Mammalian CLASP1 and CLASP2 cooperate to ensure mitotic fidelity by regulating spindle and kinetochore function

摘要

CLASPs are widely conserved microtubule plus-end–tracking proteins with essential roles in the local regulation ofmicrotubule dynamics. In yeast, Drosophila, and Xenopus, a single CLASP orthologue is present, which is required formitotic spindle assembly by regulating microtubule dynamics at the kinetochore. In mammals, however, only CLASP1has been directly implicated in cell division, despite the existence of a second paralogue, CLASP2, whose mitotic rolesremain unknown. Here, we show that CLASP2 localization at kinetochores, centrosomes, and spindle throughout mitosisis remarkably similar to CLASP1, both showing fast microtubule-independent turnover rates. Strikingly, primaryfibroblasts from Clasp2 knockout mice show numerous spindle and chromosome segregation defects that can be partiallyrescued by ectopic expression of Clasp1 or Clasp2. Moreover, chromosome segregation rates during anaphase A and B areslower in Clasp2 knockout cells, which is consistent with a role of CLASP2 in the regulation of kinetochore and spindlefunction. Noteworthy, cell viability/proliferation and spindle checkpoint function were not impaired in Clasp2 knockoutcells, but the fidelity of mitosis was strongly compromised, leading to severe chromosomal instability in adult cells.Together, our data support that the partial redundancy of CLASPs during mitosis acts as a possible mechanism to preventaneuploidy in mammals.