Original Article

Oncogene (2007) 26, 165–172. doi:10.1038/sj.onc.1209787; published online 10 July 2006

Sustained mitotic block elicits DNA breaks: one-step alteration of ploidy and chromosome integrity in mammalian cells

F Quignon1,3, L Rozier1,4, A-M Lachages1,4, A Bieth1,5, M Simili2 and M Debatisse1

  1. 1Institut Curie, Université Pierre et Marie Curie-Paris 6, CNRS UMR 7147, 26 rue d'Ulm, 75248, Paris Cédex 05, France
  2. 2Instituto Fisiologia Clinica, CNR, Area della Ricerca, Pisa, Italy

Correspondence: Dr M Debatisse, Section de Recherche, Institut Curie, 26 rue d'Ulm, UMR 7147, 75248, Paris Cédex 05, France. E-mail: michelle.debatisse@curie.fr

3Current address: Institut Curie, unité INSERM 509, Section de Recherche.

4These authors contributed equally to the work.

5Current address: Institut de Pharmacologie et de Biologie Structurale, CNRS, UPR9062, Toulouse Cedex, France.

Received 4 April 2006; Revised 23 May 2006; Accepted 23 May 2006; Published online 10 July 2006.

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Abstract

Following prolonged mitotic spindle disruption by microtubule poisons, mammalian cells delay their entry into anaphase, then progressively slip out of mitosis and become tetraploid. Normal cells then stop cycling before S-phase onset, but the mechanisms underlying this arrest are still unclear. Here we show that a double block prevents endo-reduplication. First, cells that exit mitosis without a functional microtubule network are driven toward G0. Reconstitution of the network unmasks a second block that relies on DNA double-strand breaks occurring early in the G1 phase that follows the mitotic block. We propose that a stress signal elicited upon mitotic impairment triggers breakage, which couples the leaky spindle checkpoint to the stringent DNA damage response. Consistent with this finding, cells defective for the damage response continue cycling and acquire, within a single cell cycle, both chromosome rearrangements and abnormal chromosome numbers that remarkably mimic the complex genetic hallmark of tumorigenesis.

Keywords:

double strand breaks, chromosome rearrangements, mitotic slippage, DNA damage checkpoint, spindle checkpoint, tetraploidy

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