Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest

Research output: Contribution to journalArticle

Abstract

Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of p53. p53-deficient cells fail to arrest, leading to centrosome and spindle dysfunction and aneuploidy. We propose that loss of centrosome integrity activates a checkpoint that inhibits G1-S progression. This model satisfies the definition of a checkpoint in having three elements: a perturbation that is sensed, a transducer (p53) and a receiver (p21).

Details

Authors
  • Keith Mikule
  • Benedicte Delaval
  • Philipp Kaldis
  • Agata Jurcyzk
  • Polla Hergert
  • Stephen Doxsey
External organisations
  • University of Massachusetts Medical School
  • National Cancer Institute, USA
  • Wadsworth Center for Laboratories and Research
Original languageEnglish
Pages (from-to)160-170
JournalNature Cell Biology
Volume9
Issue number2
Publication statusPublished - 2007 Feb 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes