Elucidating the Role of Protein Lysine Acetylation in Regulating DNA Replication

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The ability of cells to duplicate DNA with high accuracy is a hallmark of genome stability. This research project addresses fundamental questions about DNA replication by investigating how protein machinery at the DNA replication fork is regulated by post-translational chemical modifications in order to optimize fidelity. The project will also provide research training opportunities for graduate and undergraduate students, and broaden STEM participation through a structured program developed to recruit and mentor veteran undergraduate students in scientific research.This project addresses the hypothesis that lysine acetylation of lagging strand DNA replication proteins may function as a regulatory switch that dictates the choice of the Okazaki fragment processing (OFP) pathway. This pathway choice mechanism may allow the cell to balance replication fidelity and efficiency by triggering protein acetylation during replication of specific regions in the genome to ensure high-fidelity DNA synthesis. Experiments in the first aim will investigate how cellular perturbations influence lysine acetylation of OFP proteins, define the sites of modification, and identify the protein modifiers involved. The second aim will apply biochemical approaches to assess changes in individual protein activities following lysine acetylation and evaluate how these changes influence the entire lagging strand maturation pathway. The results will provide new insights into why cells may choose this regulatory mechanism during DNA replication, and have broad implications for understanding how organisms maintain genome stability and cellular health.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.