Spindle checkpoint–independent inhibition of mitotic chromosome segregation byDrosophilaMps1

Abstract

<jats:p>Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation.</jats:p>

A maternal effectrough dealmutation suggesting multiple pathways regulating Drosophila RZZ kinetochore recruitment

“…However, Mps1, BubR1 and the RZZ complex all participate in other mitotic functions that do not involve the SAC (Starr et al, 1998;Ditchfield et al, 2003;Jones et al, 2005;Lampson and Kapoor, 2005;Maure et al, 2007;Jelluma et al, 2008;Hewitt et al, 2010;Santaguida et al, 2010;Sliedrecht et al, 2010;Althoff et al, 2012;Wainman et al, 2012). It is therefore conceivable that the polar body decondensation is not specifically connected to a defect in SAC activity.…”

Kif2a regulates spindle organization and cell cycle progression in meiotic oocytes

“…The major components of SAC includes mitotic arrest-deficient-1 (Mad1), Mad2, budding-uninhibited by benzimidazole-1 (Bub1), Bub3, BubR1, monopolar spindle 1(Mps1)4243. SAC contributes a surveillance mechanism to ensure proper chromosome segregation.…”

“…SAC contributes a surveillance mechanism to ensure proper chromosome segregation. The SAC pathway prevents chromosome missegregation by delaying the anaphase onset until all chromosomes are attached to spindle microtubules displaying proper tension and aligned at the equatorial plate4243. Kif2a knockdown caused meiosis arrest at the Pro-M I/M I stage, and the PB1 failed to extrude.…”

UV-C irradiation delays mitotic progression by recruiting Mps1 to kinetochores

“…54 These observations are also confirmed in a recent study of Drosophila in which the kinetochore recruitment of kinase-inactive Mps1 required endogenous Mps1. 55 However, there are also conflicting reports. For example, treating HeLa cells with other Mps1 inhibitors, AZ3146 and Reversine, can promote Mps1 binding to the kinetochore, 34,56 implying that the kinase activity is not required for such binding.…”