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Plasma membrane damage limits replicative lifespan in yeast and human fibroblasts

View ORCID ProfileKeiko Kono, View ORCID ProfileYoshikazu Johmura, Yohsuke Moriyama, Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, View ORCID ProfileYoshikatsu Sato, Tetsuya Higashiyama, View ORCID ProfileMakoto Nakanishi
doi: https://doi.org/10.1101/2021.03.26.437120
Keiko Kono
1Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
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  • For correspondence: keiko.kono@oist.jp mkt-naka@ims.u-tokyo.ac.jp
Yoshikazu Johmura
2Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Yohsuke Moriyama
1Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
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Yumiko Masukagami
1Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
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Koutarou Nishimura
3Memorial Sloan Kettering Institute, Cell Biology Program and Center for Epigenetics Research, 1275 York Avenue, New York, NY 10065, USA
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Hunter Barbee
1Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
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Hiroshi Takase
4Core Laboratory, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho cho, Mizuho ku, Nagoya, Aichi 467-8601, Japan
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Shinju Sugiyama
1Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna, Okinawa 904-0495, Japan
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Yoshikatsu Sato
5Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan
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Tetsuya Higashiyama
5Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan
6Department of Biological Science, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Makoto Nakanishi
2Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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  • For correspondence: keiko.kono@oist.jp mkt-naka@ims.u-tokyo.ac.jp
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Abstract

Plasma membrane damage (PMD) occurs in all cell types due to environmental perturbation and cell-autonomous activities. However, cellular outcomes of PMD remain largely unknown except for recovery or death. Here, using yeast and human fibroblasts, we show that cellular senescence, irreversible cell cycle arrest contributing to organismal aging, is the third outcome of PMD. To identify the genes essential for PMD response, we performed a systematic yeast genome-wide screen. The screen identified 48 genes. The top hits in the screen are the endosomal sorting complexes required for transport (ESCRT) genes. Strikingly, the replicative lifespan regulator genes are enriched in our 48 hits, and indeed, PMD limits the replicative lifespan in budding yeast; the ESCRT activator AAA-ATPase VPS4-overexpression extends it. In normal human fibroblasts, PMD induces cellular senescence via p53. Our study demonstrates that PMD limits replicative lifespan in two different eukaryotic cell types and highlights an underappreciated but ubiquitous senescent cell subtype, namely PMD-dependent senescent cells.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 27, 2021.
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Plasma membrane damage limits replicative lifespan in yeast and human fibroblasts
Keiko Kono, Yoshikazu Johmura, Yohsuke Moriyama, Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, Yoshikatsu Sato, Tetsuya Higashiyama, Makoto Nakanishi
bioRxiv 2021.03.26.437120; doi: https://doi.org/10.1101/2021.03.26.437120
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Plasma membrane damage limits replicative lifespan in yeast and human fibroblasts
Keiko Kono, Yoshikazu Johmura, Yohsuke Moriyama, Yumiko Masukagami, Koutarou Nishimura, Hunter Barbee, Hiroshi Takase, Shinju Sugiyama, Yoshikatsu Sato, Tetsuya Higashiyama, Makoto Nakanishi
bioRxiv 2021.03.26.437120; doi: https://doi.org/10.1101/2021.03.26.437120

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