Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol

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Abstract
The mitotic spindle assembly checkpoint ensures proper chromosome segregation during mitosis by inhibiting the onset of anaphase until all kinetochores are attached to the mitotic spindle and tension across the kinetochores is generated. Here, we report that the stable partial downregulation of the spindle checkpoint gene MAD1, which is observed in human cancer, leads to a functional inactivation of the spindle checkpoint resulting in gross aneuploidy. Interestingly, although Mad1 is thought to act as a kinetochore based activator of Mad2 during checkpoint activation, we show that normal levels of Mad2, but not of Mad1, are required for preventing premature sister chromatid separation and for maintaining the timing of an undisturbed mitosis, suggesting a Mad1 independent function of Mad2 that operates independent of its checkpoint function. Most significantly, a partial repression of either MAD1 or MAD2 confers resistance to nocodazole, a drug that inhibits microtubule attachment. In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways.