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

Cell Rep. 2022 Dec 13;41(11):111836. doi: 10.1016/j.celrep.2022.111836.


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

Keywords: ATR; CDC45; CIN; CP: Cancer; CP: Molecular biology; DNA replication; GINS; aneuploidy; cancer; chromosome missegregation; mitosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • Chromosomal Instability / genetics
  • Chromosome Segregation
  • Humans
  • Mitosis
  • Neoplasms* / genetics
  • Replication Origin* / genetics