Identification of MAC1: A Small Molecule That Rescues Spindle Bipolarity in Monastrol-Treated Cells.
The genetic integrity of each organism is intimately tied to the correct segregation of its genome during mitosis. Insights into the underlying mechanisms are fundamental for both basic research and the development of novel strategies to treat mitosis-relevant diseases such as cancer. Due to their fast mode of action, small molecules are invaluable tools to dissect mitosis. Yet, there is a great demand for novel antimitotic compounds. We performed a chemical genetic suppression screen to identify compounds that restore spindle bipolarity in cells treated with Monastrol, an inhibitor of the mitotic kinesin Eg5. We identified one compound-MAC1-that rescued spindle bipolarity in cells lacking Eg5 activity. Mechanistically, MAC1 induces the formation of additional microtubule nucleation centers, which allows kinesin Kif15-dependent bipolar spindle assembly in the absence of Eg5 activity. Thus, our chemical genetic suppression screen revealed novel unexpected insights into the mechanism of spindle assembly in mammalian cells.
Department of Biology and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz , Universitätsstr. 10, 78467 Konstanz, Germany.
Naowras
N
Al-Obaidi
Department of Systems Biology, Harvard Medical School , Boston, Massachusetts 02115, United States.
Timothy J
TJ
Mitchison
Departments of Molecular, Cellular, and Developmental Biology, Chemistry, and Pharmacology, Yale University , 219 Prospect St., New Haven, Connecticut, United States.
Craig M
CM
Crews
Department of Biology and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz , Universitätsstr. 10, 78467 Konstanz, Germany.
Thomas U
TU
Mayer
D000072283:A549 Cells; D050256:Antimitotic Agents / Q000494:pharmacology*; D003511:Cyclohexanols / Q000494:pharmacology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022101:Microtubule-Organizing Center / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D064047:Spindle Poles / Q000187:drug effects*; D013871:Thiones / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
D050256:Antimitotic Agents; D003511:Cyclohexanols; C470243:KIF11 protein, human; C486567:KIF15 protein, human; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013871:Thiones; D014404:Tubulin; C000622570:monastrol antagonizing compound 1; C400223:monastrol; D016547:Kinesins