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

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

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

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Citation: de Lange, J., A. Faramarz, A. B. Oostra, R. X. de Menezes, I. H. van der Meulen, M. A. Rooimans, D. A. Rockx, et al. 2015. “Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function.” Nature Communications 6 (1): 8399. doi:10.1038/ncomms9399. http://dx.doi.org/10.1038/ncomms9399.
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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.
Published Version: doi:10.1038/ncomms9399
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600715/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23473960
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