Role of CDK9 in the Replication Stress Response

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DESCRIPTION (provided by applicant): The candidate is a radiation oncologist with the career objective of becoming an independent, self- funded, and productive academic physician-scientist, dedicated to unlocking the secrets of cancer biology and bridging the gap between its elucidation and improvement in clinical care. His specific research interest is in discovering the basic biological processes that govern genome integrity. His training goals during the mentored K08 award period are to acquire the foundation of knowledge and practical research skills necessary to initiate an independent research program investigating the Replication Stress Response. He will acquire a foundation of knowledge in checkpoint signaling to complement his prior training in DNA replication and DNA repair and expand his technical background with training in genetic and biochemical methodologies to complement his prior training in molecular biology and cell biology under a 5-year mentored training program using the outstanding resources and nurturing environment of Vanderbilt University Medical Center. The Replication Stress Response (RSR) is a subset of the DNA Damage Response that recognizes challenges to DNA replication and mobilizes cellular activities that lead to cell cycle arrest, DNA repair, or apoptosis. Mutations in the RSR promote the survival and proliferation of genetically unstable cells eventually leading to cancer. Thus the RSR acts as a cancer barrier. The candidate has completed a novel loss of function genetic screen using RNA interference in human cells to identify 14 high-confidence RSR genes, including the novel RSR gene, cyclin-dependent kinase 9 (CDK9). His preliminary studies show that CDK9 interacts in a complex or complexes with ATR/ATR interacting protein (ATRIP) as well as with other RSR proteins and localizes to ATRIP-containing foci. Moreover, his preliminary data indicate that the kinase activity of CDK9 is essential for recovery from replication arrest. Based on these data, he hypothesizes that CDK9 maintains genome integrity by participating in an ATR-mediated replication stress response through phosphorylation of key substrates. To test his hypothesis, he proposes the following specific aims: (1) Determine the regulation and functional significance of the interaction of CDK9 with ATR. (2) Identify substrates of CDK9. (3) Determine how the activity of CDK9 is regulated. These aims will be completed by a combination of genetic and biochemical approaches to provide a mechanistic understanding of CDK9 function. Completion of these aims will provide new insights into the how the RSR maintains genome integrity and prevents cancer. Moreover, this research has significant clinical application for developing innovative ways for diagnosing and treating cancer. PUBLIC HEALTH RELEVANCE: This proposal will be completed by a combination of genetic and biochemical approaches to provide a mechanistic understanding of CDK9 function in the RSR. Completion of these aims will provide new insights into how the RSR maintains genome integrity and prevents cancer. Moreover, this research has significant clinical application for developing innovative ways for diagnosing and treating cancer.