Mild replication stress causes aneuploidy by deregulating microtubule dynamics in mitosis

Abstract

Chromosomal instability (CIN) causes structural and numerical chromosome aberrations and represents a hallmark of cancer. Replication stress (RS) has emerged as a driver for structural chromosome aberrations while mitotic defects can cause whole chromosome missegregation and aneuploidy. Recently, first evidence indicated that RS can also influence chromosome segregation in cancer cells exhibiting CIN, but the underlying mechanisms remain unknown. Here, we show that chromosomally unstable cancer cells suffer from very mild RS, which allows efficient proliferation and which can be mimicked by treatment with very low concentrations of aphidicolin. Both, endogenous RS and aphidicolin-induced very mild RS cause chromosome missegregation during mitosis leading to the induction of aneuploidy. Moreover, RS triggers an increase in microtubule plus end growth rates in mitosis, an abnormality previously identified to cause chromosome missegregation in cancer cells. In fact, RS-induced chromosome missegregation is mediated by increased mitotic microtubule growth rates and is suppressed after restoration of proper microtubule growth rates and upon rescue of replication stress. Hence, very mild and cancer-relevant RS triggers aneuploidy by deregulating microtubule dynamics in mitosis.

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

“…Other studies have reported that mild induced replication stress or intrinsic replication stress in CIN + cells alter microtubule dynamics by increasing microtubule plus-end growth. Merotely and chromosome mis-segregation occurred here in the absence of spindle multipolarity and was entirely due to microtubule alterations [148].…”

“…In contrast, the Bastian laboratory rescued the increased microtubule polymerization rate in CIN+ cells and in cells treated with APH by using nanomolar doses of Taxol. This treatment rescued the lagging of entire chromosomes, suggesting a synthetic viable constellation in this case [148]. Altogether, these data suggest that chromosomally unstable cells are intrinsically more vulnerable to microtubule-interfering drugs and could benefit from a combination of drugs targeting repair and/or replication in interphase and microtubules in mitosis.…”

“…In conclusion, we suggest that low replication stress is the most severe threat to genome integrity, as mitotic checkpoints are either blind to detecting it or can actively override it. In the end, such a mitotic exit can be accompanied by structural and numerical chromosomal aberrations [126,142,148].…”

The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells

“…Various abnormalities in chromosomally unstable cancer cells can contribute to the generation of lagging chromosomes including supernumerary centrosomes [6,7] or hyperstable microtubule-kinetochore attachments [8,9]. More recently, we have demonstrated that abnormally increased microtubule plus end assembly rates within mitotic spindles result in the induction of W-CIN in cancer cells [10][11][12][13][14][15][16]. In fact, increased microtubule assembly rates cause merotelic microtubule-kinetochore attachments, lagging chromosomes, and chromosome missegregation [10] (Fig.…”

“…Despite the strong link between increased mitotic microtubule assembly rates and W-CIN, the cancer-associated genetic alterations leading to abnormal microtubule dynamics are not well understood. So far, only a few tumor suppressors and oncogenes including BRCA1, CHK2, AURKA, and CEP72 were shown to be involved in triggering W-CIN by increasing mitotic microtubule assembly rates [10][11][12][13][14][15].…”