Identifying aneuploidy-tolerating genes

Judith Elisabeth Simon


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    When cells mis-segregate chromosomes during cell division, this can lead to cells having an abnormal number of chromosomes, a state called aneuploid. Aneuploidy imposes a metabolic burden, reduces cellular fitness and induces a cellular stress response. Despite this aneuploidy-induced stress, two-third of the cancers are aneuploid. Apparently aneuploid cancer cells have mechanisms to tolerate the disadvantages imposed by aneuploidy. The overall aim of this thesis is to identify aneuploidy-tolerating mechanisms. Specifically, our research shows that aneuploidy combined with p53 deficiency in murine T cells deficiency accelerates T cell lymphoma development. These aneuploid murine T cell lymphomas have overexpression of Prmt5 (protein methyltransferase 5). We therefore studied the role of PRMT5 in aneuploid cells using different approaches.
    We identified that PRMT5 is a sensor for the amino acid methionine to activate mTORC1, which is essential for cell growth and metabolism, which could explain the need of Prmt5 overexpression in aneuploid cancer cells. To identify aneuploidy-tolerating genetic changes in a more unbiased fashion, we performed an in vivo genetic screen, in which we combined transposon-mediated mutagenesis with aneuploidization of the haematopoietic system. Combination of aneuploidy and transposon mutagenesis reduced tumour latency significantly compared to transposon mutagenesis alone, confirming that aneuploidy also accelerates tumorigenesis in this setting. Preliminary analysis of the transposon common insertion sites in these tumours is suggesting that Foxp1 and Notch1 are potential genes involved the aneuploidy tolerization. Altogether, we have found new mechanisms that facilitate tolerance of aneuploidy, which can be potential targets in the treatment of aneuploid cancer.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    • Foijer, Floris, Supervisor
    • de Haan, Gerald, Supervisor
    Datum van toekenning12-sep-2018
    Plaats van publicatie[Groningen]
    Gedrukte ISBN's9789463233132
    Elektronische ISBN's9789463233309
    StatusPublished - 2018

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