Control of nuclear division by the Chromosomal Passenger Complex

Abstract

Most cells within an organism function while they are in a non-dividing state. Cells enter the division cycle to initiate tissue growth or to repair damaged tissue. In the last phase of this cycle, M-phase, cytoplasmic division (cytokinesis) is accomplished after, in case of dividing human cells, 23 pairs of duplicated chromosomes are separated during nuclear division (mitosis). Faithful chromosome segregation is essential as gains and losses of chromosomes are a hallmark of cancer. To ensure fidelity of chromosome segregation microtubules coming from opposite spindle poles have to attach to kinetochores (microtubule binding interfaces of the chromosomes) in a bipolar fashion in order to pull apart the chromosome duplicates to opposite poles of the cell. The Chromosomal Passenger Complex (CPC), consisting of Aurora B kinase, Borealin, Survivin and INCENP, plays a pivotal role in the protection of genome stability as it coordinates equal segregation of the duplicated chromosomes with cytokinesis. In mitosis the CPC members Borealin and Survivin direct the complex to the inner centromere (the region where the duplicated chromosomes connect). Borealin associates with histone H2A phosphorylated on threonine 120 by Bub1 via a Shugoshin intermediate, while Survivin interacts with histone H3 phosphorylated at threonine 3 by Haspin. When cells enter mitosis, spindle microtubules are captured by kinetochores and the activity of Aurora B is critical to specifically detach those kinetochore-microtubule attachments that are not bi-polar (error correction), and when left uncorrected could give rise to chromosome mis-segregations in anaphase. The resulting unattached kinetochores activate the mitotic checkpoint, a surveillance mechanism that prevents the segregation of the duplicated chromosomes until all chromosomes have acquired bi-polar attachments. While the role of Aurora B in error correction was undisputed, its direct contribution to mitotic checkpoint signaling remained controversial. Our data show that besides generating unattached kinetochores as a result of error correction, Aurora B promotes rapid establishment of the mitotic checkpoint via kinetochore recruitment of the checkpoint kinase Mps1. Moreover, we found that impaired kinetochore recruitment of Mps1 underlies the mitotic checkpoint defects observed in cells expressing an INCENP mutant lacking its coiled coil domain. Our data further suggest that INCENP links Aurora B to the centromere recruitment subunits Survivin and Borealin, with the coiled coil domain supporting Aurora B in reaching its distant kinetochore substrates. The inner centromere localization of the CPC is essential for its proper functioning and we identified the pathways that direct this localization in space and time. Besides Aurora B being important for Mps1 kinetochore recruitment, we show that Mps1 in turn stimulates the Bub1-H2Aph-Sgo1 recruitment axis for centromere accumulation of Aurora B. Moreover, Aurora B activity enhances its own recruitment by phosphorylation of Haspin, thereby promoting its activity towards histone H3-T3, the other CPC centromere recruitment mark. We suggest that when cells enter mitosis, the feedback loops between Aurora B and Mps1 respectively Aurora B and Haspin direct timely inner centromere accumulation of the CPC to ensure effective establishment of the error correction and the mitotic checkpoint machineries, required for accurate nuclear division.