Mechanisms of Chromosome Biorientation and Bipolar Spindle Assembly Analyzed by Computational Modeling

Overview

Journal Elife

Specialty Biology

Date 2020 Feb 14

PMID 32053104

Citations 23

Authors

Christopher Edelmaier

Adam R Lamson

Zachary R Gergely

Saad Ansari

Robert Blackwell

J Richard McIntosh

Matthew A Glaser

Meredith D Betterton

Affiliations

Soon will be listed here.

Abstract

The essential functions required for mitotic spindle assembly and chromosome biorientation and segregation are not fully understood, despite extensive study. To illuminate the combinations of ingredients most important to align and segregate chromosomes and simultaneously assemble a bipolar spindle, we developed a computational model of fission-yeast mitosis. Robust chromosome biorientation requires progressive restriction of attachment geometry, destabilization of misaligned attachments, and attachment force dependence. Large spindle length fluctuations can occur when the kinetochore-microtubule attachment lifetime is long. The primary spindle force generators are kinesin-5 motors and crosslinkers in early mitosis, while interkinetochore stretch becomes important after biorientation. The same mechanisms that contribute to persistent biorientation lead to segregation of chromosomes to the poles after anaphase onset. This model therefore provides a framework to interrogate key requirements for robust chromosome biorientation, spindle length regulation, and force generation in the spindle.

Citing Articles

Kinesin-5/Cut7 C-terminal tail phosphorylation is essential for microtubule sliding force and bipolar mitotic spindle assembly.

Jones M, Gergely Z, Steckhahn D, Zhou B, Betterton M Curr Biol. 2024; 34(20):4781-4793.e6.

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Unveiling inter-embryo variability in spindle length over time: Towards quantitative phenotype analysis.

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Measuring and modeling the dynamics of mitotic error correction.

Ha G, Dieterle P, Shen H, Amir A, Needleman D Proc Natl Acad Sci U S A. 2024; 121(25):e2323009121.

PMID: 38875144 PMC: 11194551. DOI: 10.1073/pnas.2323009121.

CKAP5 stabilizes CENP-E at kinetochores by regulating microtubule-chromosome attachments.

Lakshmi R, Nayak P, Raz L, Sarkar A, Saroha A, Kumari P EMBO Rep. 2024; 25(4):1909-1935.

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Distinct regions of the kinesin-5 C-terminal tail are essential for mitotic spindle midzone localization and sliding force.

Gergely Z, Jones M, Zhou B, Cash C, McIntosh J, Betterton M Proc Natl Acad Sci U S A. 2023; 120(39):e2306480120.

PMID: 37725645 PMC: 10523502. DOI: 10.1073/pnas.2306480120.

References

Bouck D, Bloom K . Pericentric chromatin is an elastic component of the mitotic spindle. Curr Biol. 2007; 17(9):741-8. PMC: 1937037. DOI: 10.1016/j.cub.2007.03.033. View

Gluncic M, Maghelli N, Krull A, Krstic V, Ramunno-Johnson D, Pavin N . Kinesin-8 motors improve nuclear centering by promoting microtubule catastrophe. Phys Rev Lett. 2015; 114(7):078103. DOI: 10.1103/PhysRevLett.114.078103. View

Kawaguchi K, Ishiwata S . Nucleotide-dependent single- to double-headed binding of kinesin. Science. 2001; 291(5504):667-9. DOI: 10.1126/science.291.5504.667. View

Lacroix B, Letort G, Pitayu L, Salle J, Stefanutti M, Maton G . Microtubule Dynamics Scale with Cell Size to Set Spindle Length and Assembly Timing. Dev Cell. 2018; 45(4):496-511.e6. PMC: 6360954. DOI: 10.1016/j.devcel.2018.04.022. View

Wollman R, Civelekoglu-Scholey G, Scholey J, Mogilner A . Reverse engineering of force integration during mitosis in the Drosophila embryo. Mol Syst Biol. 2008; 4:195. PMC: 2424291. DOI: 10.1038/msb.2008.23. View

Maiato H, Deluca J, Salmon E, Earnshaw W . The dynamic kinetochore-microtubule interface. J Cell Sci. 2004; 117(Pt 23):5461-77. DOI: 10.1242/jcs.01536. View

Griffiths K, Masuda H, Dhut S, Toda T . Fission yeast dam1-A8 mutant is resistant to and rescued by an anti-microtubule agent. Biochem Biophys Res Commun. 2008; 368(3):670-6. DOI: 10.1016/j.bbrc.2008.01.156. View

Salmon E, Bloom K . Tension sensors reveal how the kinetochore shares its load. Bioessays. 2017; 39(7). PMC: 5543933. DOI: 10.1002/bies.201600216. View

Zaytsev A, Grishchuk E . Basic mechanism for biorientation of mitotic chromosomes is provided by the kinetochore geometry and indiscriminate turnover of kinetochore microtubules. Mol Biol Cell. 2015; 26(22):3985-98. PMC: 4710231. DOI: 10.1091/mbc.E15-06-0384. View

10.

Cane S, Ye A, Luks-Morgan S, Maresca T . Elevated polar ejection forces stabilize kinetochore-microtubule attachments. J Cell Biol. 2013; 200(2):203-18. PMC: 3549975. DOI: 10.1083/jcb.201211119. View

11.

Olmsted Z, Colliver A, Riehlman T, Paluh J . Kinesin-14 and kinesin-5 antagonistically regulate microtubule nucleation by γ-TuRC in yeast and human cells. Nat Commun. 2014; 5:5339. PMC: 4220466. DOI: 10.1038/ncomms6339. View

12.

Chen C, Porche K, Rayment I, Gilbert S . The ATPase pathway that drives the kinesin-14 Kar3Vik1 powerstroke. J Biol Chem. 2012; 287(44):36673-82. PMC: 3481271. DOI: 10.1074/jbc.M112.395590. View

13.

Hueschen C, Galstyan V, Amouzgar M, Phillips R, Dumont S . Microtubule End-Clustering Maintains a Steady-State Spindle Shape. Curr Biol. 2019; 29(4):700-708.e5. PMC: 6383811. DOI: 10.1016/j.cub.2019.01.016. View

14.

Loiodice I, Staub J, Gangi Setty T, Nguyen N, Paoletti A, Tran P . Ase1p organizes antiparallel microtubule arrays during interphase and mitosis in fission yeast. Mol Biol Cell. 2005; 16(4):1756-68. PMC: 1073658. DOI: 10.1091/mbc.e04-10-0899. View

15.

Nannas N, OToole E, Winey M, Murray A . Chromosomal attachments set length and microtubule number in the Saccharomyces cerevisiae mitotic spindle. Mol Biol Cell. 2014; 25(25):4034-48. PMC: 4263447. DOI: 10.1091/mbc.E14-01-0016. View

16.

Gardner M, Odde D, Bloom K . Kinesin-8 molecular motors: putting the brakes on chromosome oscillations. Trends Cell Biol. 2008; 18(7):307-10. PMC: 2866008. DOI: 10.1016/j.tcb.2008.05.003. View

17.

Yukawa M, Okazaki M, Teratani Y, Furuta K, Toda T . Kinesin-6 Klp9 plays motor-dependent and -independent roles in collaboration with Kinesin-5 Cut7 and the microtubule crosslinker Ase1 in fission yeast. Sci Rep. 2019; 9(1):7336. PMC: 6517423. DOI: 10.1038/s41598-019-43774-7. View

18.

Gay G, Courtheoux T, Reyes C, Tournier S, Gachet Y . A stochastic model of kinetochore-microtubule attachment accurately describes fission yeast chromosome segregation. J Cell Biol. 2012; 196(6):757-74. PMC: 3308688. DOI: 10.1083/jcb.201107124. View

19.

Gao T, Blackwell R, Glaser M, Betterton M, Shelley M . Multiscale polar theory of microtubule and motor-protein assemblies. Phys Rev Lett. 2015; 114(4):048101. PMC: 4425281. DOI: 10.1103/PhysRevLett.114.048101. View

20.

Smith C, McAinsh A, Burroughs N . Human kinetochores are swivel joints that mediate microtubule attachments. Elife. 2016; 5. PMC: 5050023. DOI: 10.7554/eLife.16159. View