Roles of Checkpoint and DNA Repair Proteins in Fission Yeast Telomere Maintenance

描述（由申请人提供）：端粒的稳定维持对于保持基因组完整性和防止可能导致各种人类疾病的非期望突变的积累至关重要。在哺乳动物细胞中，富含gt的端粒重复序列由六蛋白“庇护蛋白”复合体（由TRF1、TRF2、RAP1、TIN2、TPP1和POT1组成）结合，并通过被称为端粒酶的特殊逆转录酶进行延伸。保护蛋白复合物对于防止DNA修复蛋白融合端粒和DNA损伤检查点蛋白导致永久性细胞周期阻滞至关重要。另一方面，这些DNA损伤反应因子必须至少短暂进入端粒，因为它们在端粒保护和端粒酶募集中都起着关键作用。因此，端粒的适当维护涉及到“封闭”（受保护）和“开放”（可访问）状态之间的动态变化。然而，目前还不完全清楚庇护蛋白复合体的单个亚基是如何被调节以确保端粒状态的适当过渡的。此外，DNA损伤检查点蛋白的关键端粒靶点仍有待建立。因此，我们建议利用分裂酵母Schizosaccharomyces pombe作为模型系统来研究端粒特异性因子和DNA损伤反应因子如何协同确保端粒维持。裂变酵母作为研究哺乳动物端粒维持机制的一个有吸引力的模型系统，其庇护蛋白复合物、端粒酶组分和DNA损伤反应蛋白在裂变酵母和哺乳动物之间高度保守。

DESCRIPTION (provided by applicant): Stable maintenance of telomeres is critical to preserve genomic integrity and prevent accumulation of undesired mutations that might lead to various human diseases. In mammalian cells, GT-rich telomeric repeats are bound by the six-protein "shelterin" complex (composed of TRF1, TRF2, RAP1, TIN2, TPP1 and POT1) and extended by the specialized reverse transcriptase known as telomerase. The shelterin complex is essential to prevent DNA repair proteins from fusing telomeres and DNA damage checkpoint proteins from causing permanent cell cycle arrest. On the other hand, these DNA damage response factors must gain at least transient access to telomeres, since they play critical roles in both telomere protection and telomerase recruitment. Thus, the proper maintenance of telomeres involves dynamic changes between "closed" (protected) and "open" (accessible) states. However, it is still not fully understood how individual subunits of the shelterin complex are regulated to ensure proper transition of the telomere status. In addition, the critical telomere target(s) for DNA damage checkpoint proteins remain to be established. Therefore, we propose to utilize fission yeast Schizosaccharomyces pombe as a model system to investigate how telomere maintenance is ensured by collaboration among telomere specific factors and DNA damage response factors. Fission yeast should serve as an attractive model system for mammalian telomere maintenance mechanism, since the shelterin complex, telomerase components, and DNA damage response proteins are highly conserved between fission yeast and mammals.