Journal Article

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

Chan, Ying Wai, West, Stephen C., Fugger, Kasper

2018

Overview

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. Chan et al. show that unresolved recombination intermediates form a previously unappreciated type of ultra-fine bridge. These bridges are broken upon cell division, leading to chromosome breaks and instability.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/1427 / 631/337/149 / 631/337/641 / Aberration / Anaphase / Biomedical and Life Sciences / Biotechnology / Bridges / Cancer Research / Care and treatment / Cell Biology / Cell cycle / Cell Death / Cell division / Cell Line, Tumor / Chromatids / Chromatin diminution / Chromosomal Instability / Chromosome Aberrations / Chromosome abnormalities / Chromosome Breakage / Chromosome Fragile Sites / Chromosome Segregation / Chromosomes / Deoxyribonucleic acid / Developmental Biology / DNA / DNA binding proteins / DNA damage / DNA End-Joining Repair / DNA helicase / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / Endonucleases - deficiency / Endonucleases - genetics / Fluorescent antibody technique / Fragile sites / Genomic instability / HEK293 Cells / Holliday Junction Resolvases - deficiency / Holliday Junction Resolvases - genetics / Homologous Recombination / Homology / Humans / Intermediates / Life Sciences / Mitosis / Non-homologous end joining / Nuclease / Nucleases / Osteoblasts - metabolism / Osteoblasts - pathology / Ploidies / RecQ Helicases - genetics / RecQ Helicases - metabolism / Risk factors / Sister chromatids / Stability / Stem Cells