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

• Published in: Nature communications Vol. 6; no. 1; p. 8399
• Main Authors: de Lange, Job, Faramarz, Atiq, Oostra, Anneke B., de Menezes, Renee X., van der Meulen, Ida H., Rooimans, Martin A., Rockx, Davy A., Brakenhoff, Ruud H., van Beusechem, Victor W., King, Randall W., de Winter, Johan P., Wolthuis, Rob M. F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/1; 13/106; 13/31; 13/89; 14/35; 14/63; 631/67/1059/602; 631/80/641/2187; 631/80/641/2351; Adenomatous polyposis coli; Anaphase-Promoting Complex-Cyclosome - physiology; Biotechnology; Breakage; Cancer; Cell Cycle Checkpoints; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Chemical compounds; Chromosome Segregation; Cohesion; Defects; Deoxyribonucleic acid; Depletion; DNA; DNA helicase; Genetic screening; Genomes; Humanities and Social Sciences; Humans; Immune checkpoint; Inhibitors; Lethality; Mitosis - physiology; Morpholines - pharmacology; multidisciplinary; Nocodazole - pharmacology; Paclitaxel; Paclitaxel - pharmacology; Pharmacology; Protein Kinase Inhibitors - pharmacology; Purines - pharmacology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); siRNA; Sister Chromatid Exchange - drug effects; Sister Chromatid Exchange - physiology; Tubulin Modulators - pharmacology; Tumor cell lines; Yeast
• ISSN: 2041-1723; 2041-1723
• 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. Cohesion is associated with many forms of cancer. De Lange et al . show that such cohesion defects can sensitise cells to apoptosis in response to a new APC/C ubiquitin ligase inhibitor, by prolonging mitotic arrest and checkpoint activation due to cohesion fatigue.