Therapeutic S and G2 checkpoint override causes centromere fragmentation in mitosis

Positioning of the cell division plane is critically important for tissue morphogenesis and architecture. 1 it is therefore not surprising that mitotic spindle orientation must be tightly regulated in living tissues, a phenomenon that is also observed in cells cultured in vitro. Because of the amenability of cultured cells to molecular and physical manipulation, many investigators have used such approaches to identify the unifying rules that control spindle positioning. 2,3 One long-standing idea is that in tissue culture cells, the long axis of the mitotic spindle aligns with the long axis of the cell. 1 However, many cell types round up during mitosis, which possibly erases pre-mitotic geometric cues. what then, if anything, controls spindle orientation in rounded mitotic cells? some very elegant studies have recently shown that the extracellular matrix can control spindle positioning via forces that are transmitted through the plasma membrane and which are linked to the retraction fibers formed as the cell rounds up. On the other (intracellular) side of the plasma membrane, spindle positioning is believed to be controlled by the astral microtubules interacting with the cell cortex via the dynein/dynactin complex. 4 what has been unclear so far is the force transmission mechanism linking extra-cellular space and astral microtubules. A new study by Maier et al. identifies MisP (mitotic interactor and substrate of Plk1) as the missing link in this network of force-transmitting elements 5 (Fig. 1). The authors had previously identified this protein in a genome-wide siRNA screen for proteins required for centro-some clustering in cancer cells with supernu-merary centrosomes. 6 in the present study, the authors used MisP-siRNA and immunohisto-chemistry to better understand the role of this protein in spindle assembly and function. Key findings of this study include: (1) MisP depletion causes defects in spindle orientation and positioning, and (2) MisP colocalizes with the actin cytoskeleton and focal adhesions (specifically , the focal adhesion kinase, FAK). 5 The authors also find that MisP interacts with the plus-end-tracking protein eB1 and the p150 glued subunit of the dynein/dynactin complex , and that cells depleted of MisP display a mitotic arrest/delay. 5 Further insight on the role of MisP in spindle positioning was provided by another recent study also showing that MisP is an actin-associated protein important for spindle positioning. 7 in this study, using live-cell imaging, Zhu et al. showed that MisP depletion resulted in " unstable " spindle position, in which …