----------------------------------------------------------------------- BIOINFORMATICS COLLOQUIUM College of Science George Mason University ----------------------------------------------------------------------- Exploring mechanisms of the DNA-damage response by computational study: p53 pulses and their possible relevance to apoptosis Paul Brazhnik Virginia Tech Abstract: The p53 protein is a transcription factor controlling expressions of manygenes involved in cell cycle regulation, repair of DNA damage, and programmed cell death. Activity of the p53 protein cannot be understood by study of simple genomic events, because the gene coding for the p53 protein is constitutively expressed in normal cells. Functioning of this important transcriptional regulator is tightly controlled by post-transcriptional modifications and interactions with other proteins. Recent experiments in breast cancer cells have shown that p53 protein level rises and falls in distinct pulses in response to DNA damage. The amplitudes of and intervals between pulses seem to be independent of the extent of damage, and some cells generate regular pulses of p53 over many days. Identifying molecular mechanisms responsible for generating p53 pulses and developing understanding of how these pulses can determine cell fate (stop cell cycle, initiate DNA repair or apoptosis) are important for understanding of the processes and events that lead to certain pathologies and diseases, e.g. cancer. In this presentation I will describe four pulse-generating mechanisms based on feedback loops known to be present in the p53 regulation network. Computational mathematical models of all four mechanisms are analyzed to determine if they are consistent with experimental observations and to characterize subtle differences among the possible mechanisms. In addition, a novel molecular mechanism is proposed whereby p53 pulses may induce, at first, cell cycle arrest and, if sustained, cell death. The proposal accounts for basic features of p53-mediated responses to DNA damage and suggests new experiments to probe the dynamics of p53 signaling.