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

Elife. 2020 Nov 3:9:e58020. doi: 10.7554/eLife.58020.

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.

Keywords: DNA replication; cell biology; chromosomes; gene expression; human; replication stress; splicing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle
  • Cell Line
  • Cell Nucleus / genetics*
  • Cell Nucleus / metabolism
  • DNA Replication*
  • G1 Phase*
  • Humans
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Splicing
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*

Substances

  • Protein Isoforms
  • Rif1 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor p53-Binding Protein 1