Our goal is to contribute a better understanding of the mechanisms that control the cell-cycle and ensure the faithful transmission of the genetic material, and how these mechanisms are deregulated in the development and progression of cancer. We propose to identify, by biochemical and genetical means, the elements involved in crucial control pathways that preserve chromosome integrity, preventing the generation of mutations, genomic instability and aneuploidy, key conditions for malignant transformation. Thus, our first objective is to study how the mechanisms that control cell-cycle regulate the activation of origins of replication in the human chromosomes, and how these mechanisms are regulated in cancer cells. This work may unveil new factors involved in de-regulated AND replication modes characteristic of cancer cells, e.g. the amplification of genes such as c-myc, c-erbB2 or MDR1, that contribute to the progression of different tumors. Our second objective is to study the way how the checkpoint mechanism responsible for the surveillance of DNA damage and replicative stress operates, identifying novel elements involved in the pathways that mediate its response. Starting from our interest in the pathway that blocks the activation of origins of replication, we propose an experimental strategy that will extend our focus to the global response elicited by the checkpoint. Finally we will analyze the potential of the factors identified along the project as targets for the development of new therapeutic strategies against tumor cell proliferation.
|Effective start/end date||1/12/03 → 30/11/06|
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