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Chromosomal Instability Mediated by Telomere Insufficiency

端粒不足介导的染色体不稳定性

基本信息

批准号：
12213043
负责人：
ISHIKAWA Fuyuki
金额：
$ 169.79万
依托单位：
Kyoto University (2002-2004)Tokyo Institute of Technology (2000-2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

All eukaryotes maintain nuclear genetic materials as linear DNAs. The end of DNAs is called the telomere, and is essential for the stability of chromosomes. When telomere functions are lost, the chromosomes undergo the end-to-end fusion, producing aberrant chromosomes and cell death. We previously have reported that telomere dysfunction can be bypassed by self-circularizing the chromosome in fission yeast. In this study, we isolated novel fission yeast telomere components, spRapl and spRif1. We furthermore demonstrated that part of telomeric functions can be maintained epigenetically in the absence of telomeric repeats. Thus, the telomere function may be maintained robustly when telomere DNA is transiently lost. When the telomeric DNA is critically shortened, normal mammalian cells exhibit a state called cellular senescence, where the cells irreversibly stop growing. We found that the stress-induced MAPK p38 plays an important role in this process. When p38 is activated, the cells induce cell cycle arrest in an Rb-dependent manner, and exhibit morphological changes in an Rb-independent manner, suggesting that the downstream pathway of p38 bifurcates. Using the SV40 DNA replication system in vitro, we found that telomeric DNA and chromatin are not good substrates for DNA replication. Accordingly, it is expected that there is a mechanism facilitating the telomeric replication in vivo. We found that telomeric chromatin is dynamically changed in Xenopus egg extracts. Together, all of these observations suggest that the telomere is one of the loci that are particularly vulnerable to chromatin stress, and contribute to the chromosomal instability in cancer cells

所有真核生物都以线性DNA的形式保持核遗传物质。DNA的末端被称为端粒，对染色体的稳定性至关重要。当端粒功能丧失时，染色体进行端对端融合，产生异常染色体和细胞死亡。我们以前曾报道过，端粒功能障碍可以绕过自环化的染色体在裂变酵母。在这项研究中，我们分离出新的裂变酵母端粒组件，spRap1和spRif1。我们进一步证明，部分端粒功能可以维持在端粒重复序列的情况下表观遗传。因此，当端粒DNA短暂丢失时，端粒功能可以稳健地维持。当端粒DNA严重缩短时，正常哺乳动物细胞会表现出一种称为细胞衰老的状态，其中细胞不可逆地停止生长。我们发现应激诱导的MAPK p38在此过程中起重要作用。当p38被激活时，细胞以Rb依赖的方式诱导细胞周期停滞，并以Rb非依赖的方式表现出形态学变化，表明p38的下游通路分叉。利用SV40 DNA体外复制系统，我们发现端粒DNA和染色质都不是DNA复制的良好底物。因此，预期存在促进端粒在体内复制的机制。我们发现，端粒染色质是动态变化的爪蟾卵提取物。总之，所有这些观察结果表明，端粒是特别容易受到染色质应激的位点之一，并有助于癌细胞中染色体的不稳定性