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Kinetochore Stretching-Mediated Rapid Silencing of Mitotic Checkpoint Required for Failsafe Chromosome Segregation

50 Pages Posted: 24 Oct 2019 Sneak Peek Status: Review Complete

See all articles by Kazuhiko S.K. Uchida

Kazuhiko S.K. Uchida

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Minji Jo

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Kota Nagasaka

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Motoko Takahashi

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Norihisa Shindo

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Kozo Tanaka

Tohoku University - Department of Molecular Oncology

Hiroshi Masumoto

Kazusa DNA Research Institute - Laboratory of Chromosome Engineering

Tatsuo Fukagawa

Osaka University - Graduate School of Frontier Biosciences

Toru Hirota

Japanese Foundation for Cancer Research - Division of Experimental Pathology

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Abstract

The spindle-assembly checkpoint facilitates mitotic fidelity by delaying anaphase onset in response to microtubule vacancy at kinetochores. Following microtubule attachment, kinetochores receive microtubule-derived forces, which causes kinetochores to undergo repetitive cycles of deformations, the motion referred to as kinetochore stretching. The nature of forces and the relevance relating this motion are not well understood. Here we show that kinetochore stretching occurs within a framework of single end-on attached kinetochores, irrespectively of microtubule poleward pulling-force. An experimental setup to conditionally interfere with the stretching allowed us to define that kinetochore stretching comprises an essential process of checkpoint silencing by promoting PP1 phosphatase recruitment, after establishing of end-on attachments and removing the majority of checkpoint-activating kinase Mps1 from kinetochores. Remarkably, we found that the lower frequency of kinetochore stretching correlates with prolonged metaphase and also with the degree of chromosomal instability in cancer cell lines. Perturbation of kinetochore stretching and checkpoint silencing in chromosomally stable cells produced anaphase bridges which can be alleviated by reducing chromosome-loaded cohesin. These observations indicate that kinetochore stretching-mediated checkpoint silencing provides an unanticipated etiology underlying chromosomal instability, and underscore the significance of a rapid metaphase-to-anaphase transition in sustaining mitotic fidelity.

Keywords: Cell division, Chromosomal instability, Kinetochore, Mitosis, Metaphase-to-Anaphase transition, Spindle-assembly checkpoint

Suggested Citation

Uchida, Kazuhiko S.K. and Jo, Minji and Nagasaka, Kota and Takahashi, Motoko and Shindo, Norihisa and Tanaka, Kozo and Masumoto, Hiroshi and Fukagawa, Tatsuo and Hirota, Toru, Kinetochore Stretching-Mediated Rapid Silencing of Mitotic Checkpoint Required for Failsafe Chromosome Segregation (October 21, 2019). Available at SSRN: https://ssrn.com/abstract=3473262 or http://dx.doi.org/10.2139/ssrn.3473262
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kazuhiko S.K. Uchida

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Japan

Minji Jo

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Japan

Kota Nagasaka

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Japan

Motoko Takahashi

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Japan

Norihisa Shindo

Japanese Foundation for Cancer Research - Division of Experimental Pathology

Japan

Kozo Tanaka

Tohoku University - Department of Molecular Oncology

Japan

Hiroshi Masumoto

Kazusa DNA Research Institute - Laboratory of Chromosome Engineering

Japan

Tatsuo Fukagawa

Osaka University - Graduate School of Frontier Biosciences ( email )

Japan

Toru Hirota (Contact Author)

Japanese Foundation for Cancer Research - Division of Experimental Pathology ( email )

Japan

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