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Control of structure specific endonucleases and implications in the biology of cancer


Structure-specific endonucleases are key players in the maintenance of genome integrity. They act as specialized surgical tools for the processing of secondary DNA structures generated during important DNA repair and recombination events. However, cleaving DNA opens windows of opportunity for the occurrence of potentially dangerous chromosome rearrangements at the origin of cancer.

The action of structure-specific endonucleases must therefore be tightly coordinated with downstream events that restore the full integrity of the chromosome. Additional challenge for the cell stems from the fact that for many of these nucleases the minimal structural requirement for cleaving DNA is a junction between double-strand and single-strand DNA.

Therefore, in addition to controlling these enzymes in the context of their physiological reaction, the cell must ensure that they do not act randomly on structures generated during other DNA transactions associated with DNA unwinding. Despite their fundamental nature, the mechanisms that control structure-specific endonucleases remain poorly understood.

This research project proposes to tackle this fundamental question by focusing on a conserved class of eukaryote heteromeric structure-specific endonucleases, each involved in sever al DNA repair and recombination pathways. A detailed analysis of the regulation of these endonucleases will be carried out throughout the cell-cycle and in response to genotoxic stresses in the fission yeast Schizosaccharomyces pombe; a proven model system for the analysis and understanding of evolutionary conserved processes involved in genome maintenance in higher eukaryotes.

The remarkable investigational potential of S. pombe will allow to combine genetic and cellular analysis with proteomic and biochemical studies. Results from our investigations in yeast will provide a platform to extend our analyses to mammalian cells, with a constant focus on assessing their relevance in the context of cancer biology.

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