Developmental Cell
Volume 52, Issue 6, 23 March 2020, Pages 683-698.e7
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Article
WAPL-Dependent Repair of Damaged DNA Replication Forks Underlies Oncogene-Induced Loss of Sister Chromatid Cohesion

https://doi.org/10.1016/j.devcel.2020.01.024Get rights and content
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Highlights

  • Cohesion loss is a common feature of cancer cells

  • DNA replication stress induces cohesion loss

  • The cohesin remover WAPL is essential in replication stress conditions

  • WAPL promotes repair and restart of a broken replication fork

Summary

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

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

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