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变得更短，因为细胞无法完全复制这些称为端粒的位点。过度短的端粒功能失调，导致细胞停止分裂，并在许多情况下自杀。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命运的遗传机制。特别设计的染色体被用来提供一个系统，有效地，并在命令下，导致细胞中的一个端粒的损失。大多数细胞在反应中死亡，但少数细胞逃脱并重复分裂。本提案中描述的实验将定义细胞逃避死亡的机制，为了解癌变的最早阶段提供重要见解。在生殖细胞中，端粒的丢失通常伴随着新端粒的构建。拟议的工作将定义对这种染色体愈合的遗传控制。不适当的修复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，这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.