Unresolved recombination intermediates lead to ultra-fine anaphase bridges, chromosome breaks and aberrations

Nat Cell Biol. 2018 Jan;20(1):92-103. doi: 10.1038/s41556-017-0011-1. Epub 2017 Dec 18.

Abstract

The resolution of joint molecules that link recombining sister chromatids is essential for chromosome segregation. Here, we determine the fate of unresolved recombination intermediates arising in cells lacking two nucleases required for resolution (GEN1 -/- knockout cells depleted of MUS81). We find that intermediates persist until mitosis and form a distinct class of anaphase bridges, which we term homologous recombination ultra-fine bridges (HR-UFBs). HR-UFBs are distinct from replication stress-associated UFBs, which arise at common fragile sites, and from centromeric UFBs. HR-UFBs are processed by BLM helicase to generate single-stranded RPA-coated bridges that are broken during mitosis. In the next cell cycle, DNA breaks activate the DNA damage checkpoint response, and chromosome fusions arise by non-homologous end joining. Consequently, the cells undergo cell cycle delay and massive cell death. These results lead us to present a model detailing how unresolved recombination intermediates can promote DNA damage and chromosomal instability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase*
  • Cell Death
  • Cell Line, Tumor
  • Chromatids
  • Chromosomal Instability
  • Chromosome Aberrations*
  • Chromosome Breakage*
  • Chromosome Fragile Sites
  • Chromosome Segregation*
  • DNA End-Joining Repair
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Endonucleases / deficiency
  • Endonucleases / genetics
  • HEK293 Cells
  • Holliday Junction Resolvases / deficiency
  • Holliday Junction Resolvases / genetics
  • Homologous Recombination*
  • Humans
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Ploidies
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism

Substances

  • DNA-Binding Proteins
  • Endonucleases
  • MUS81 protein, human
  • GEN1 protein, human
  • Holliday Junction Resolvases
  • Bloom syndrome protein
  • RecQ Helicases