The RIF1-Long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
- University of Aberdeen Institute of Medical Sciences, United Kingdom
- National Institute of Genetics, Japan
- University of Edinburgh, United Kingdom
Abstract
Human cells lacking RIF1 are highly sensitive to replication inhibitors, but the reasons for this sensitivity have been enigmatic. Here we show that RIF1 must be present both during replication stress and in the ensuing recovery period to promote cell survival. Of two isoforms produced by alternative splicing, we find that RIF1-Long alone can protect cells against replication inhibition, but RIF1-Short is incapable of mediating protection. Consistent with this isoform-specific role, RIF1-Long is required to promote the formation of the 53BP1 nuclear bodies that protect unrepaired damage sites in the G1 phase following replication stress. Overall, our observations show that RIF1 is needed at several cell cycle stages after replication insult, with the RIF1-Long isoform playing a specific role during the ensuing G1 phase in damage site protection.
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
Cancer Research UK (C1445/A20596)
- Anne D Donaldson
Cancer Research UK (C1445/A19059)
- Anne D Donaldson
Japan Society for the Promotion of Science (17K15068)
- Masato T Kanemaki
Japan Society for the Promotion of Science (18H02170)
- Masato T Kanemaki
Japan Society for the Promotion of Science (18H04719)
- Masato T Kanemaki
Medical Research Council (MC_UU_00007/13)
- Nick Gilbert
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Raymund J Wellinger, Fac Medecine/Université de Sherbrooke, Canada
Version history
- Received: April 17, 2020
- Accepted: November 2, 2020
- Accepted Manuscript published: November 3, 2020 (version 1)
- Version of Record published: November 17, 2020 (version 2)
Copyright
© 2020, Watts 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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The RIF1-Long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
eLife 9:e58020.
https://doi.org/10.7554/eLife.58020
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