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

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, Johan P. de Winter and Rob M. F. Wolthuis ()
Additional contact information
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9399

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