Department of Cell and Developmental Biology
Cell Cycle Checkpoints; Cell Line; Cell Proliferation; Centrioles; Chromosome Segregation; *Genomic Instability; Humans; Microtubules; Mitosis; Protein Transport; Protein-Serine-Threonine Kinases; Tumor Suppressor Protein p53
Cell Biology | Cellular and Molecular Physiology | Genetics | Genomics
Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin and restoration of endogenous Plk4 levels in cells that lack centrioles led to the penetrant formation of de novo centrioles that gained the ability to organize microtubules and duplicate. In summary, we uncover a p53-dependent surveillance mechanism that protects against genome instability by preventing cell growth after centriole duplication failure.
Rights and Permissions
© 2015 Lambrus et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
DOI of Published Version
J Cell Biol. 2015 Jul 6;210(1):63-77. doi: 10.1083/jcb.201502089. Link to article on publisher's site
The Journal of cell biology
Lambrus, Bramwell G.; Uetake, Yumi; Clutario, Kevin M.; Daggubati, Vikas; Snyder, Michael; Sluder, Greenfield; and Holland, Andrew J., "p53 protects against genome instability following centriole duplication failure" (2015). Cell and Developmental Biology Publications. 165.