Cell fate after DNA damage

Anne Margriet Heijink

    Research output: ThesisThesis fully internal (DIV)

    1081 Downloads (Pure)

    Abstract

    Essential for life, is that every cell delivers its genetic material, unchanged and intact, to its offspring. However, each cell in the human body receives tens of thousands of DNA lesions per day. To solve these lesions, cells are equipped with several systems – together called the DNA damage response (DDR) – to detect DNA damage, signal its existence and facilitate its repair. The importance of a functional DNA repair machinery is illustrated by the fact that, women with a deleterious germline mutation in HR-genes BRCA1 or BRCA2 have up to 70% risk of developing breast cancer by the age of 70.
    Importantly, defects in the DDR can, next to causing the development of cancer, also create opportunities for targeted therapy. For example, when time to repair DNA damage is limited, tumor cells can gain too much damage and thereby activate a program to eliminate themselves.
    The overall aim of this PhD-project was to uncover factors that determine cell fate after DNA damage. This aim was addressed in the context of intrinsic DNA damage, inflicted by defective DNA repair, or extrinsically-induced DNA damage. Specifically, we performed a genetic screen to unravel how tumor cells deal with loss of BRCA2, an essential DNA repair gene. Moreover, we investigated how tumor cells can escape cell death after administration of chemotherapy or inhibition of the DDR. We conclude that how tumor cells cope with DNA damage is different between tumor cells. This generates many opportunities for targeted therapies, but also makes predicting therapeutic responses difficult.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van Vugt, Marcel, Supervisor
    • de Vries, Liesbeth, Supervisor
    • Heinemann, Matthias, Assessment committee
    • Rots, Marianne, Assessment committee
    • van Attikum, H., Assessment committee, External person
    Award date28-Mar-2018
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-623-3915-6
    Publication statusPublished - 2018

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