Career Goals and Development Plan: My strengths as a cancer researcher have been to approach problems from a fundamental, genetic perspective, searching for common elements and connecting them in new ways. This approach has led me to some provocative hypotheses that could have important implications for tumorigenesis in humans. My immediate career objectives are to extend the results I have already accomplished with fission yeast, and to acquire the new skills necessary to apply them in human cells. The Stanford medical school is an ideal environment in which to accomplish both these goals under the mentorship of my current supervisor, T. Wang, and in consultation with colleagues in the departments of oncology, pharmacology and biological sciences. I intend to continue forging ties with my coworkers, learning from them about the art of conducting research and managing a research laboratory, and establishing myself in the field. Following this, I plan to make the transition to an independent research career in academia, specializing in the mechanisms of cancer development. Description of Research Project: Based on work with fission yeast, I have recently hypothesized that the cell cycle checkpoint orchestrates both repair and replication mechanisms to prevent genomic instability and cell death. My objectives in this research project will be to test this hypothesis further in the context of fission yeast, and then to apply it to human cell lines. This objective will be carried out in three stages: First, establish whether the checkpoint is involved in the Rhp6 (Rad6 in budding yeast) and other repair pathways. Second, extend the study to mammalian cells, creating the required cell lines and investigating the role of checkpoint factors in the error-free repair pathway. Third, look for explicit evidence of the critical role of phosphorylation in preventing genomic instability by focusing on gross chromosomal rearrangements. Given the highly conserved nature of the checkpoint pathways in eukaryotic organisms, I expect that checkpoint, repair and replication mechanisms are tightly coordinated in human, as well as fission yeast cells. This coordination, if properly exploited, would open up significant new possibilities for the design of diagnostic and therapeutic tools in the fight against cancer. Relevance to Public Health (Lay Summary): The cell cycle checkpoint is the guardian of the genome: it senses DNA damage and stops or slows down the cell cycle to prevent runaway replication when it is inappropriate. I have discovered that the checkpoint also does something else in response to damage: it coordinates repair processes. Learning precisely how and why this repair coordination can go wrong is critical to understanding genome instability, a precursor to cancer - one of the greatest threats to public health.
|Shin, Min Hwa; Yuan, Ming; Zhang, Hao et al. (2012) ATM-dependent phosphorylation of the checkpoint clamp regulates repair pathways and maintains genomic stability. Cell Cycle 11:1796-803|