STRUCTURAL STUDIES OF DNA REPAIR PROTEINS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Tel 2是一种非常保守的蛋白质，对酵母的生存力至关重要。确定Tel 2的确切作用已经复杂化了，因为它在各种生物体中报告了许多明显不重叠的功能。除了维持S.在酿酒酵母中，它在裂殖酵母裂殖酵母和人类中的DNA复制检查点中起作用，将细胞分裂的开始与DNA的成功复制偶联。然而，在线虫秀丽隐杆线虫中，与野生型等位基因相比，TEL 2/rad-5（C.线虫（线虫）不仅可以在DNA复制过程中引起应激和对DNA双链断裂的超敏反应，而且可以延长寿命并降低许多生理过程的速率，包括胚胎和胚后发育以及繁殖。通过对Tel 2缺失小鼠细胞表型的系统分析和生物化学蛋白质相互作用研究，确定了Tel 2直接与哺乳动物磷脂酰肌醇3-激酶的所有六种相互作用相关蛋白激酶（PIKK）。TEL 2的缺乏显著降低了小鼠细胞中所有PIKK的表达水平，影响了它们的功能。由于最近在裂殖酵母中也观察到Tel 2和PIKK之间的直接物理关联，因此Tel 2作为这些激酶的稳定剂的功能也可能是保守的。这些结果为哺乳动物Tel 2及其直系同源物的所有已报道的功能提供了一个统一的模型。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tel2 is a well-conserved protein that is essential for yeast viability. Determining the precise role of Tel2 has been complicated by its many apparently nonoverlapping functions reported in various organisms. In addition to maintaining telomere length in S. cerevisiae, it functions in the DNA replication checkpoint in the fission yeast Schizosaccharomyces pombe and in humans, coupling the onset of cell division with the successful replication of DNA. In the nematode Caenorhabditis elegans, however, hypomorphic alleles (forms of agene in which the encoded protein has reduced function compared with the wild type allele) of clk-2/rad-5 (the TEL2 ortholog in C. elegans) not only can cause stress during DNA replication and hypersensitivity to DNA double-strand breaks, but also can increase life span and reduce the rate of numerous physiological processes, including embryonic and postembryonic development, and reproduction. Through systematic analysis of the phenotype of Tel2-null mouse cells and biochemical protein interaction studies, it was determined that TEL2 directly interacts with all six of the mammalian phosphatidylinositol3-kinaserelated protein kinases (PIKKs). Absence of TEL2 substantially reduced the expression level of all PIKKs in mouse cells, impinging on their function. Because a direct physical association between Tel2 and PIKKs was also recently observed in fission yeast, the function of Tel2 as a stabilizer of these kinases may also be conserved. These results provide a unifying model for all the reported functions of mammalian Tel2 and its orthologs.