Mammalian cells proliferate through a controlled sequence of events, generally referred to as the cell division cycle. Progression from one phase to the next one within one division cycie is controlled by checkpoint mechanisms, which monitor the intra- and extra-cellular conditions and block the cell cycle in the presence of faulty conditions. Possibly, the best characterised checkpoint system induces cell cycle arrest or cell death following DMA damage, therefore preventing the transmission of damaged gene tic material to daughter cells. In mammalian cells the DNA replication cycle is strictly coordinated with the duplication cycle of a cellular organelle, the centrosome: DNA and cenirosomes have to duplicate once and only once in a cell cycle and in the sam e temporal window, under the control of common regulators. The centrosome is the main microtubule (MT) organising centre, and through its ability to organize MTs. it controls essential cellular processes, i.e. mitosis., transport and positioning of vesicle s in interphase cells, cell migration, establishment of cell shape and polarity. Especially important for proper mitotic entry is a process termed centrosome maturation which occurs during the G2 phase of the cell cycle. Objective of this project is to est ablish if the DNA damage checkpoint is also effective in targeting the centrosome maturation process in order to inhibit it, as part of the mechanisms blocking mitotic entry in the presence of damaged genetic material. If so, the identification of molecul ar effectors of such a control will be undertaken. This would be a new indication of theconnection between centrosomes and cell cycle and would place them as key players in the signalling cascade which inhibits mitotic entry when conditions are not approp riate. This control is extremely important since abnormal mitosis may lead to the generation of daughter cells with unbalanced or damaged genetic material, a condition often occuring in cancer development.
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