On Wednesday, May 14th, 2008 Anja Duursma will defend her thesis titled “Molecular dissection of Cdc6 and the miR-148 family; two stories with common themes” in order to obtain the doctorate degree from Leiden University.
Her promoter is professor Jacques Neefjes. The research was performed in the lab of dr. Reuven Agami.
Her thesis describes the molecular dissection of the function of Cdc6 and the miR-148/152 family. We demonstrate that phosphorylation of the DNA replication initiation protein Cdc6 by CDK2/Cyclin E at serine 54 plays a key role in regulating its protein stability. In response to DNA damage, CDK2/Cyclin E activity will be inhibited, which results in reduced Cdc6 protein level.
This regulatory mechanism might prevent initiation of DNA replication in the presence of DNA damage. Loss of p53 results in increased CDK2/cyclin E activity, and our data suggests that the increased stability of Cdc6 in p53 negative cells might be involved in the increased proliferative capacity of these cells. Next we studied several aspects of the miR-148/152 family.
We revealed a novel mechanism of miRNA regulation, as we found that Dnmt3b is regulated by miR-148 through interaction with its protein coding region. We studied the function of this miRNA family in more detail in human T-cell development and in cell cycle progression of primary fibroblasts. Theses studies revealed a possible role of this miRNA family in regulation of proper S-phase progression and cell proliferation.
Proposition 12 which accompanies the thesis states: It takes courage to start, to finish takes persuasiveness.
The thesis defence is open to the public and will take place in the Lokhorstkerk, Leiden, at 13.45 hours.