See instaicKons);
We aim to understand how telomeres solve the end-protection problem. Specifically, this proposal describesexperiments to gain insight Into the mechanism by which the telomeric protein complex, shelterin, repressesthe two main DNA repair reactions, NHEJ and HDR at chromosome ends.
Our aim I s to delineate the natureof the repair reactions at telomeres, their outcomes, what factors are involved, how these pathways areregulated, and how telomeres prevent inappropriate pnscessing by repair pathways.Telomere dysfunction is thought to be main source of genome instability in human cancer, has beenimplicated in aging, and is at the core of several human diseases that are caused by loss of telomeric DNA(e.g. dyskeratosis congenita, anaplastic anemia). When telomeres become dysfunctional, inappropriaterepair at chromosome ends is a major determinant of the pathological outcomes. Detailed understanding ofthe repair pathways at dysfunctional telomeres is therefore expected to impact the treatment and preventionhuman disease.We will use genetic, molecular genetic, and cell biological techniques to address the mechanism by whichtelomeres repress inappropriate repair and define the pathological repair reactions at dysfunctionaltelomeres. The experimental approaches will involve the tools for studying mammalian telomeres that wehave developed under the auspices of this grant over the past 16 years. Specifically, we will use mouseembryo fibroblast cell lines from which shelterin components can be deleted with the Cre recombinase. Bychanging the genetic background of these cells, using compound genotypes, we can monitor the repair atdysfuncUonanl telomere, delineate the genes involved In the reactions, and define how shelterin repressesthese reactions at functional telomeres.
;A growing number of human disease states are now understood to involve a failure in the function oftelomeres, the protective elements at the ends of human chromosomes. This project is aimed at gainingInsight into how telomeres protect chromosome ends and what happens when this protection is lost. Thework is expected to be significant in the context of cancer, aging, and telomere-related diseases such asdyskeratosis congetica.
Showing the most recent 10 out of 33 publications
