Mechanisms of chromsome end protection

The proper replication of chromosome ends and their protection from DNA repair activities is essential for genome stability and long-term cell survival. The formation of an aberrant chromosome end capping structure can induce cell cycle arrest, cellular senescence and apoptosis. Telomere metabolism, thus, has important implications for human cancer and aging, and hence, understanding the molecular mechanisms that govern the processes leading to the formation of chromosome end structure is a fundamental question in cell biology. Although the major function of telomeres is to avoid the DNA damage response, recent data indicate that a limited processing of chromosome termini by the DNA repair machinery is an essential part of telomere metabolism. For example, proteins involved in homologous recombination (HR) are expected to contribute to the formation of the t- loop, which appears to be the key structural element of telomeres in the majority of eukaryotes. Here, I propose to use Arabidopsis thaliana to study the role of the evolutionary conserved Ku70/Ku80 DNA repair complex in telomere metabolism. In the first part of the proposal, we focus on deciphering the molecular mechanism that underlies the telomeric function of the Ku70/Ku80 heterodimer. This non-homologous end joining (NHEJ) complex associates with telomeres in the majority of eukaryotes, but its exact role at chromosome termini is, to a large extent, unknown. The second part of the project aims at the discovery of novel genes involved in protecting chromosome ends from aberrant DNA repair activities. I propose a forward genetic screen to identify novel factors that suppress chromosome end-to-end fusions and intrachromatid recombination at telomeres. Because telomeres are evolutionary highly conserved, the data obtained from the proposed project will be of great relevance to other organisms, including humans.