Abstract
Author SummaryWhen cells divide, their chromosomes segregate to the two daughter cells on the mitotic spindle, a dynamic macromolecular scaffold composed of microtubules. Each chromosome consists of two sister chromatids. Microtubules attach to the chromatids at structures called kinetochores, which assemble at the surface of the constricted centromere region where the sister chromatids are most closely paired. To segregate correctly, sister kinetochores must attach to microtubules emanating from opposite spindle poles. Kinetochore attachment to microtubules occurs randomly and mistakes occur frequently. For example, both sister kinetochores may attach to one pole, or one kinetochore may attach to both poles simultaneously. Two protein kinases, Aurora B and Polo, have essential roles in regulating this process: Aurora B triggers the release of incorrect attachments and Polo strengthens the grip that correctly attached kinetochores have on microtubules. In this work, we have investigated the potential functional links between these two crucial enzymes at centromeres in cells of the fruitfly. We found that early in division, Aurora B and Polo both interact with a structural partner protein named INCENP at centromeres. This allows Aurora B to phosphorylate Polo, thereby activating it. We show that coordinating the activities of these two central mitotic kinases is crucial for successful cell division, and that this mechanism is conserved in human cells.
Highlights
Executive decisions concerning when cells enter and exit mitosis are made by Cdk1 with cyclins A and B as cofactors
Polo kinase in these early stages is localized at centromeres (Figure 1, arrows; Figure S1A), at centrosomes, where it colocalizes with Aurora A (Figure 1A–D, asterisks; Figure S2), and at the nuclear envelope (Figure 1A3, blue arrowhead), where it has been proposed to promote nuclear envelope breakdown (NEB) [8]
B depletion was due to a cell cycle block outside mitosis caused by OA treatment, we examined the effects of RNAi depletion of Aurora A, Aurora B, and INCENP on the PoloT182ph signal at centromeres in individual mitotic cells without okadaic acid treatment
Summary
Executive decisions concerning when cells enter and exit mitosis are made by Cdk with cyclins A and B as cofactors. Once cells have entered mitosis, Plk and the Aurora kinases direct spindle formation, regulate chromosome attachments to spindle microtubules, ensure the operation of the spindle checkpoint, and enable daughter cells to complete cytokinesis (reviewed in [1,2,3,4]). Plk and Aurora A function in the regulation of mitotic entry (reviewed in [5]). Plk and Aurora B have potentially antagonistic activities during the early stages of chromosome attachment and alignment on the mitotic spindle. Plk phosphorylation of kinetochore components and microtubule plus-endassociated proteins is required for the establishment of stable kinetochore-microtubule (KT-MT) interactions. Plk phosphorylates components of the Ska and KNL-1/Mis12/Ndc (KMN) kinetochore complexes as well as centromere proteins CENP-B, CENP-C, CENP-E, and CENP-F. The function of these phosphorylations is not known [10]
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