WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion

Dev Cell. 2020 Mar 23;52(6):683-698.e7. doi: 10.1016/j.devcel.2020.01.024. Epub 2020 Feb 20.


Premature loss of sister chromatid cohesion at metaphase is a diagnostic marker for different cohesinopathies. Here, we report that metaphase spreads of many cancer cell lines also show premature loss of sister chromatid cohesion. Cohesion loss occurs independently of mutations in cohesion factors including SA2, a cohesin subunit frequently inactivated in cancer. In untransformed cells, induction of DNA replication stress by activation of oncogenes or inhibition of DNA replication is sufficient to trigger sister chromatid cohesion loss. Importantly, cell growth under conditions of replication stress requires the cohesin remover WAPL. WAPL promotes rapid RAD51-dependent repair and restart of broken replication forks. We propose that active removal of cohesin allows cancer cells to overcome DNA replication stress. This leads to oncogene-induced cohesion loss from newly synthesized sister chromatids that may contribute to genomic instability and likely represents a targetable cancer cell vulnerability.

Keywords: DNA double strand breaks; DNA repair; DNA replication stress; KRAS; RAD51; STAG2; WAPL; cohesinopathies; oncogene-induced cohesion loss; sister chromatid cohesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Chromatids / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Repair*
  • DNA Replication
  • HEK293 Cells
  • Humans
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • ras Proteins / metabolism*


  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • WAPL protein, human
  • cohesins
  • ras Proteins