Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function

Nat Commun. 2015 Oct 1:6:8399. doi: 10.1038/ncomms9399.


Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion. Here, a paired genome-wide siRNA screen in patient-derived cell lines reveals that WABS cells do not tolerate partial depletion of individual APC/C subunits or the spindle checkpoint inhibitor p31(comet). A combination of reduced cohesion and impaired APC/C function also leads to fatal mitotic arrest in diploid RPE1 cells. Moreover, WABS cell lines, and several cancer cell lines with cohesion defects, display a highly increased response to a new cell-permeable APC/C inhibitor, apcin, but not to the spindle poison paclitaxel. Synthetic lethality of APC/C inhibition and cohesion defects strictly depends on a functional mitotic spindle checkpoint as well as on intact microtubule pulling forces. This indicates that the underlying mechanism involves cohesion fatigue in response to mitotic delay, leading to spindle checkpoint re-activation and lethal mitotic arrest. Our results point to APC/C inhibitors as promising therapeutic agents targeting cohesion-defective cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome / physiology*
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromosome Segregation
  • Humans
  • Mitosis / physiology
  • Morpholines / pharmacology
  • Nocodazole / pharmacology
  • Paclitaxel / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Purines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Sister Chromatid Exchange / drug effects
  • Sister Chromatid Exchange / physiology*
  • Tubulin Modulators / pharmacology


  • Cell Cycle Proteins
  • Morpholines
  • Protein Kinase Inhibitors
  • Purines
  • RNA, Small Interfering
  • Tubulin Modulators
  • Anaphase-Promoting Complex-Cyclosome
  • Paclitaxel
  • Nocodazole
  • 2-(4-morpholinoanilino)-6-cyclohexylaminopurine