Final Report Summary - AAMDDR (DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex)
DNA is continuously subjected to exogenous and endogenous damaging insults. DNA damage must be detected in order to prevent loss of vital genetic information. Cells respond to DNA damage by activating checkpoint pathways that delay progression through the cell cycle. Activation of DNA damage checkpoints can induce cell cycle transient delay, trigger irreversible arrest such as senescence, promote DNA repair or induce cell death. Failure to monitor and to signal DNA damage lead to genome instability, the hallmark of cancer cells. We have explored biochemical mechanisms underlying the maintenance of genome stability in higher eukaryotes. We have clarified the mechanism of activation of cellular DNA damage response in the presence of chromosome breaks. We have identified novel mechanisms involved in the repair and in the processing of chromosome breaks. We have provided evidence that DNA damage response controls nucleotide metabolism. We have identified GEMC1, novel factor involved in the initiation of DNA replication in vertebrate cells. Finally, we have identified CEP63 as new vertebrate target of ATM and ATR. We have studied the function of these new genes and discovered that they play an essential role in the context of normal cell cycle and in the presence of DNA damage. In particular we have shown that CEP63 is required for centrosome-mediated spindle assembly, the apparatus responsible for cell division. Importantly, these genes are exclusively present in vertebrate genomes and represent ideal targets for the DNA damage response mediated regulation of cell cycle progression in complex organisms.