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The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress

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 alternati...

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Autores principales: Watts, Lotte P, Natsume, Toyoaki, Saito, Yuichiro, Garzon, Javier, Dong, Qianqian, Boteva, Lora, Gilbert, Nick, Kanemaki, Masato T, Hiraga, Shin-ichiro, Donaldson, Anne D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671687/
https://www.ncbi.nlm.nih.gov/pubmed/33141022
http://dx.doi.org/10.7554/eLife.58020
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author Watts, Lotte P
Natsume, Toyoaki
Saito, Yuichiro
Garzon, Javier
Dong, Qianqian
Boteva, Lora
Gilbert, Nick
Kanemaki, Masato T
Hiraga, Shin-ichiro
Donaldson, Anne D
author_facet Watts, Lotte P
Natsume, Toyoaki
Saito, Yuichiro
Garzon, Javier
Dong, Qianqian
Boteva, Lora
Gilbert, Nick
Kanemaki, Masato T
Hiraga, Shin-ichiro
Donaldson, Anne D
author_sort Watts, Lotte P
collection PubMed
description 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.
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spelling pubmed-76716872020-11-18 The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress Watts, Lotte P Natsume, Toyoaki Saito, Yuichiro Garzon, Javier Dong, Qianqian Boteva, Lora Gilbert, Nick Kanemaki, Masato T Hiraga, Shin-ichiro Donaldson, Anne D eLife Cell Biology 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. eLife Sciences Publications, Ltd 2020-11-03 /pmc/articles/PMC7671687/ /pubmed/33141022 http://dx.doi.org/10.7554/eLife.58020 Text en © 2020, Watts et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Watts, Lotte P
Natsume, Toyoaki
Saito, Yuichiro
Garzon, Javier
Dong, Qianqian
Boteva, Lora
Gilbert, Nick
Kanemaki, Masato T
Hiraga, Shin-ichiro
Donaldson, Anne D
The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title_full The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title_fullStr The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title_full_unstemmed The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title_short The RIF1-long splice variant promotes G1 phase 53BP1 nuclear bodies to protect against replication stress
title_sort rif1-long splice variant promotes g1 phase 53bp1 nuclear bodies to protect against replication stress
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671687/
https://www.ncbi.nlm.nih.gov/pubmed/33141022
http://dx.doi.org/10.7554/eLife.58020
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