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Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination deficient mammalian cells

Wilhelm T, Magdalou I, Barascu A, Técher H, Debatisse M, Lopez BS.

Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):763-8.

Université Paris Sud, F-91405 Orsay, Cedex, France; &
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; &
Université Pierre et Marie Curie, 75005 Paris, France; &
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3244, F-75248 Paris, France; &
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8200, Institut de Cancérologie Gustave-Roussy, 94805 Villejuif, France; and
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 217, Commissariat à l’Energie Atomique, Direction des Sciences du Vivant, Institut de Radiobiologie Cellulaire et Moléculaire, Fontenay aux Roses, F-92265, France.

 

Abstract
Homologous recombination deficient (HR(-)) mammalian cells spontaneously display reduced replication fork (RF) movement and mitotic extra centrosomes. We show here that these cells present a complex mitotic phenotype, including prolonged metaphase arrest, anaphase bridges, and multipolar segregations. We then asked whether the replication and the mitotic phenotypes are interdependent. First, we determined low doses of hydroxyurea that did not affect the cell cycle distribution or activate CHK1 phosphorylation but did slow the replication fork movement of wild-type cells to the same level than in Homologous recombination deficientcells. Remarkably, these low hydroxyurea doses generated the same mitotic defects (and to the same extent) in wild-type cells as observed in unchallenged Homologous recombination deficient cells. Reciprocally, supplying nucleotide precursors to Homologous recombination deficient cells suppressed both their replication deceleration and mitotic extra centrosome phenotypes. Therefore, subtle replication stress that escapes to surveillance pathways and, thus, fails to prevent cells from entering mitosis alters metaphase progression and centrosome number, resulting in multipolar mitosis. Importantly, multipolar mitosis results in global unbalanced chromosome segregation involving the whole genome, even fully replicated chromosomes. These data highlight the cross-talk between chromosome replication and segregation, and the importance of HR at the interface of these two processes for protection against general genome instability.

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Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination deficient mammalian cells. Global Medical Discovery