Biased spindle formation

Abstract

A microtubule-stabilizing protein called HURP forms a gradient around chromosomes that stabilizes spindles, say Wong and Fang (page 879). Figure 1 HURP (green) is localized close to chromosomes (blue). HURP was previously associated with hepatocellular carcinoma, but Wong and Fang picked it out as being induced during mitosis and showing covariation with known mitotic regulators. Almost half of all HURP-depleted cells had one or more unaligned chromosome during metaphase. The kinetochores of these chromosomes were not attached to microtubules, and even attached kinetochores were under less tension than in a normal spindle. HURP has also shown up recently as part of a complex from frog egg extracts that is required for the conversion of aster-like to spindle-like structures (Koffa, M.D., et al. 2006. Curr. Biol. 16:743-754). The complex consists of two characterized microtubule-associated proteins (TPX2 and XMAP215), a plus end-directed microtubule motor (Eg5), a mitotic kinase (Aurora A), and HURP. This complex is dependent on the activity of chromatin-localized Ran-GTP, thus helping to focus the spindle around chromosomes. This is consistent with Wong and Fang's finding that HURP is found on microtubules and in a gradient that peaks around chromosomes. They also found that HURP binds to and stabilizes microtubules. HURP's activity may be needed as, based on mathematical modeling, unbiased microtubule growth is too inefficient for kinetochore capture given the time constraints of mitosis. The HeLa cells depleted of HURP eventually escaped from their cell cycle arrest induced by unattached chromosomes. The same was true if the cells were treated with low levels of microtubule depolymerizing drugs that induced some chromosome detachment. This suggests that the mitotic checkpoint is weak in certain tumor-derived cells, which would promote genomic instability.