Mild replication stress causes chromosome mis-segregation via premature centriole disengagement

Therese Wilhelm (), Anna-Maria Olziersky, Daniela Harry, Filipe De Sousa, Helène Vassal, Anja Eskat and Patrick Meraldi ()
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Therese Wilhelm: University of Geneva
Anna-Maria Olziersky: University of Geneva
Daniela Harry: University of Geneva
Filipe De Sousa: University of Geneva
Helène Vassal: University of Geneva
Anja Eskat: University of Geneva
Patrick Meraldi: University of Geneva

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structural chromosomal aberrations. Recent studies demonstrated that it could also lead to numerical chromosomal instability (CIN). The mechanism, however, remains elusive. Here, we show that inducing replication stress in non-cancerous cells stabilizes spindle microtubules and favours premature centriole disengagement, causing transient multipolar spindles that lead to lagging chromosomes and micronuclei. Premature centriole disengagement depends on the G2 activity of the Cdk, Plk1 and ATR kinases, implying a DNA-damage induced deregulation of the centrosome cycle. Premature centriole disengagement also occurs spontaneously in some CIN+ cancer cell lines and can be suppressed by attenuating replication stress. Finally, we show that replication stress potentiates the effect of the chemotherapeutic agent taxol, by increasing the incidence of multipolar cell divisions. We postulate that replication stress in cancer cells induces numerical CIN via transient multipolar spindles caused by premature centriole disengagement.

Date: 2019
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DOI: 10.1038/s41467-019-11584-0

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