Research Unit 2800: Chromosome Instability: „Cross-talk of DNA replication stress and mitotic dysfunction”

In this research unit we are collaborating with biologists to better understand the link between chromosomal instability (CIN) and replication stress (RS), both important phenomena closely related to cancer. Chromosomal instability is commonly observed in cancer and inheritable diseases, characterized by increased structural or whole chromosome alterations. While mitotic defects and replication stress (RS) are traditionally linked to CIN, our research challenges this view. We've found that replication genes like GINS1 and CDC45 are overexpressed in tumors with whole chromosome CIN (W-CIN), suggesting a novel mechanism. In collaboration with Holger Bastians (Göttingen), we've identified that increased replication origin firing triggered by these genes or mild RS induces W-CIN. We aim to develop a model for DNA replication, using data from DNA combing experiments to constrain parameters. By linking this model to mitotic defects, we'll simulate interventions (e.g., GINS1 overexpression) on origin firing rate, chromosome segregation, and CIN.