Academic Journal
Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function
| العنوان: | Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function |
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| المؤلفون: | 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. |
| المصدر: | Nature Communications ; volume 6, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2015 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/ncomms9399 |
| الاتاحة: | http://dx.doi.org/10.1038/ncomms9399 https://www.nature.com/articles/ncomms9399.pdf https://www.nature.com/articles/ncomms9399 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.B5C27C11 |
| قاعدة البيانات: | BASE |
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