Aurora A Kinase Contributes to a Pole-Based Error Correction Pathway

Abstract

Summary Chromosome biorientation, where sister kinetochores attach to microtubules (MTs) from opposing spindle poles, is the configuration that best ensures equal partitioning of the genome during cell division. Erroneous kinetochore-microtubule (kt-MT) attachments are commonplace but often corrected prior to anaphase [1, 2]. Error correction, thought to be mediated primarily by the centromere-enriched Aurora B kinase (ABK) [3-5], typically occurs near spindle poles [6]; albeit, the relevance of this locale is unclear. Furthermore, polar ejection forces (PEFs), highest near poles [7], can stabilize improper attachments by pushing mal-oriented chromosome arms away from spindle poles [8, 9]. Hence, a conundrum: erroneous kt-MT attachments are weakened where PEFs are most likely to strengthen them. Here, we report that Aurora A kinase (AAK) opposes the stabilizing effect of PEFs. AAK activity contributes to phosphorylation of kinetochore substrates near poles and its inhibition results in chromosome mis-alignment and an increased incidence of erroneous kt-MT attachments. Furthermore, AAK directly phosphorylates a site in the N-terminal tail of Ndc80/Hec1 that has been implicated in reducing the affinity of the Ndc80 complex for MTs when phosphorylated [10-12]. We propose that an AAK activity gradient contributes to correcting mal-oriented kt-MT attachments in the vicinity of spindle poles.

Dynein prevents erroneous kinetochore-microtubule attachments in mitosis

“…51 Additionally, Aurora A might play other important roles in chromosome congression by regulating proteins directly involved in this process. 53,54 Two recent studies further confirmed our observation about the role of Aurora A in error correction near the poles in mitosis and also in meiosis I. Ye and colleagues 41 demonstrated the existence of an Aurora A activity gradient centered on the spindle poles in Drosophila S2 cells using a Fluorescence Resonance Energy Transfer sensor bound to microtubules that was Figure 1. Dynein "locks" peripheral chromosomes at the spindle poles after CENP-E inhibition.…”

“…Moreover, they used live-cell imaging to show that Mad1-GFP signal accumulated on kinetochores near the spindle pole, both in trivalents and syntelically-attached bivalents that became efficiently corrected as they approached the spindle pole. Altogether, these studies in 4 different systems 5,41,42 demonstrate that, in addition to a centromeric-based error correction mechanism mainly driven by Aurora B, an Aurora A-regulated error correction mechanism exists in the vicinity of the spindle poles to prevent the premature stabilization of end-on kinetochore microtubule attachments. This is likely to be important for subsequent CENP-E-mediated congression of polar chromosomes along preexisting spindle microtubules.…”

“…[36][37][38] Once chromosomes become bi-oriented and tension is applied between sister kinetochores, Ndc80 moves away from Aurora B, resulting in kinetochoremicrotubule attachment stabilization. 39,40 Here we elaborate on recent studies that demonstrated a role of Dynein, 5 chromokinesins 5,41 and Aurora A kinase 5,41,42 in the prevention and correction of erroneous kinetochore-microtubule attachments during chromosome congression.…”

Chromosomal instability: A common feature and a therapeutic target of cancer

“…Another Aurora kinase family member, Aurora A, localizes to spindle poles and phosphorylates overlapping substrates with Aurora B, including Hec1. Recently, it was reported that Aurora A also plays a role in the correction of erroneous attachments, whose dysfunction gives rise to misoriented chromosomes near the spindle poles [68,69].…”

Building an integrated model of chromosome congression

“…It has been established that a gradient of Plk1 and Ran-GTP concentrations control spindle position (Kiyomitsu and Cheeseman, 2012), and Aurora A forms a spatial gradient that originates at the spindle pole (Ye et al, 2015;Hochegger et al, 2013). Abrogation of the Ran-GTP gradient that is established around aligned chromosomes using a dominant-negative RanT24N mutant has no effect on congression (Barisic et al, 2015).…”