title: Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function.
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 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.
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Job
authors.initials: J
authors.lastname: de Lange
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Atiq
authors.initials: A
authors.lastname: Faramarz
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Anneke B
authors.initials: AB
authors.lastname: Oostra
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Renee X
authors.initials: RX
authors.lastname: de Menezes
authors.affiliation: Department of Medical Oncology, RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ida H
authors.initials: IH
authors.lastname: van der Meulen
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Rooimans
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Davy A
authors.initials: DA
authors.lastname: Rockx
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Ruud H
authors.initials: RH
authors.lastname: Brakenhoff
authors.affiliation: Department of Medical Oncology, RNA Interference Functional Oncogenomics Laboratory, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Victor W
authors.initials: VW
authors.lastname: van Beusechem
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.affiliation: Department of Clinical Genetics, section Oncogenetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Rob M F
authors.initials: RMF
authors.lastname: Wolthuis
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000502:physiology*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D020090:Chromosome Segregation; D006801:Humans; D008938:Mitosis / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000502:physiology*; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011687:Purines; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D064173:Anaphase-Promoting Complex-Cyclosome; D017239:Paclitaxel; D015739:Nocodazole; C484369:2-(4-morpholinoanilino)-6-cyclohexylaminopurine