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.
Highlights
Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion
We generated SV40-immortalized fibroblasts derived from a WABS patient and functionally corrected the cohesion defects in this cell line by stable transfection of DDX11 cDNA
We show that impaired sister chromatid cohesion, which is in itself not fatal, could become detrimental when a cell encounters a substantial reduction of anaphase promoting complex or cyclosome (APC/C) activity
Summary
Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion. Defects in the cohesion network are the cause of several rare genetic diseases named cohesinopathies These include Cornelia de Lange Syndrome (CdLS, caused by mutations in NIPBL, Smc1A, Smc[3], Rad[21] or HDAC8 (refs 2–5)), Roberts Syndrome (RBS, caused by ESCO2 mutations6,7) and Warsaw Breakage Syndrome (WABS, caused by DDX11 mutations[8]). The MCC blocks the anaphase promoting complex or cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase, so that three of its substrates remain stable for multiple hours: Securin, which blocks Separase[27], cyclin B1, which keeps Cdk[1] active to keep cells in mitosis[28], and geminin, which blocks premature DNA replication licensing[29]. Achievement of proper attachment and centromere tension silences the SAC, activating APC/C-Cdc[20] This leads to degradation of securin to release Separase, cleaving the cohesin subunit Rad[21] and allowing chromatid separation to opposite spindle poles. P31comet promotes the release of Mad[2] from the MCC, thereby initiating Cdc[20] release downstream of kinetochores[34,35,36,37]
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