TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells

Chihiro Yamada; Aya Morooka; Seira Miyazaki; Masayoshi Nagai; Satoru Mase; Kenji Iemura; Most Naoshia Tasnin; Tsuneyuki Takuma; Shotaro Nakamura; Shamsul Morshed; Naoki Koike; Md Golam Mostofa; Muhammad Arifur Rahman; Tasnuva Sharmin; Haruko Katsuta; Kotaro Ohara; Kozo Tanaka; Takashi Ushimaru

doi:10.1016/j.isci.2021.103675

TORC1 inactivation promotes APC/C-dependent mitotic slippage in yeast and human cells

iScience. 2021 Dec 27;25(2):103675. doi: 10.1016/j.isci.2021.103675. eCollection 2022 Feb 18.

Authors

Chihiro Yamada¹, Aya Morooka², Seira Miyazaki², Masayoshi Nagai^{1

3}, Satoru Mase¹, Kenji Iemura³, Most Naoshia Tasnin⁴, Tsuneyuki Takuma¹, Shotaro Nakamura¹, Shamsul Morshed⁴, Naoki Koike⁴, Md Golam Mostofa⁴, Muhammad Arifur Rahman⁴, Tasnuva Sharmin⁴, Haruko Katsuta¹, Kotaro Ohara², Kozo Tanaka³, Takashi Ushimaru^{1

2

4}

Affiliations

¹ Department of Science, Graduate School of Integrated Science and Technology, Shizuoka University, Shizuoka 422-8021, Japan.
² Department of Biological Science, Faculty of Science, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan.
³ Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
⁴ Graduate School of Science and Technology, Shizuoka University, Ohya 836, Suruga-ku, Shizuoka 422-8021, Japan.

Abstract

Unsatisfied kinetochore-microtubule attachment activates the spindle assembly checkpoint to inhibit the metaphase-anaphase transition. However, some cells eventually override mitotic arrest by mitotic slippage. Here, we show that inactivation of TORC1 kinase elicits mitotic slippage in budding yeast and human cells. Yeast mitotic slippage was accompanied with aberrant aspects, such as degradation of the nucleolar protein Net1, release of phosphatase Cdc14, and anaphase-promoting complex/cyclosome (APC/C)-Cdh1-dependent degradation of securin and cyclin B in metaphase. This mitotic slippage caused chromosome instability. In human cells, mammalian TORC1 (mTORC1) inactivation also invoked mitotic slippage, indicating that TORC1 inactivation-induced mitotic slippage is conserved from yeast to mammalian cells. However, the invoked mitotic slippage in human cells was not dependent on APC/C-Cdh1. This study revealed an unexpected involvement of TORC1 in mitosis and provides information on undesirable side effects of the use of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.

Keywords: Biological sciences; Cell biology; Molecular biology.