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.
Metrics
-
- 5,941
- views
-
- 820
- downloads
-
- 32
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Cancer Biology
- Cell Biology
Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.
-
- Cancer Biology
- Cell Biology
Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.
