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

Author

Listed:
  • Job de Lange

    (section Oncogenetics, VU University Medical Center)

  • Atiq Faramarz

    (section Oncogenetics, VU University Medical Center)

  • Anneke B. Oostra

    (section Oncogenetics, VU University Medical Center)

  • Renee X. de Menezes

    (VU University Medical Center)

  • Ida H. van der Meulen

    (RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center)

  • Martin A. Rooimans

    (section Oncogenetics, VU University Medical Center)

  • Davy A. Rockx

    (section Oncogenetics, VU University Medical Center)

  • Ruud H. Brakenhoff

    (VU University Medical Center)

  • Victor W. van Beusechem

    (RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center)

  • Randall W. King

    (Harvard Medical School)

  • Johan P. de Winter

    (section Oncogenetics, VU University Medical Center)

  • Rob M. F. Wolthuis

    (section Oncogenetics, VU University Medical Center)

Abstract

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 p31comet. 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.

Suggested Citation

  • Job de Lange & Atiq Faramarz & Anneke B. Oostra & Renee X. de Menezes & Ida H. van der Meulen & Martin A. Rooimans & Davy A. Rockx & Ruud H. Brakenhoff & Victor W. van Beusechem & Randall W. King & Jo, 2015. "Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9399
    DOI: 10.1038/ncomms9399
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