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: De novo centriole assembly required cell cycle progression, as arresting cells in G1 phase with mimosine or the CDK2/4 inhibitor PD0332991 greatly reduced the frequency of de novo centriole formation by 2 d after IAA washout (Fig. S5, A–C; Watson et al., 1991; Fry et al., 2004). To examine the composition of de novo centrioles we performed immunostaining for several centriole components at 1, 2, 3, and 4 d after IAA washout. By 2 d after IAA washout, Plk4, CPAP, CEP135, CEP152, CEP164, and CEP192 colocalized with at least one Centrin-marked, de novo centriole in >75% of cells (Fig. 6 G and Fig. S5 D). In contrast, only 40–55% of cells with de novo centrioles contained centriole-localized STIL or SAS6, consistent with the fact that STIL and SAS6 are absent from centrioles during G1 phase (Strnad et al., 2007; Tang et al., 2011; Arquint et al., 2012; Arquint and Nigg, 2014). Importantly, all of the de novo centrioles observed in transverse sections by EM exhibited a normal morphology, with triplet microtubules arranged with ninefold rotational symmetry (n = 83 total de novo centrioles, 13 of which were sectioned transversely and could be assessed for rotational symmetry; Fig. 7, A–B).
Affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.