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不期望的突变的积累至关重要。在哺乳动物细胞中，富含GT的端粒重复序列被六蛋白“shelterin”复合物（由TRF1、TRF2、RAP 1、TIN 2、TPP 1和POT1组成）结合，并被称为端粒酶的专门逆转录酶延伸。shelterin复合物对于防止DNA修复蛋白融合端粒和DNA损伤检查点蛋白引起永久性细胞周期停滞至关重要。另一方面，这些DNA损伤反应因子必须至少暂时进入端粒，因为它们在端粒保护和端粒酶募集中起关键作用。因此，端粒的正确维护涉及“封闭”（受保护）和“开放”（可访问）状态之间的动态变化。然而，它仍然没有完全理解如何个别亚基的shelterin复合物进行调节，以确保适当的端粒状态的过渡。此外，DNA损伤检查点蛋白的关键端粒靶标仍有待建立。因此，我们建议利用裂殖酵母粟酒裂殖酵母作为一个模型系统，研究如何确保端粒的维护端粒特异性因子和DNA损伤反应因子之间的合作。由于shelterin复合物、端粒酶组分和DNA损伤反应蛋白在裂殖酵母和哺乳动物之间高度保守，因此裂殖酵母应该作为哺乳动物端粒维持机制的有吸引力的模型系统。

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.