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Cell overgrowth during G1 arrest triggers an osmotic stress response and chronic p38 activation to promote cell cycle exit

Lisa Crozier, Reece Foy, Rozita Adib, Mihaly Badonyi, Ananya Kar, Jordan A. Holt, Rona Wilson, Clement Regnault, Phil Whitfield, View ORCID ProfileJoseph A. Marsh, View ORCID ProfileAdrian Saurin, Alexis R. Barr, View ORCID ProfileTony Ly
doi: https://doi.org/10.1101/2022.09.08.506843
Lisa Crozier
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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Reece Foy
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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Rozita Adib
2MRC London Institute of Medical Sciences, London, UK
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Mihaly Badonyi
3MRC Human Genetics Unit, University of Edinburgh, UK
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Ananya Kar
4Centre for Gene Regulation and Expression, School of Life Sciences, Dundee, UK
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Jordan A. Holt
2MRC London Institute of Medical Sciences, London, UK
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Rona Wilson
5Wellcome Centre for Cell Biology, University of Edinburgh, UK
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Clement Regnault
6Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
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Phil Whitfield
6Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
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Joseph A. Marsh
3MRC Human Genetics Unit, University of Edinburgh, UK
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  • ORCID record for Joseph A. Marsh
Adrian Saurin
1Cellular and Systems Medicine, Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Dundee, UK
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  • For correspondence: a.saurin@dundee.ac.uk a.barr@lms.mrc.ac.uk tly@dundee.ac.uk
Alexis R. Barr
2MRC London Institute of Medical Sciences, London, UK
7Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, UK
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  • For correspondence: a.saurin@dundee.ac.uk a.barr@lms.mrc.ac.uk tly@dundee.ac.uk
Tony Ly
4Centre for Gene Regulation and Expression, School of Life Sciences, Dundee, UK
5Wellcome Centre for Cell Biology, University of Edinburgh, UK
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  • For correspondence: a.saurin@dundee.ac.uk a.barr@lms.mrc.ac.uk tly@dundee.ac.uk
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SUMMARY

Cell size and the cell cycle are intrinsically coupled and abnormal increases in cell size are associated with senescence. The mechanism by which overgrowth primes cells to exit the cell cycle remains unclear. We investigate this using CDK4/6 inhibitors that arrest cell cycle progression in G0/G1 and are used to treat ER+/HER2-metastatic breast cancer. We demonstrate that long-term CDK4/6 inhibition promotes cellular overgrowth during the G0/G1 arrest, causing widespread proteome remodeling and p38-p53-p21-dependent cell cycle exit. Cell cycle exit is triggered by two waves of p21 induction. First, overgrowth during a G0/G1 arrest induces an osmotic stress response, producing the first wave of p21 induction. Second, when CDK4/6 inhibitors are removed, a fraction of cells escape G0/G1 arrest and enter S-phase where overgrowth-driven replication stress results in a second wave of p21 induction that causes cell cycle withdrawal from G2, or the subsequent G1. This could explain why cellular hypertrophy is associated with senescence and why CDK4/6 inhibitors have long-lasting anti-proliferative effects in patients.

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 4.0 International license.
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Posted September 08, 2022.
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Cell overgrowth during G1 arrest triggers an osmotic stress response and chronic p38 activation to promote cell cycle exit
Lisa Crozier, Reece Foy, Rozita Adib, Mihaly Badonyi, Ananya Kar, Jordan A. Holt, Rona Wilson, Clement Regnault, Phil Whitfield, Joseph A. Marsh, Adrian Saurin, Alexis R. Barr, Tony Ly
bioRxiv 2022.09.08.506843; doi: https://doi.org/10.1101/2022.09.08.506843
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Cell overgrowth during G1 arrest triggers an osmotic stress response and chronic p38 activation to promote cell cycle exit
Lisa Crozier, Reece Foy, Rozita Adib, Mihaly Badonyi, Ananya Kar, Jordan A. Holt, Rona Wilson, Clement Regnault, Phil Whitfield, Joseph A. Marsh, Adrian Saurin, Alexis R. Barr, Tony Ly
bioRxiv 2022.09.08.506843; doi: https://doi.org/10.1101/2022.09.08.506843

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