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.