Faithful DNA replication and repair of DNA damage are required for genome stability and contribute to the health and survival of all organisms. Checkpoint pathways modulate DNA replication during normal cell cycles and during DNA damage repair, but little is known about the genetic and molecular determinants. The genome cycle requires DNA to be organised and manipulated, during replication, mitosis and repair. Eukaryotic genomes contain six highly conserved SMC proteins forming three types of heterodimers, which are the core of distinct multiprotein complexes involved in different aspects of DNA metabolism, including chromosome condensation and sister chromatid cohesion (Nasmyth, 2001). The Smc5/6 complex has been thought to be involved in DNA repair (Lehman n et al., 1995). However, all subunits of the complex are essential even in the absence of extrinsic DNA damage, demonstrating that this complex must have additional uncharacterised roles during some aspect of DNA metabolism. Recent studies have raised the possibility that the complex is involved in replication fork biology. The proposed research plan is aimed at testing the hypothesis that the Smc5/6 complex is directly involved in the stability of replication forks during unperturbed cell cycles and in re sponse to the DNA damaging agent hydroxyurea. To this end, I have conceived a multidisciplinary research approach that combines genetics, biochemistry and cytology in S. cerevisiae to investigate the function of this protein complex at replication forks. P rocesses related to replication fork stalling or collapse are, unsurprisingly, essential for the maintenance of genomic integrity and for the prevention of tumorigenesis. The proposed research will contribute to the understanding of genome stability and th us could ultimately be exploited to treat cancer.
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