p53 protects against genome instability following centriole duplication failure.
Bottom Line: 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.
Affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.Show MeSH
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Mentions: RPE1 cells maintain a normal p53 response. Plk4AID/AID cells but not Plk4+/+ cells showed stabilization of p53 at 2 and 3 d after IAA addition (Fig. S4 A). We therefore tested whether stabilization of p53 contributes to the irreversible cell cycle arrest that occurs after Plk4 depletion and centriole duplication failure. Preventing p53 accumulation using a stably expressed p53 shRNA (Fig. S4 B) allowed the continued growth of cells lacking Plk4 (Fig. 5 A) and led to a partial recovery of the clonogenic survival of this population (Fig. S4, C and D). Our findings indicate that a failure of centriole duplication increases p53 levels, eliciting a p53-dependent cell cycle arrest. This is consistent with prior work showing that knockout cells lacking proteins essential for centriole duplication also fail to proliferate in the presence of p53 (Bazzi and Anderson, 2014; Izquierdo et al., 2014).
Affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.