International Journal of Molecular Sciences Review Aurora B Tension Sensing Mechanisms in the Kinetochore Ensure Accurate Chromosome Segregation Shelby L. McVey, Jenna K. Cosby and Natalie J. Nannas * Department of Biology, Hamilton College, 198 College Hill Road, Clinton, NY 13323, USA; [email protected] (S.L.M.); [email protected] (J.K.C.) * Correspondence: [email protected] Abstract: The accurate segregation of chromosomes is essential for the survival of organisms and cells. Mistakes can lead to aneuploidy, tumorigenesis and congenital birth defects. The spindle assembly checkpoint ensures that chromosomes properly align on the spindle, with sister chromatids attached to microtubules from opposite poles. Here, we review how tension is used to identify and selectively destabilize incorrect attachments, and thus serves as a trigger of the spindle assembly checkpoint to ensure fidelity in chromosome segregation. Tension is generated on properly attached chromosomes as sister chromatids are pulled in opposing directions but resisted by centromeric cohesin. We discuss the role of the Aurora B kinase in tension-sensing and explore the current models for translating mechanical force into Aurora B-mediated biochemical signals that regulate correction of chromosome attachments to the spindle. Keywords: chromosome segregation; Aurora B; spindle assembly checkpoint; kinetochore Citation: McVey, S.L.; Cosby, J.K.; Nannas, N.J. Aurora B Tension 1. Introduction Sensing Mechanisms in the Organisms package their genetic material into chromosomes; faithful segregation Kinetochore Ensure Accurate of these structures through cell division is critical as mistakes can lead to disease, infer- Chromosome Segregation. Int. J. Mol. tility and congenital defects [1,2]. Eukaryotic chromosomes take on the characteristic Sci. 2021, 22, 8818. https://doi.org/ X-shape after replication and chromatin condensation, consisting of two identical sister 10.3390/ijms22168818 chromatids. Chromatids are separated in mitosis by the microtubule-based spindle appara- tus. Attachment to the spindle occurs through the kinetochore, a large structure containing Academic Editor: George Zachos 80–100 proteins in sub complexes that are organized into inner and outer domains. The inner kinetochore assembles on centromeres through interactions with chromatin, and the Received: 11 July 2021 outer kinetochore binds to spindle microtubules (for a review of kinetochore structure Accepted: 13 August 2021 Published: 16 August 2021 and function, see [3]). Depending on the species, approximately 1–30 microtubules attach per kinetochore. Budding yeast have the simplest architecture with a single kinetochore Publisher’s Note: MDPI stays neutral microtubule [4,5] while vertebrates average 15–20 microtubules/kinetochore [6]. To ensure with regard to jurisdictional claims in dividing cells receive equal numbers of chromosomes, sister chromatids must bi-orient published maps and institutional affil- with their kinetochores attached to microtubules from opposite spindle poles (Figure1A). iations. Mistakes in attachment can occur: kinetochores can attach to microtubules from the same pole (syntelic attachment), a single kinetochore can attach to microtubules from both poles (merotelic attachment), or only one kinetochore can be attached (monotelic attachment) (Figure1B). These errors must be corrected into the amphitelic configuration with all chromosomes achieving bi-orientation before anaphase. If not corrected, errors lead to Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. chromosome segregation mistakes that result in aneuploidy. Meiotic aneuploidy is the most This article is an open access article common cause of congenital birth defects and miscarriage [1] with approximately 10–30% distributed under the terms and of fertilized human eggs having an incorrect number of chromosomes [7]. Aneuploidy also conditions of the Creative Commons remains the predominant cause of congenital birth defects [1]. Mitotic aneuploidy is linked Attribution (CC BY) license (https:// to tumorigenesis [8], metastasis [9] and cancer cell motility [10]. The prognosis becomes creativecommons.org/licenses/by/ more grim with increasing levels of aneuploidy as these cells are often less susceptible to 4.0/). chemotherapies [2]. Int. J. Mol. Sci. 2021, 22, 8818. https://doi.org/10.3390/ijms22168818 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 8818 2 of 19 Int. J. Mol. Sci. 2021, 22, 8818 2 of 20 prognosis becomes more grim with increasing levels of aneuploidy as these cells are often less susceptible to chemotherapies [2]. FigureFigure 1. 1.Attachment Attachment of of chromosomes chromosomes (blue) (blue) to to the the spindle spindle (black) (black) is is facilitated facilitated by by kinetochores kinetochores (yellow).(yellow). Sister Sister chromatids chromatids areare heldheld togethertogether by cohesin cohesin (orange). (orange). (A (A) )Unattached Unattached chromosomes chromosomes ex- perience no tension, but when they are correctly attached or bi-oriented, they experience tension experience no tension, but when they are correctly attached or bi-oriented, they experience tension force as the two chromatids are pulled apart by depolymerizing microtubules but resisted by cohe- force as the two chromatids are pulled apart by depolymerizing microtubules but resisted by co- sin. Both pericentric chromatin and kinetochores on bi-oriented chromosomes become visibly hesin.stretched Both under pericentric tension. chromatin (B) Correct and attachm kinetochoresents are onalso bi-oriented referred to chromosomes as amphitelic attachments become visibly with stretchedkinetochores under on tension. sister chromatids (B) Correct attachmentsattached to microtubules are also referred from to opposite as amphitelic spindle attachments poles. Incorrect with kinetochoresattachments on include: sister chromatidssyntelic attachment attached where to microtubules kinetochores from on opposite sister chromatids spindle poles. are attached Incorrect to attachmentsthe same pole, include: monotelic syntelic attachment attachment where where only kinetochores a single kinetochore on sister chromatids is attached, are and attached merotelic to theattachment same pole, where monotelic a kinetochore attachment is attached where to only both a poles. single Incorrect kinetochore attachments is attached, generate and merotelic no tension attachment(syntelic and where monotelic) a kinetochore or improper is attached tension to both (merotelic) poles. Incorrect on the chromosome. attachments generate no tension (syntelic and monotelic) or improper tension (merotelic) on the chromosome. The accuracy of chromosome segregation is protected by the spindle assembly check- pointThe (SAC) accuracy which of chromosomemonitors kinetochore segregation-microtubule is protected attachments by the spindle and assembly activates check- in re- pointsponse (SAC) to errors. which monitorsThe SAC kinetochore-microtubuledelays anaphase until all attachments chromosomes and are activates bi-oriented in response on the tospindle errors. [11] The. The SAC checkpoint delays anaphase consists untilof many all chromosomescomponents originally are bi-oriented identified on in the classical spin- dlebudding [11]. The yeast checkpoint genetic screens, consists including of many componentsMitotic Arrest originally Deficient identified (MAD) proteins in classical [12], buddingBudding yeast Uninhibited genetic screens,by Benzimidazoles including Mitotic(BUB) proteins Arrest Deficient [13], the (MAD)Mps1 kinase proteins [14] [12 and], Buddingthe cell Uninhibitedcycle regulator by BenzimidazolesCdc20 [15,16]. Extensive (BUB) proteins work [13over], the the Mps1 last decade kinase [has14] andrevealed the cellthat cycle the regulatorcheckpoint Cdc20 operates [15,16 through]. Extensive a diffusible work over inhibitor the last initiating decade has at revealedkinetochores that thethat checkpointblocks the operates Anaphase through Promoting a diffusible Complex inhibitor (APC) initiating [17,18]. at Specifical kinetochoresly, the that main blocks effector the Anaphaseprotein, Mad2, Promoting is recruited Complex to kinetochores, (APC) [17,18]. where Specifically, it catalyzes the main the formation effector protein, of the Mad2,Mitotic isCheckpoint recruited to Complex kinetochores, that binds where and it sequesters catalyzes the Cdc20 formation from the of APC. the Mitotic For a review Checkpoint of SAC Complexcomponents that bindsand function, and sequesters see [19] Cdc20. Delaying from anaphase the APC. gives For a reviewcells time of SACto turn components over incor- andrect function, attachments see [and19]. generate Delaying correct anaphase attachments. gives cells The time SAC to turnis inactivated over incorrect by correct attach- at- mentstachments and generate through correcta silencing attachments. network Thethat SACdisplaces is inactivated checkpoint by correctproteins attachments from the ki- through a silencing network that displaces checkpoint proteins from the kinetochore [20,21]. Debate has surrounded the SAC trigger; some argue that SAC activation is caused by lack of tension on incorrect attachments and others argue activation is caused by unattached Int. J. Mol. Sci. 2021, 22, 8818 3 of 20 kinetochores [11]. The basis of this debate will be discussed below, but our review will focus on the role of tension in sensing and correcting improper attachments. 2. Tension Generation on Correct Attachments Chromosomes