Sensing Properly Aligned Chromosomes

Abstract

Cell division is all about precise separation of sister chromatids to the daughter cells. In fact, cells have a fail-safe mechanism known as the mitotic checkpoint through which the cell division process is only allowed to proceed if every chromosome is attached to the microtubules of the mitotic spindle. Malfunction of this process is thought to contribute to chromosome instability in cancer cells. Some controversy has surrounded the question of whether the checkpoint mechanism actually senses attachment to microtubules per se or the tension that results from it. Mao et al. provide new experiments that support the former model. BubR1 is a protein kinase that is active at unattached kinetichores and contributes to the signal that stops progression of anaphase. The centromere-associated kinesin family member CENP-E binds to and stimulates BubR1, and the motor domain of CENP-E binds microtubules. Mao et al. show in Xenopus egg extracts or transfected mammalian cells that a form of CENP-E that cannot bind microtubules keeps BubR1 in an active state and prevents completion of mitosis, even if chromosomes are all attached to the spindle. In vitro, the authors could reconstitute the checkpoint signal. They mixed microtubules formed from purified tubulin with recombinant BubR1 and CENP-E and showed that after interaction with microtubules, CENP-E became an inhibitor of BubR1 activity. Thus, the authors contend that CENP-E is the critical signal-transducing sensor that inactivates the checkpoint signal once chromosomes are properly attached to the spindle. Y. Mao, A. Desai, D. W. Cleveland, Microtubule capture by CENP-E silences BubR1-dependent mitotic checkpoint signaling. J. Cell Biol. 170 , 873-880 (2005). [Abstract] [Full Text]