Pericentric chromatin loops function as a nonlinear spring in mitotic force balance

Stephens, Andrew D.; Haggerty, Rachel A.; Vasquez, Paula A.; Vicci, Leandra; Snider, Chloe E.; Shi, Fu Dong; Quammen, Cory; Mullins, Christopher; Haase, Julian; Taylor, Russell M.; Verdaasdonk, Jolien S.; Falvo, Michael R.; Jin, Yuan; Forest, M. Gregory; Bloom, Kerry

doi:10.1083/jcb.201208163

Cited by 58 publications

(98 citation statements)

References 77 publications

(132 reference statements)

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“…8D). Importantly, it has been shown that chromosomes can act like springs to counteract the motive force of the mitotic spindle, which would also support this model (60). Because separated SPBs also collapse back together in some nimA7 cells, this suggests that some connection is maintained between the segregated kinetochores and the separated SPBs before kinetochores are pulled back together via unresolved sister chromatids (Fig.…”

Section: Initiation Of Mitosis In the Absence Of Sufficient Nima Funcmentioning

confidence: 72%

The NIMA Kinase Is Required To Execute Stage-Specific Mitotic Functions after Initiation of Mitosis

2014

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The G 2 -M transition in Aspergillus nidulans requires the NIMA kinase, the founding member of the Nek kinase family. Inactivation of NIMA results in a late G 2 arrest, while overexpression of NIMA is sufficient to promote mitotic events independently of cell cycle phase. Endogenously tagged NIMA-GFP has dynamic mitotic localizations appearing first at the spindle pole body and then at nuclear pore complexes before transitioning to within nuclei and the mitotic spindle and back at the spindle pole bodies at mitotic exit, suggesting that it functions sequentially at these locations. Since NIMA is indispensable for mitotic entry, it has been difficult to determine the requirement of NIMA for subaspects of mitosis. We show here that when NIMA is partially inactivated, although mitosis can be initiated, a proportion of cells fail to successfully generate two daughter nuclei. We further define the mitotic defects to show that normal NIMA function is required for the formation of a bipolar spindle, nuclear pore complex disassembly, completion of chromatin segregation, and the normal structural rearrangements of the nuclear envelope required to generate two nuclei from one. In the remaining population of cells that enter mitosis with inadequate NIMA, two daughter nuclei are generated in a manner dependent on the spindle assembly checkpoint, indicating highly penetrant defects in mitotic progression without sufficient NIMA activity. This study shows that NIMA is required not only for mitotic entry but also sequentially for successful completion of stage-specific mitotic events.

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Section: Initiation Of Mitosis In the Absence Of Sufficient Nima Funcmentioning

confidence: 72%

The NIMA Kinase Is Required To Execute Stage-Specific Mitotic Functions after Initiation of Mitosis

2014

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“…At least one function of pericentric cohesion is to facilitate kinetochore biorientation by resisting the pulling forces of microtubules and/or by promoting the architecture of sister kinetochores (Eckert et al 2007;Fernius and Marston 2009;Ng et al 2009;Bloom and Joglekar 2010). Consistent with this, the geometry and elasticity of the pericentromere and inner kinetochore can change in response to alterations in microtubule dynamics (Haase et al 2012;Stephens et al 2013). These properties are regulated by the Bub1 and Sgo1 proteins as well as various chromatin-remodeling complexes (Haase et al 2012;Verdaasdonk et al 2012).…”

Section: The Centromerementioning

confidence: 92%

The Composition, Functions, and Regulation of the Budding Yeast Kinetochore

2013

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The propagation of all organisms depends on the accurate and orderly segregation of chromosomes in mitosis and meiosis. Budding yeast has long served as an outstanding model organism to identify the components and underlying mechanisms that regulate chromosome segregation. This review focuses on the kinetochore, the macromolecular protein complex that assembles on centromeric chromatin and maintains persistent load-bearing attachments to the dynamic tips of spindle microtubules. The kinetochore also serves as a regulatory hub for the spindle checkpoint, ensuring that cell cycle progression is coupled to the achievement of proper microtubule-kinetochore attachments. Progress in understanding the composition and overall architecture of the kinetochore, as well as its properties in making and regulating microtubule attachments and the spindle checkpoint, is discussed. TABLE OF CONTENTS Abstract 817Introduction 818

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“…Although force-balance ideas had previously been proposed to explain metaphase chromosome positioning (9, 10), Saunders and Hoyt's work appears to be the first force-balance model of the spindle structure. The force-balance picture was supported by further work in yeasts showing that kinesin-14s can counteract kinesin5s (11,12) and since then has been both widely adopted as a conceptual framework (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) and used in mathematical models (23)(24)(25)(26)(27) of yeast spindles. Quantitative force-balance models were later applied to Drosophila spindle assembly (28)(29)(30)(31), and the same ideas have more recently been extended to human cells (32).…”

Section: Introductionmentioning

confidence: 97%

Physical Determinants of Bipolar Mitotic Spindle Assembly and Stability in Fission Yeast

Betterton

Blackwell

Edelmaier

et al. 2017

Biophysical Journal

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Mitotic spindles use an elegant bipolar architecture to segregate duplicated chromosomes with high fidelity. Bipolar spindles form from a monopolar initial condition; this is the most fundamental construction problem that the spindle must solve. Microtubules, motors, and cross-linkers are important for bipolarity, but the mechanisms necessary and sufficient for spindle assembly remain unknown. We describe a physical model that exhibits de novo bipolar spindle formation. We began with physical properties of fission-yeast spindle pole body size and microtubule number, kinesin-5 motors, kinesin-14 motors, and passive cross-linkers. Our model results agree quantitatively with our experiments in fission yeast, thereby establishing a minimal system with which to interrogate collective selfassembly. By varying the features of our model, we identify a set of functions essential for the generation and stability of spindle bipolarity. When kinesin-5 motors are present, their bidirectionality is essential, but spindles can form in the presence of passive cross-linkers alone. We also identify characteristic failed states of spindle assemblythe persistent monopole, X spindle, separated asters, and short spindle, which are avoided by the creation and maintenance of antiparallel microtubule overlaps. Our model can guide the identification of new, multifaceted strategies to induce mitotic catastrophes; these would constitute novel strategies for cancer chemotherapy.

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Pericentric chromatin loops function as a nonlinear spring in mitotic force balance

Abstract: During mitosis, cohesin- and condensin-based pericentric chromatin loops function as a spring network to balance spindle microtubule force.

Cited by 58 publications

References 77 publications

The NIMA Kinase Is Required To Execute Stage-Specific Mitotic Functions after Initiation of Mitosis

The NIMA Kinase Is Required To Execute Stage-Specific Mitotic Functions after Initiation of Mitosis

The Composition, Functions, and Regulation of the Budding Yeast Kinetochore

Physical Determinants of Bipolar Mitotic Spindle Assembly and Stability in Fission Yeast

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