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

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.

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

“…We hypothesized that, under these circumstances, cells survive or at least exit mitosis, which we showed to be the case for noncancerous RPE1 cells challenged by low doses of APH. As RPE1 cells are supposed to be proficient in all checkpoints, we concluded that low replication stress remained below the threshold of detection in mitosis [142].…”

From tumorigenesis to cell death: the aneuploidy paradox

“…In line with these results, several studies have demonstrated that increasing aneuploidy in breast cancer cells either by inducing DNA damage, or altering mitotic regulators or centrosome numbers, potentiates the antitumoral effect of taxanes. [8][9][10] Interestingly, using a breast cancer patient's cohort in which aneuploidy has been evaluated, we found that 65% of low-ATIP3 expressing breast tumors are aneuploid as compared to 42% of high-ATIP3 tumors. The genomic alterations were also evaluated in breast tumors using a 25-genes signature of chromosomal instability (CIN).…”

Exploiting Chromosomal Instability of PTEN-Deficient Triple-Negative Breast Cancer Cell Lines for the Sensitization Against PARP1 Inhibition in a Replication-Dependent Manner

“…Recently, we determined the HR competence of the cell lines investigated here and we could show that HR was reduced in TNBC cell lines [ 20 ]. Since CIN often occurs as a result of defective DNA repair and replication stress [ 21 , 22 ], we performed the DNA fiber assay to analyze the performance of PTEN-deficient cells in DNA replication. Exponentially growing breast cancer cell lines were sequentially pulse-labeled for 30 min each with 5-Chloro-2′-deoxyuridine (CldU) and Iododeoxyuridine (IdU).…”