The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Click here to participate in the public defence
Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Digital Trial Lecture – time and place
Adjudication committee
- First opponent: (IMA) Theme Lead and FCCF Director Andrew Filby, Newcastle University
- Second opponent: Professor Matthias Altmeyer, University of Zurich
- Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo
Chair of the Defence
Associate Professor Tor Erik Rusten, University of Oslo
Principal Supervisor
Senior scientist Trond Stokke, Oslo University Hospital
Summary
PARP inhibitors are clinically approved for cancer treatment, and the side effects are in general tolerable and transient. Tumor cells with defects in homologous recombination repair (HR), like BRCA1/2 mutations, are profoundly sensitive to the DNA damage induced by PARP inhibitors (PARPis). Repair by HR is linked to the cell cycle stage, yet when and how PARP inhibitors worked in the cell cycle was not well understood.
The work presented in the thesis aimed to develop and refine methods to study the cell cycle by flow and mass cytometry. The improved methods were used to address the biological aims of the thesis; how PARPi affect induction of DNA-damage in relation to cell cycle phase and the possibility of repurposing PARPi towards lymphoma and leukemia with ATM loss-of-function.
Ataxia telangiectasia mutated (ATM) transduce the DNA damage signal, and is thought to promote repair by HR. The effect of PARPi treatment was studied in a panel of malignant lymphocyte cell lines in the presence and absence of ATM inhibitor. PARPi toxicity was shown to require replication, and caused a prolonged G2 phase. Further, the study showed how the amount of replication-induced DNA damage of each cell determines its G2 phase duration, also in unperturbed culture.
An improved cell cycle-panel and analysis pipeline for mass cytometry was developed in this work. The revised method made it possible to exclude all non-single cells while retaining the larger single cells. Thus, achieving accurate assessment of cell cycle distribution and enabling the use of up to 40 additional markers. The method strengthen the robustness of mass cytometry when used for both cycling and heterogeneous cell samples and may lead to new discoveries in the field.
Overall, the thesis have shed light on the toxicity of PARPi and improved methods to study the cell cycle.
Additional information
Contact the research support staff.