Responses to Telomere Loss

描述(由申请人提供)： 在体内细胞的生长和分裂过程中，染色体末端的DNA会变短，这是因为细胞无法完全复制这些位置，这就是所谓的端粒。过短的端粒会导致细胞功能失调，导致细胞停止分裂，在许多情况下会导致自杀。因此，端粒缩短提供了一个“计时器”，限制了体内大多数细胞的生长潜力。细胞如何逃脱这一限制是理解癌症起源的一个关键问题。这里提出的工作使用果蝇作为模型系统，以确定引导细胞自杀或允许它们逃脱这种命运的遗传机制。特殊设计的染色体被用来提供一种系统，该系统在命令下有效地导致细胞中的一个端粒丢失。大多数细胞会因此而死亡，但也有少数细胞逃逸并反复分裂。这项提案中描述的实验将定义细胞用来逃避死亡的机制，为癌症发生的早期阶段提供重要的洞察力。在生殖细胞中，端粒的丢失通常伴随着新的端粒的构建。这项拟议的工作将定义对染色体修复的基因控制。不适当修复的染色体与许多人类疾病有关。此外，愈合是癌细胞的一个共同特征，进一步增加了与人类健康的相关性。

DESCRIPTION (provided by applicant): During growth and division of cells in the body, the DNA at the ends of chromosomes becomes shorter owing to an inability of cells to fully replicate these sites, which are called telomeres. Excessively short telomeres are dysfunctional and cause cells to stop dividing, and in many cases commit suicide. Thus, telomere shortening provides a "timer" that limits the growth potential of most cells in the body. How cells escape this limit is a critical question for understanding the genesis of cancer. The work proposed here uses the fruitfly, Drosophila melanogaster, as a model system to identify the genetic mechanisms either guide cells to suicide, or allow them to escape that fate. Specially engineered chromosomes are used to provide a system that efficiently, and on command, causes loss of one telomere in a cell. Most cells die in response, but a few cells escape and divide repeatedly. The experiments described in this proposal will define the mechanisms that cells use to escape death, providing important insight into the earliest stages of carcinogenesis. In reproductive cells, the loss of a telomere is often followed by construction of a new telomere. The proposed work will define the genetic control over this chromosome healing. Inappropriately healed chromosomes are associated with a number of human disorders. Moreover, healing is a common feature of cancer cells, adding further relevance to human health.