood, despite its importance as a presumed tumor suppressor pathway. The attrition of human telomeres is much faster than expected from the `end-replication problem' but the process underlying this accelerated terminal sequence loss is not known. Our preliminary data suggests that telomere attrition involves shelterin regulated degradation of the C-rich telomeric DNA strand. We propose to identify the genes responsible for telomere shortening in (pre-) malignant cells and study the regulation of this processing step. It is anticipated that insights into the molecular basis of telomere length control will provide opportunities for therapeutic intervention in a wide variety of human cancers, including leukemias, lymphomas, and most carcinomas.

描述（由申请人提供）：人类致癌的关键步骤之一是端粒维持系统的激活，该系统允许转化细胞持续增殖。原代人类细胞的端粒随着每次细胞分裂而缩短，这种损耗最终导致细胞周期停滞，从而限制新兴致瘤克隆的增殖能力。众所周知，恶性肿瘤细胞可以通过激活端粒酶来克服这一障碍，端粒酶是一种将端粒 DNA 合成到染色体末端的 RNP 逆转录酶。在之前的资助期间，我们描述了癌细胞中控制个体染色体末端端粒酶作用的调控途径。这种端粒长度调节依赖于端粒特异性蛋白质复合物，shelterin，它以顺式作用抑制端粒酶。 Shelterin 在端粒上的积累与端粒重复序列的长度成正比，从而在较长的端粒处对端粒酶产生更大的抑制作用。在下一个资助期内，我们将进一步明确shelterin（AIM 1）抑制端粒酶的机制。 AIM 2 的工作重点是人类肿瘤细胞系中端粒酶介导的端粒延伸的正向调节。虽然端粒酶成分的表达和酶的生物发生已被详细分析，但人们对端粒酶如何被募集到染色体末端、如何调节这种募集以及端粒酶是否需要额外的激活步骤知之甚少。我们的初步数据揭示了端粒酶介导的端粒延长的假定正调节因子，我们建议进一步定义这些途径和其他类似途径。在第二个新方向中，我们将重点关注端粒缩短（AIM 3）的机制和调节，尽管它作为假定的肿瘤抑制途径很重要，但人们对其知之甚少。人类端粒的磨损比“末端复制问题”预期的要快得多，但这种加速的末端序列丢失背后的过程尚不清楚。我们的初步数据表明，端粒磨损涉及到富含 C 的端粒 DNA 链的庇护蛋白调节的降解。我们建议鉴定（前）恶性细胞中负责端粒缩短的基因，并研究该处理步骤的调节。预计对端粒长度控制的分子基础的深入了解将为多种人类癌症（包括白血病、淋巴瘤和大多数癌症）的治疗干预提供机会。