The DNA of multicellular organisms is packaged into linear chromosomes. The goal of this project is to understand how cells deal with DNA breaks, specifically how breaks near the ends of linear chromosomes are treated differently from breaks in other locations. The outcomes will help clarify why breaks near the ends of chromosomes do not trigger a DNA damage response while those at other locations do, and how this differential treatment maintains genome integrity. The project will offer research training and career development opportunities for graduate and undergraduate students, and a post-doctoral scientist, particularly aimed at increasing diversity in the STEM workforce. Results from the project will also be integrated into coursework in order to teach students current concepts of genomic stability.
A fundamental question in the field of chromosome biology is why telomeres, the ends of linear eukaryotic chromosomes, are stable while internal double-strand breaks are not. DNA double-strand breaks promote genomic instability by DNA recombination and cause growth arrest by activating cell cycle checkpoints, but telomeres are stable and allow continuous cell growth. Telomeres are composed of DNA repeat tracts bound by specific proteins that "cap" the chromosome end to prevent its degradation and block checkpoint activation. This project will investigate how telomeres accomplish these functions by using an inducible telomere formation system that leverages powerful molecular genetics tools in the Schizosaccharomyces pombe model system. The specific hypothesis to be tested is whether S. pombe telomeres recruit effectors that post-translationally modify checkpoint proteins to block DNA damage signaling. Known candidate proteins will be tested and new candidate proteins will be sought by proteomic approaches in a comprehensive approach to identify the effectors of DNA damage checkpoint suppression at telomeres. The project will offer research training for graduate and undergraduate students, and a post-doctoral scientist, and project outcomes will be integrated into coursework.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
