1. The first project addresses how DSBs are sensed and repaired. Although many of the proteins involved in DSB repair are known, how they actually work is unclear. Initially this project will focus on how the repair mechanisms are coordinated with signaling. It will then be extended to understanding how multiple proteins determine DSB repair pathway choice. Overall, this project will establish the basic mechanisms of DSB sensing, signaling, and repair.
2. The second project will determine how telomeres are protected from DSB repair machinery. Telomeres shorten with each cell division they reach a critically short length that can no longer repress the DSB repair proteins. How critically short telomeres fail to suppress DSB repair mechanisms will inform on how normal-length telomeres suppress these responses and also provide interesting insights into aging processes.
3. The third project will examine how cancer cells achieve replicative immortality. Many cancers maintain their telomeres through telomerase, but a subset (10-15%) use an alternative mechanism of lengthening called ALT. Many DSB repair mechanisms factor into ALT at telomeres, but how this process actually works remains unknown. We will test the role of several critical factors in ALT to understand their functions in this pathway and gain an overall sense of how it works.
Mechanisms of DNA double-strand break repair and telomere maintenance
DNA double-strand breaks (DSBs) are the most deleterious of DNA lesions and must be timely and accurately repaired to prevent genome instability. Telomeres, the ends of our linear chromosomes, resemble DSBs and must be protected from improper DNA damage signaling and repair. Telomeres also shorten with every cell division, which provides a tumor suppressor function, but critically short telomeres activate senescence and aging phenotypes. How DSBs are recognized and repaired but telomeres are protected from an improper DNA damage response is a major question in both cancer and aging biology. My laboratory combines cell biology, biochemistry, and single-molecule microscopy to answer these fundamental questions in order to understand the growth of cancer cells and develop new therapeutic avenues for targeting tumors.