Telomere length control by shelterin

端粒长度通过庇护蛋白控制

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7541401
• 关键词: Address; Affect; Biogenesis; Carcinoma; Cell Cycle Arrest; Cell division; Cells; Chromosomes; DNA; Data; Enzymes; Feedback; Funding; Genes; Goals; Human; Individual; Length; Malignant Neoplasms; Mediating; Molecular; Pathway interactions; Premalignant; Process; Proteins; RNA-Directed DNA Polymerase; Recruitment Activity; Regulation; Regulatory Pathway; System; Telomerase; Telomerase inhibition; Telomere Maintenance; Telomere Shortening; Therapeutic Intervention; Tumor Cell Line; Tumor Suppressor Proteins; Work; base; cancer cell; carcinogenesis; cell transformation; insight; leukemia/lymphoma; malignant phenotype; neoplastic cell; protein complex; telomere; tumor; tumorigenic

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）：人类致癌作用的关键步骤之一是端粒维护系统的激活，该系统允许持续扩散转化的细胞。原代人细胞的端粒随着每个细胞分裂而缩短，这种损耗最终诱导细胞周期停滞，从而限制了新兴的肿瘤克隆的增殖能力。已知恶性细胞可以通过激活端粒酶（RNP逆转录酶）将端粒DNA在染色体末端合成。在前一个资金期间，我们描述了癌细胞中的调节途径，该途径控制端粒酶在单个染色体末端的作用。该端粒长度调节取决于端粒特异性蛋白质复合物，庇护素，其作用在顺式中抑制端粒酶。庇护素在端粒中的积累与端粒重复阵列的长度成正比，从而导致较长的端粒抑制端粒酶。在下一个资金期间，我们将进一步定义庇护素抑制端粒酶抑制的机制（AIM 1）。 AIM 2中的工作将集中于人类肿瘤细胞系中端粒酶介导的端粒扩展的正调控。详细分析了端粒酶成分的表达和酶的生物发生，但对于如何将端粒酶募集到染色体末端，如何调节端粒剂以及是否需要其他激活步骤。我们的初步数据揭示了端粒酶介导的端粒伸长率的假定阳性调节剂，我们建议将这些途径和其他类似的途径定义。在第二个新的方向上，我们将重点关注端粒缩短的机制和调节（AIM 3），尽管它是假定的肿瘤抑制途径，但它的理解很少。人类端粒的损耗远比“最终复制问题”所预期的要快得多，但是该加速末端序列损失的过程尚不清楚。我们的初步数据表明，端粒损耗涉及富含C型端粒DNA链的庇护所调节的降解。我们建议确定负责（前）恶性细胞中端粒缩短的基因，并研究该处理步骤的调节。可以预料，对端粒长度控制的分子基础的见解将为包括白血病，淋巴瘤和大多数大多数癌的各种人类癌症提供治疗干预的机会。