A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis

Bramwell G. Lambrus, Vikas Daggubati, Yumi Uetake, Phillip M. Scott, Kevin M. Clutario, Greenfield Sluder, Andrew Holland

Research output: Contribution to journalArticle

Abstract

Precise regulation of centrosome number is critical for accurate chromosome segregation and the maintenance of genomic integrity. In nontransformed cells, centrosome loss triggers a p53-dependent surveillance pathway that protects against genome instability by blocking cell growth. However, the mechanism by which p53 is activated in response to centrosome loss remains unknown. Here, we have used genome-wide CRI SPR/Cas9 knockout screens to identify a USP28-53BP1-p53-p21 signaling axis at the core of the centrosome surveillance pathway. We show that USP28 and 53BP1 act to stabilize p53 after centrosome loss and demonstrate this function to be independent of their previously characterized role in the DNA damage response. Surprisingly, the USP28-53BP1-p53-p21 signaling pathway is also required to arrest cell growth after a prolonged prometaphase. We therefore propose that centrosome loss or a prolonged mitosis activate a common signaling pathway that acts to prevent the growth of cells that have an increased propensity for mitotic errors.

Original languageEnglish (US)
Pages (from-to)143-153
Number of pages11
JournalJournal of Cell Biology
Volume214
Issue number2
DOIs
StatePublished - Jul 18 2016

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Centrosome
Mitosis
Growth
Prometaphase
Chromosome Segregation
Genomic Instability
DNA Damage
Maintenance
Genome

ASJC Scopus subject areas

  • Cell Biology

Cite this

Lambrus, B. G., Daggubati, V., Uetake, Y., Scott, P. M., Clutario, K. M., Sluder, G., & Holland, A. (2016). A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. Journal of Cell Biology, 214(2), 143-153. https://doi.org/10.1083/jcb.201604054

A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. / Lambrus, Bramwell G.; Daggubati, Vikas; Uetake, Yumi; Scott, Phillip M.; Clutario, Kevin M.; Sluder, Greenfield; Holland, Andrew.

In: Journal of Cell Biology, Vol. 214, No. 2, 18.07.2016, p. 143-153.

Research output: Contribution to journalArticle

Lambrus, BG, Daggubati, V, Uetake, Y, Scott, PM, Clutario, KM, Sluder, G & Holland, A 2016, 'A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis', Journal of Cell Biology, vol. 214, no. 2, pp. 143-153. https://doi.org/10.1083/jcb.201604054
Lambrus BG, Daggubati V, Uetake Y, Scott PM, Clutario KM, Sluder G et al. A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. Journal of Cell Biology. 2016 Jul 18;214(2):143-153. https://doi.org/10.1083/jcb.201604054
Lambrus, Bramwell G. ; Daggubati, Vikas ; Uetake, Yumi ; Scott, Phillip M. ; Clutario, Kevin M. ; Sluder, Greenfield ; Holland, Andrew. / A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. In: Journal of Cell Biology. 2016 ; Vol. 214, No. 2. pp. 143-153.
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