The importance of the mitotic spindle integrity in DNA repair

Resumen del trabajo presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.Maintenance of genome integrity is a vital aspect of our cellular physiology. Our hereditary information encoded in the DNA is constantly threatened by both endogenous and environmental genotoxic stresses that could alter our genomic material. To combat this threat, eukaryotic cells have evolved a series of mechanisms, collectively known as DDR, to survey several features of the cellular response, including the detection of the lesion, a transient cell cycle arrest and the repair of the broken DNA. During the last years it has becoming clearer the biochemical mechanisms operating at each stage of the DDR. However, little is known about the spatial regulation of their components during the DNA damage response and how the relocation of the DNA lesion itself can influence in the repair process. Interestingly, previous studies have indicated that DNA breaks are re-localized from the nucleoplasm to the nuclear periphery, suggesting that nuclear compartmentalization of DNA lesions could comprise another layer in the regulation of the DNA repair pathway. Nevertheless, whether the nuclear periphery harbours an environment that is permissive for DNA repair and its implications in maintaining genome integrity is a subject that still under debate. Remarkably, new data coming from our group indicate that the cell cycle phosphatase Cdc14 is involved in DNA repair by controlling the tethering of a DNA lesion into the spindle pole body (SPB) region of the nuclear envelope. This function is attained by preserving the integrity of the metaphase spindle, a vital requirement to stimulate DSB-SPB interaction and thus DNA repair. Accordingly, disruption of spindle stability impairs both DSB-SPB interaction and DNA repair by homologous recombination. These observations directly connect spindle integrity with DNA repair and reveal that DSBs are preferentially tethered to the SPBs to be restored. Importantly, this new function of Cdc14 could provide a physiological mechanism that spatially regulates the DNA damage response and therefore the fate of the repair process.Peer Reviewe