Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Principal Investigator Eric van Dyck, Luxembourg Institute of Health
- Second opponent: Senior Lecturer Gabriella Ficz, Queen Mary University of London
- Third member and chair of the evaluation committee: Professor Bjørn Steen Skålhegg, University of Oslo
Chair of the Defence
Associate Professor Ragnhild Eskeland, University of Oslo
Principal Supervisor
Professor Arne Klungland, University of Oslo
Summary
5-hydroxymethylcytosine (5hmC), also called the sixth base in the mammalian genome, is widely reported to influence transcription. However, this transcriptional regulatory function is only apparent when 5hmC is present at promoter or enhancer regions. Interestingly, 5hmC is present most prominently in gene bodies; regions where 5hmC has nominal effects on transcription. The presence of 5hmC at regions unrelated to transcription suggests that this DNA modification has an alternative purpose.
The first part of the thesis identifies 5hmC-binding proteins. Gene ontology analysis reveals that 5hmC-binding proteins are involved in mitosis and chromosome organization, which led us to examine the role of 5hmC in cell cycle regulation. We demonstrate that 5hmC influences cell division by increasing the time a cell resides in a G1 phase. We show that 5hmC marks origins of replication and inhibits replication licensing. We show that 5hmC acts as a barrier to genomic re-replication.
By targeting this mechanism, we identified two molecules with cytotoxic properties. One compound has a broad cytotoxicity profile, whereas the second compound shows increased specificity towards glioblastoma multiforme (GBM). We evaluated the anti-cancer properties of these compounds in mouse xenograft models; indeed, both compounds are able to reduce human GBM tumors in mouse xenograft models.
Taken together, findings in this PhD thesis significantly advance understanding of 5hmC involvement in cell proliferation. Moreover, this work could be an important step in drug development for GBM, a disorder with one of the highest unmet needs in oncology.
Additional information
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