Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural (S-CIN) and numerical CIN (W-CIN). Recent work indicated that replication stress (RS), known to contribute to S-CIN, also affects mitotic chromosome segregation, thereby possibly explaining the common co-existence of S-CIN and W-CIN in human cancer. Here, we show that RS-induced dormant origin firing is sufficient to trigger W-CIN in human cancer cells. We discovered that overexpression of origin firing genes including GINS1 and CDC45, which correlates with W-CIN in human cancer specimens, causes W-CIN and aneuploidy. Furthermore, modulation of the ATR-CDK1-RIF1 axis in unperturbed cells induces dormant origin firing leading to W-CIN. Importantly, chromosome missegregation upon dormant origin firing is mediated by increased mitotic microtubule growth rates, a mitotic defect prevalent in chromosomally unstable cancer cells. Thus, our study identified dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.