Genomic instability is a characteristic of most cancers and it refers to an increased tendency of alterations in the genome during the life cycle of cells. The fidelity of DNA replication is highly ensured by different checkpoints; the activation of spindle checkpoints prevents cells from premature entry into mitosis, avoiding incorrect chromosome segregation and aneuploidy, a typical feature of many cancers. Mitostatin, a novel protein, endowed with tumor suppressor activity, has been reported to bind centrosomal proteins Odf2 and ninein, and its depletion causes an alteration of the anchorage of microtubules to the centrosome. Since functional defects of centrosomes are associated to mitotic failure, Mitostatin may have a key role in guarding the fidelity of mitosis in cells. Here we show that the depletion of Mitostatin in cancer cells, synchronized by aphidicolin (G1/S) block and released into nocodazole-containing medium, leads to mitotic slippage and adaptation to the spindle checkpoint (SAC) in the presence of a spindle inhibitor. Concomitantly, Mitostatin depletion promotes the early degradation of Mad2 and cyclin B1. Since the activated spindle checkpoint delays cell exit from mitosis by preventing cyclin B1 proteolysis, the cyclin B1 early degradation leads to mitotic checkpoint escape and resulting chromosome instability. In this study, we report for the first time that the depletion of Mitostatin induces an increase of numerical and structural chromosomal aberrations compared to control cells. These aberrations include aneuploidy, the formation of triradials and broken chromosomes. Taken together, our observations suggest that Mitostatin plays a critical role in guarding the fidelity of mitosis, enabling the optimal activation of the spindle checkpoint (SAC). Thus, low levels of Mitostatin found in certain human tumors may contribute to cellular transformation by promoting genomic instability.
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|Data di pubblicazione:||2017|
|Titolo:||The key role of Mitostatin in the maintenance of genome stability|
|Autori:||Lauriola, Angela; Caporali, Andrea; Mai, Sabine; D'Arca, Domenico|
|Nome del convegno:||AACR Annual Meeting 2017;|
|Luogo del convegno:||Washington, DC|
|Data del convegno:||April 1-5, 2017|
|Appare nelle tipologie:||Abstract in Rivista|
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