Elucidating the molecular mechanisms underlying quiescence entry

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Project Summary/Abstract The decision by a cell to divide or not is a highly regulated and vitally important process in all organisms from yeast to human. Most cells remain in a reversible non-dividing state referred to as quiescence for much of their lifetime. Although some environmental signals as well as the signaling pathways and genes that respond to them to promote quiescence entry have been identified, the molecular mechanisms involved in initiating the quiescence program are not well understood. Defining these mechanisms is essential to our understanding of how the misregulation of quiescence contributes to developmental defects, premature aging, and diseases such as cancer. Yeast cells enter quiescence similar to human cells, but do so in response to nutrient limitation. The yeast quiescence program is thus easily manipulated in the laboratory. Furthermore, the signaling pathways utilized by yeast are conserved in humans, rendering yeast an excellent model organism in which to study the mechanisms of quiescence regulation. Prior studies of quiescence entry relied on information obtained from comparing quiescent cells to dividing cells, due to difficulty in identifying quiescent cells prior to their entry. Because the quiescence program is initiated long before cells actually enter, I propose to develop a method for identifying cells that are destined to become quiescent prior to the initiation of the program. By analyzing gene expression in these cells as compared to cells that will not enter quiescence, I will elucidate the molecular mechanisms involved in initiating the quiescence program. In addition to transcription, the fine tuned regulation of DNA replication in response to environmental cues is essential to the survival of all organisms. By analyzing the role of the SWI/SNF chromatin remodeling complex in regulating replication during quiescence entry, I will determine how transcription and replication are co-regulated to induce quiescence. Overall, the proposed research is expected to define the mechanisms underlying the early stages of quiescence entry, and to provide novel therapeutic targets for diseases such as cancer. !