Consequences of chromosome segregation errors

Abstract

Errors in chromosome segregation contribute to tumor heterogeneity and evolution by driving karyotype diversification. However, it is poorly understood how cancer cells tolerate abnormal karyotypes so well. In this thesis we focus on understanding the immediate and long-term consequences of de novo induced aneuploidies. We have developed a system to induce segregation errors, and hence generate aneuploid cells. This system led to the generation of cells harboring whole chromosome imbalances, segmental aneuploidies and micronuclei. We made use of this heterogeneity to study the immediate and long-term consequences of different types of imbalances. Although aneuploidy was previously associated with the activation of the p53 pathway, we showed that aneuploidy per se is not sufficient to do so. We found three features that result in the activation of p53 and are thus determinant for the tolerance to imbalanced chromosomes. These three features involve the presence of broken chromosomes (chapter 2), the loss of chromosomes, and the extent of aneuploidy itself (chapter 3). Moreover, we explored the link between aneuploidy and chromosomal instability (CIN), an important driver of tumor evolution. We found that this relationship was also heavily influenced by the type of aneuploidy that was involved. Whole chromosome losses were shown to be more harmful for cell survival, only chromosome gains triggered CIN (chapter 3). We propose that this is a consequence of the proteotoxic stress response by enhanced demand on protein folding and turnover. Finally, we investigated the defects associated to micronuclei that result from a segregation error. Importantly, we demonstrated that cells fail to sense the presence of these small structures (chapter 4). Moreover, we found that chromatids from micronuclei are prone to missegregate in subsequent cell divisions, due to defects in the assembly of a functional kinetochore (chapter 4). We showed that a fraction of micronuclei accumulates high levels of DNA damage and binding of cGAS. Although both events are triggered by membrane rupture, we showed that these two events act independent from each other (chapter 5). We also tested a potential role for cytoplasmic nucleases in the processing of micronuclei but we could not find evidence for that. Altogether, we provided a comprehensive overview of the cellular consequences of chromosome segregation errors and we brought new insights into the understanding of how abnormal karyotypes are tolerated in non-transformed versus transformed cells.