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

检查点和 DNA 修复蛋白在裂殖酵母端粒维护中的作用

• 批准号: 8511693
• 负责人: Toru Nakamura
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511693
• 关键词: Affect; Aging; Amino Acids; Binding; Biological Models; Cell Cycle Arrest; Cell Proliferation; Cells; Chromosomes; Collaborations; Complex; DNA Damage; DNA damage checkpoint; DNA repair protein; Disease; Ensure; Event; Excision; Fission Yeast; Functional disorder; Funding; Future; Genes; Genomics; Goals; Homeostasis; Homologous Gene; Human; Individual; Inherited; Investigation; Knowledge; Lead; Length; Maintenance; Mammalian Cell; Mammals; Mediating; Modeling; Molecular; Mutagenesis; Mutation; Organism; Orthologous Gene; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Proteins; RNA-Directed DNA Polymerase; Regulation; Research; Role; S Phase; Series; Structure; TERF1 gene; TINF2 gene; Telomerase; Telomerase Inhibitor; Telomere Maintenance; Testing; Tissues; Work; age related; effective therapy; human disease; insight; prevent; research study; response; sensor; telomerase reverse transcriptase; telomere; treatment strategy; tumor

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.

描述(申请人提供)：保持端粒的稳定对于保持基因组的完整性和防止可能导致各种人类疾病的有害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6种蛋白质组成的复合体(由TRF1、TRF2、RAP1、TIN2、TPP1和POT1组成)结合，并由被称为端粒酶的特殊逆转录酶延伸。Shelterin复合体对于防止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停滞至关重要。另一方面，这些DNA损伤反应因子必须至少获得与端粒的瞬时接触，因为它们在端粒保护和端粒酶募集中都发挥着关键作用。因此，端粒的适当维护涉及“关闭”(受保护)和“打开”(可访问)状态之间的动态变化。然而，人们仍然不完全清楚如何调节掩蔽素复合体的各个亚基，以确保端粒状态的适当转变。此外，DNA损伤检查点蛋白的关键端粒靶点(S)仍有待建立。因此，我们建议利用裂解酵母作为一个模型系统来研究端粒特异性因子和DNA损伤反应因子之间的协同作用如何确保端粒的维持。由于分裂酵母和哺乳动物之间的保护素复合体、端粒酶成分和DNA损伤反应蛋白高度保守，因此分裂酵母可以作为哺乳动物端粒维持机制的一个有吸引力的模型系统。