Genotoxic stresses that damage the chromosomal DNA or inhibit the progression of a DNA replication fork can lead to instability of the genetic information and hence cause cellular transformation. One key factor that both signals the presence of genotoxic stress and serves to minimize DNA damage is RPA, the eukaryotic single-stranded DNA-binding protein. A focus of our research is to understand the roles of RPA in enhancing genomic stability. A major line of investigation analyzes the functional significance of RPA phosphorylation by checkpoint (e.g., ATR, ATM) and cell-cycle (e.g., cyclin A-Cdk2) kinases under stress conditions. We have recently found that: 1) in interphase cells with DNA damage, RPA phosphorylation is required for efficient DNA repair; 2) under conditions of DNA replication stress, RPA phosphorylation by ATR stimulates repair DNA synthesis and prevents ssDNA accumulation; and 3) in cells experiencing mitotic DNA damage, mitotic RPA hyper-phosphorylation facilitates release of cells from a damaged mitosis into a 2N G1 phase, thereby increasing cell viability. Future work will pursue mechanistic understanding of these various effects. A second area of research interest is elucidating the roles of nucleolin in controlling cell cycle progression. The nucleolin protein is a key factor in ribosome biogenesis and is found over-expressed in many tumors. What is the significance of this over-expression? Recent work from my laboratory demonstrate that heightened nucleolin expression, mimicking that occurring under pathophysiological conditions, elevates the protein levels and activity of the tumor suppressor p53. These effects are caused by nucleolin binding to and inhibiting the p53-antagonist Hdm2, an E3 ubiquitin ligase, resulting in p53 stabilization. We and others have found that nucleolin physically interacts with the tumor suppressors p53 and p14ARF, as well as Hdm2. Future work will continue to investigate the synergistic interplay between nucleolin and factors in the p53 tumor suppression pathway, and how these interactions allow nucleolin to modulate the activity of p53 in the regulation of cell cycle progression and apoptosis.