RIF1-Long promotes G1 phase 53BP1 nuclear bodies to protect against replication stress

Human RIF1 functions in DNA replication and damage repair. Of clinical interest, RIF1-depleted cells are highly sensitive to replication inhibitors such as Aphidicolin, but the reasons for this sensitivity have been enigmatic. Here we show that RIF1 must be present both during replication stress and...

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Bibliographic Details
Published inbioRxiv
Main Authors Watts, Lotte P, Natsume, Toyoaki, Saito, Yuichiro, Garzon, Javier, Kanemaki, Masato T, Shin-Ichiro Hiraga, Donaldson, Anne D
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.02.2020
Subjects
Alternative splicing
Aphidicolin
Cell cycle
Cell survival
DNA biosynthesis
DNA damage
DNA repair
G1 phase
Genomes
Isoforms
Replication
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Summary:Human RIF1 functions in DNA replication and damage repair. Of clinical interest, RIF1-depleted cells are highly sensitive to replication inhibitors such as Aphidicolin, 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. RIF1 Long and Short isoforms are produced by alternative splicing. We find that RIF1-Long alone can protect cells against replication inhibition, but RIF1-Short is completely incapable of mediating protection. Consistent with its isoform-specific role in enabling survival, RIF1-Long is specifically 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 to support genome maintenance following replication insult, with the RIF1-Long isoform playing a previously unsuspected but crucial role in damage site protection during the ensuing G1 phase.
DOI:10.1101/859199