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Passerini, Verena (2016): Aneuploidy triggers a conserved global response and impairs cellular homeostasis. Dissertation, LMU München: Fakultät für Biologie
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Abstract

Aneuploidy, or unbalanced chromosome number, has often detrimental physiological effects in eukaryotic cells. Aneuploidy is associated with congenital trisomy syndromes, e.g. Down syndrome, but it is also linked to several other pathological states such as Alzheimer's disease, schizophrenia and autism. In addition, aneuploidy is often found in cancer cells and high rates of aneuploidy in tumors correlate with poor prognosis and drug resistance. Although it has been proposed that aneuploidy could contribute to tumorigenesis by facilitating genomic instability, whether and how aneuploidy can lead to genomic instability remains elusive. To study aneuploidy in human cells, we have previously generated cell lines carrying one or two supernumerary chromosomes in an otherwise diploid background by microcell mediated chromosome transfer. Similarly to other aneuploid model systems of earlier studies, our human aneuploid cell lines showed impaired proliferation and a conserved cellular response to the presence of extra chromosomes. Moreover, we found that aneuploidy alters protein homeostasis and impairs induction of heat shock response in human cells. Pathway analysis based on transcriptome and proteome data revealed characteristic gene expression changes called aneuploidy response pattern that is defined, among others, by down-regulation of factors involved in DNA replication and repair. Consistent with these observations we found that aneuploidy increases the frequency of anaphase chromatin bridges, broken chromosomes and ultrafine DNA bridges. Moreover, aneuploid cells accumulate more DNA damage even in unperturbed conditions and display higher sensitivity to replication stress than diploids. Using next generation sequencing we determined that a presence of extra chromosomes elevates frequency of chromosomal rearrangements with a breakpoint junction pattern suggestive of replication defects. Finally, we demonstrated that the observed decreased levels of MCM2-7 contribute to the replication stress and consequent genomic instability detected in aneuploid cells. Taken together, these results provide a new insight into the possible mechanisms responsible for impaired genomic stability in response to aneuploidy. Our study provides the first evidence that a gain of chromosomes triggers replication defects and accumulation of DNA lesions, thus promoting genomic instability and possibly contributing to tumor development.