Cortical dynein drives centrosome clustering in cells with centrosome amplification

Abstract

During cell division, the microtubule nucleating and organizing organelle, known as the centrosome, is a critical component of the mitotic spindle. In cells with two centrosomes, each centrosome functions as an anchor point for microtubules, leading to the formation of a bipolar spindle and progression through a bipolar cell division. When extra centrosomes are present, multipolar spindles form and the parent cell may divide into more than two daughter cells. Cells that are born from multipolar divisions are not viable and hence clustering of extra centrosomes and progression to a bipolar division are critical determinants of viability in cells with extra centrosomes. We combine experimental approaches with computational modeling to define a role for cortical dynein in centrosome clustering. We show that centrosome clustering fails and multipolar spindles dominate when cortical dynein distribution or activity is experimentally perturbed. Our simulations further reveal that centrosome clustering is sensitive to the distribution of dynein on the cortex. Together, these results indicate that dynein's cortical localization alone is insufficient for effective centrosome clustering and instead, dynamic relocalization of dynein from one side of the cell to the other throughout mitosis promotes timely clustering and bipolar cell division in cells with extra centrosomes.

Surviving the Storm: The Role of Poly‐ and Depolyploidization in Tissues and Tumors

“…A process named “centrosome clustering” was observed in PACCs, where amplified centrosomes were clustered at two mitotic poles, and pseudo‐bipolar spindles were formed to segregate chromosomes with higher fidelity. [ 73 ] It is notable that mammalian tetraploid cells capable of centrosome clustering exhibit higher rates of merotelic attachment and lagging chromosomes than diploid cells. [ 74 ] As the SAC poorly senses merotelic attachment, PACCs deploy centrosome clustering to avoid disastrous outcomes by allowing low‐grade but viable chromosome instability (Figure 3a,b ).…”

Cell cycle–dependent centrosome clustering precedes proplatelet formation

“…Amplified centrosomes in diploid or tetraploid cancer cells can cluster, thus preventing aneuploidy by consolidation into a bipolar spindle ( 29 ). Centrosome clustering is dependent on the activity of a plethora of centrosomal proteins such as aurora kinases, c-terminally encoded peptide (CEP) family proteins, and the Augmin complex ( 30 ), as well as microtubule regulators such as kinesin family members and dynein ( 31 , 32 ). Recently, centrosome clustering has also been identified in noncancerous, polyploid cells such as osteoclasts and dendritic cells, where it induces cytoskeletal remodeling ( 33 , 34 ).…”