Increased Aurora B activity causes continuous disruption of kinetochore–microtubule attachments and spindle instability

Abstract

Aurora B kinase regulates the proper biorientation of sister chromatids during mitosis. Lack of Aurora B kinase function results in the inability to correct erroneous kinetochore-microtubule attachments and gives rise to aneuploidy. Interestingly, increased Aurora B activity also leads to problems with chromosome segregation, and overexpression of this kinase has been observed in various types of cancer. However, little is known about the mechanisms by which an increase in Aurora B kinase activity can impair mitotic progression and cell viability. Here, using a yeast model, we demonstrate that increased Aurora B activity as a result of the overexpression of the Aurora B and inner centromere protein homologs triggers defects in chromosome segregation by promoting the continuous disruption of chromosome-microtubule attachments even when sister chromatids are correctly bioriented. This disruption leads to a constitutive activation of the spindle-assembly checkpoint, which therefore causes a lack of cytokinesis even though spindle elongation and chromosome segregation take place. Finally, we demonstrate that this increase in Aurora B activity causes premature collapse of the mitotic spindle by promoting instability of the spindle midzone.

Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development

“…1 and 5). The mouse model described here confirms the effect of Aurora B overexpression in the generation of misaligned chromosomes and in triggering an SAC-dependent response, as recently reported in yeast cells (11). These defects could be a consequence of kinetochore-microtubule attachment defects induced by saturated levels of the kinase at the kinetochores.…”

“…Previous cellular studies indicate that sustained overexpression of Aurora B in murine epithelial cells induces tetraploidy and chromosomal instability, increasing the oncogenic potential of cultured cells (12,39,40). A recent report in yeast cells suggests that these defects may be a consequence of the continuous disruption of chromosome-microtubule attachments even when sister chromatids are properly bioriented (11).…”

“…Aurora B kinase plays a central role in correcting kinetochore attachment errors, including merotelic attachments, through the phosphorylation of kinetochore substrates, thus leading to the destabilization of incorrect attachments and allowing reorientation of the kinetochore toward the correct spindle pole (8,9). It has been proposed that correct attachment requires fine-tuning of tension across sister kinetochores and that either increasing or decreasing Aurora B activity may cause merotelic and syntelic attachments, which in turn can lead to aneuploidy (5,7,(10)(11)(12).…”

The Agrobacterium VirD5 protein hyperactivates the mitotic Aurora kinase in host cells

“…Ipl1/Aurora kinase plays crucial roles in sensing and correcting erroneous kinetochore–spindle microtubule attachments by phosphorylating key substrates involved in the kinetochore–spindle binding. Both loss and overexpression of the Ipl1/Aurora kinases leads to massive chromosome mis‐segregation and aneuploidy in yeast cells (Chan & Botstein, ; Muñoz‐Barrera & Monje‐Casas, ) . To determine whether VirD5 may affect the kinase activity of Ipl1, we carried out an in vitro kinase assay using the microtubule binding protein Dam1 as the substrate (Kang et al ., ).…”

“…Therefore, a reduction in the activity of Aurora B/Ipl1 leads to chromosome mis‐segregation and aneuploidy. Overexpression of Aurora B/Ipl1, however, also leads to defective chromosome segregation, as the repeated disruption of kinetochore–microtubule attachments not only activates the SAC, but in the end generates lagging chromosomes and aneuploid cells (Muñoz‐Barrera & Monje‐Casas, ).…”