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-kinase[unreadable]related 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.