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

基本信息

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
项目类别：
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

项目摘要

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）：端粒的稳定维护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希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蛋白“庇护素”复合物（由TRF1，TRF2，RAP1，TIN2，TPP1和POT1组成），并由专用逆转录酶（称为端粒酶）扩展。庇护素复合物对于防止DNA修复蛋白融合端粒和DNA损伤检查点蛋白会导致永久性细胞周期停滞至关重要。另一方面，这些DNA损伤响应因子必须至少在端粒中瞬时访问，因为它们在端粒保护和端粒募集中都起着关键作用。因此，端粒的适当维护涉及“封闭”（受保护）和“开放”（可访问）状态之间的动态变化。但是，仍然尚不完全了解庇护素综合体的单个亚基如何受到调节，以确保端粒状态的正确过渡。此外，DNA损伤检查点蛋白的关键端粒靶标仍有待确定。因此，我们建议利用裂变酵母菌型酸糖菌POMBE作为模型系统，以研究如何通过端粒特定因素和DNA损伤响应因子之间的协作来确保端粒维持。裂变酵母应作为哺乳动物端粒维持机制的有吸引力的模型系统，因为庇护素复合物，端粒酶成分和DNA损伤反应蛋白在裂变酵母和哺乳动物之间高度保守。