Causes and consequences of mitotic DNA damage

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    In order to divide, a cell has to successfully duplicate its DNA during S-phase, followed by the division of genomic content during mitosis. Faithful cell division in cancer cells can be challenged in various ways. First, an increase in the formation of DNA lesions can challenge correct DNA duplication, for instance, due to oncogene overexpression or the inability to resolve DNA lesions due to defective DNA repair mechanisms. Second, the faithful division of genomic content over the emerging daughter cells can be impaired due to mitotic aberrations. The overall aim of this thesis was to dissect the mechanisms by which replication-born DNA lesions affect mitotic behavior of cancer cells, to ultimately improve treatment of genomically instable cancers. We describe how replication-born DNA lesions induced by BRCA1/2 inactivation combined with PARP and ATR inhibitor treatment affect mitotic behavior. We show that ATR inhibition potentiates PARP inhibitor treatment in homologous recombination-deficient cells, which was related to the role of ATR in regulating cell cycle control. Furthermore, we studied how overexpression of the CCNE1 oncogene (encoding Cyclin E1) affects mitotic behavior. We found that overexpression of Cyclin E1 caused mitotic aberrancies, which could be exacerbated by the inhibition of the G2/M checkpoint kinases ATR or WEE1. Moreover, we found Cyclin E1 overexpression to result in the activation of RAD52-dependent Mitotic DNA synthesis (MiDAS) pathway. Inhibition of the MiDAS pathway resulted in an increase in residual DNA damage following mitosis, implicating a possible crucial role for MiDAS in dealing with increased levels of DNA lesions in mitosis.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    Begeleider(s)/adviseur
    • van Vugt, Marcel, Supervisor
    • Foijer, Floris, Supervisor
    Datum van toekenning24-jun-2022
    Plaats van publicatie[Groningen]
    Uitgever
    DOI's
    StatusPublished - 2022

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