Science 10.1126/science.aaa5111

Credit: YAO WONG

Centrioles are microtubule-based organelles that generate centrosomes, the main microtubule-organizing centers of animal cells. During mitosis, centrosomes form the opposing ends of the bipolar mitotic spindle. Surprisingly, more than 100 years after their discovery, it is still not clear whether centrosomes are needed for cellular proliferation. Previous attempts to remove centrosomes either surgically or through laser ablation resulted in transient centrosome loss with little to no disruption of cell division. An approach that would 'permanently' remove centrosomes would be to target Plk4, a serine/threonine kinase that regulates centriole assembly. Although a number of small-molecule inhibitors of Plk4 have been described, none deplete centrioles and centrosomes from cells. Wong et al. have synthesized two selective Plk4 inhibitors, centrinone and centrinone B, based on the pan–Aurora kinase inhibitor VX680. The centrinones are >1,000-fold more selective for Plk4 than Aurora A or B because they target an uncommon hinge region methionine of Plk4. Treating cancer cells with the centrinones resulted in the progressive loss of centriolar and pericentriolar markers and in continuous proliferation, albeit with increased mitotic errors. Interestingly, centrinone inhibition was reversible, with centrioles re-forming within one day of compound removal. In contrast to its effects on cancer cells, the authors found that centrinone-mediated loss of centrosomes in normal cells was associated with a G1 cell-cycle arrest. This arrest was attributed to increased p53 levels, as knockdown of p53 allowed cells to proliferate in the absence of centrosomes. This p53-mediated cell-cycle arrest was not due to changes in DNA damage or stress signaling, suggesting a potentially new mechanism. Numerous cancer cells that proliferate in the presence of centrinone contained p53-pathway mutations. Overall, the use of centrinone has addressed a longstanding question about the functional requirement of centrosomes and offers a potential route for investigating additional cell biological questions.