Roles of impairment of centrosome maturation in leukemogenesis

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During prometaphase, dense microtubule nucleation sites at centrosomes form robustspindles that align chromosomes promptly. Failure of centrosome maturation leaves chromosomes scattered, as seen in cancer cells, including myelodysplastic syndrome (MDS).We previously reported that the Miki (LOC253012) gene is frequently deleted in MDS patients, and that low levels of Miki are associated with abnormal mitosis. Here we demonstrate that Miki localizes to the Golgi apparatus and is poly (ADP-ribosyl)ated by tankyrase-1 during late G2 and prophase. PARsylated Miki then translocates to mitotic centrosomes and anchors CG-NAP, a large scaffold protein of the g-tubulin ring complex . Due to impairment of microtubule aster formation, cells in which tankyrase-1, Miki, or CG-NAP expression is downregulated all show prometaphase disturbance, scattered and lagging chromosomes. Our data suggest that PARsylation of Miki by tankyrase-1 is a key initial event promoting prometaphase.