SP2: Molecular mechanisms of replication stress-induced mitotic chromosome missegregation

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Chromosome instability (CIN) leading to chromosome aberrations is highly prevalent in human cancer and other human diseases. CIN is categorized into structural CIN (S-CIN) and numerical CIN (W-CIN). While S-CIN can be triggered by defects during DNA replication, a condition known as replication stress (RS), mitotic dysfunction can account for W-CIN. First evidence indicated that S-CIN and W-CIN might be mechanistically linked. In fact, cancer cells showing mitotic errors and W-CIN also suffer from replication stress. During the first funding period of the FOR2800, we found that W-CIN cancer cells are characterized by mild replication stress that is sufficient to trigger whole chromosome missegregation in mitosis. This is mediated by abnormal microtubule dynamics within mitotic spindles that leads to chromosome missegregation. Importantly, we discovered that not slowed replication kinetics, but rather an increase in dormant origin firing that is triggered by RS is responsible for the mitotic defects and for W-CIN. In fact, selective induction of dormant origin firing is sufficient to cause W-CIN and, surprisingly, this requires the activation of DNA damage-induced ATM-signaling. Moreover, in collaboration with Maik Kschischo (FOR2800, SP3) we found that genes directly involved in origin firing are frequently upregulated in chromosomally unstable cancer specimens and their overexpression is sufficient to increase origin firing and to induce W-CIN. We will now build on our results and will investigate how unscheduled origin firing causes whole chromosome missegregation and W-CIN. We will address the role of ATM signaling and investigate how DNA damage is induced in response to dormant origin firing. Since oncogene-induced replication stress has been linked to abnormal origin firing, we will investigate whether and how oncogene activation contributes to W-CIN and whether other forms of DNA damage are also contributing to mitotic errors. Finally, we will investigate the consequences of origin firing and DNA damage signaling on the integrity of the genome, both on a structural and numerical level.