Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells
- The Netherlands Cancer Institute, Netherlands
- VU University Medical Center, Netherlands
- University of Birmingham, United Kingdom
- University Medical Center Groningen, Netherlands
Abstract
In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks (DSBs). In this system, loss of p53 allowed mitogen-independent proliferation, not by suppressing apoptosis, but rather by restoring origin firing and reducing DNA breakage. Loss of G1/S control also caused DNA damage and activation of p53 in an in vivo retinoblastoma model. Moreover, in a teratoma model, loss of Trp53 reduced DNA breakage. Thus, loss of p53 may promote growth of incipient cancer cells by reducing replication-stress-induced DNA damage.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
KWF Kankerbestrijding (2007-3790)
- Tanja van Harn
- Asli Kucukosmanoglu
European Molecular Biology Organization (194-2011)
- Tanja van Harn
KWF Kankerbestrijding (2014-6702)
- Bente Benedict
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Katharina Schlacher, UT MD Anderson Cancer Center, United States
Ethics
Animal experimentation: All experiments involving animals comply with local and international regulations and ethical guidelines (protocol 12026) and have been authorized by the local experimental animal ethical committee at the Netherlands Cancer Institure (DEC-NKI).
Version history
- Received: May 1, 2018
- Accepted: September 28, 2018
- Accepted Manuscript published: October 16, 2018 (version 1)
- Version of Record published: November 7, 2018 (version 2)
Copyright
© 2018, Benedict et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells
eLife 7:e37868.
https://doi.org/10.7554/eLife.37868
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