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

Therese Wilhelm,Daniela Harry,Filipe De Sousa,Helène Vassal,Anna-Maria Olziersky,Patrick Meraldi,Anja Eskat

doi:10.1038/s41467-019-11584-0

Therese Wilhelm, Daniela Harry + Show 5 more

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https://doi.org/10.1038/s41467-019-11584-0

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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.

Highlights

Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structural chromosomal aberrations
Here we show that mild replication stress in non-cancerous cells provokes spindle architecture defects that are classically associated with chromosome gain/loss in cancer cells
Pre-cancerous lesions and cancer cells are frequently chromosomally instable, and chromosome gain or loss during mitosis is an important component of chromosomal instability (CIN), that results in numerical aneuploidy

Summary

Introduction

Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structural chromosomal aberrations. 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. We postulate that replication stress in cancer cells induces numerical CIN via transient multipolar spindles caused by premature centriole disengagement. We identify premature centriole disengagement as a key mechanism by which replication stress can induce numerical CIN in non-cancerous, checkpoint proficient human cell lines. This causes transient multipolar spindles, leading to lagging chromosomes in anaphase and micronuclei formation. We demonstrate that replication stress potentiates the effect of taxol, a chemotherapeutic agent that kills cancer cells via multipolar cell divisions[35]

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