Genome duplication is central to cell division. Conversely, terminal differentiation of mammalian cells is normally associated to non-proliferation and DMA replication quiescence. Although both DNA replication and cell differentiation have been widely in vestigated, still poorly understood are the signal mechanisms and regulatory targets that couple and mutually regulate the two processes. The aim of my project is to characterize the features that lead to replication blockage in cells induced to termina l differentiation. The experiments will be carried out in a model of neuroblastoma cells engineered to express the estrogen receptor (ERa). Previous studies have demonstrated that upon addition of 17p-estradiol (E2), these cells undergo growth arrest and differentiation. The timing and the number of cell cycles necessary to convert the neuroblastoma from proliferation to differentiation have been well described as well as several effects underlying the hormonal effects. Thus the model provides a unique opportunity to pursue the research interest above presented. My work will be organized as follows: 1. Analysis of the elements and the mechanisms leading to replicative quiescence in differentiated cells. This line will concern the regulatory path to d ifferentiation, focusing on specific transcription and replication factors. 2. Analysis of replication dynamics in differentiating cells. DNA replication seems to be developmental^ regulated. Shift from proliferation to terminal differentiatio n requires few rounds of DNA replication. This research line will shed light on dynamics of origin usage and replication fork progression during this process.
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