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

Autor: de Lange J; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Faramarz A; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Oostra AB; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., de Menezes RX; Department of Epidemiology and Biostatistics, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands., van der Meulen IH; Department of Medical Oncology, RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands., Rooimans MA; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Rockx DA; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Brakenhoff RH; Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands., van Beusechem VW; Department of Medical Oncology, RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands., King RW; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA., de Winter JP; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands., Wolthuis RMF; Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2015 Oct 01; Vol. 6, pp. 8399. Date of Electronic Publication: 2015 Oct 01.
DOI: 10.1038/ncomms9399
Abstrakt: 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.
Databáze: MEDLINE