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14Mar 2017

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Thesis defense of Hanneke Vlaming

On Thursday, March 16 Hanneke Vlaming will defend her PhD thesis. As a member of the group of Fred van Leeuwen she studied histones, the proteins which form the 'spools' that our DNA is wrapped around. Problems with histones can cause a range of diseases, and can also play a role in certain types of cancer.

Vlaming focused on a histone called H3, and even more specifically on an area on this histone called H3K79. Small chemical changes to this area can have a large impact on the DNA that's wrapped around it and on the behavior of the cell. One such changes is methylation, which happens when a protein - it the case of H3K79 a protein called DOT1L - attaches methyl groups to the histone. Misregulation of H3K79 methylation occurs in infant leukemia. At the moment, a DOT1L inhibitor shows promising results against this type of leukemia in clinical trials. But there are still many open questions when it comes to H3K79 methylation. Vlaming's work has helped to elucidate some of these questions.

One of the things she showed is the mechanism through which the well-known regulatory protein ubiquitin is involved in H3K79 methylation. It takes on the role as a sort of guidance protein, which helps DOT1L find the exact right spot on the histone. Vlaming also developed a technique for detecting new regulatory proteins that are somehow involved with H3K79. Using this technique, she found all of the known regulators - proving the technique works - as well as a number of new ones. One of the proteins that wasn't known to be a regulator of H3K79 is the protein known in mice as HDAC1. This protein can inhibit methylation by DOT1L. It is known that white blood cells from mice who lack HDAC1 develop into lymphoma, a malignant type of cancer. At the moment there are already clinical trials ongoing that focus on HDAC1. Since both HDAC1 and DOT1L are at the moment a point of focus in clinical trials, it is important to now know that these two proteins are connected.

Details of the defense:

Vlaming's thesis is entitled: Connecting the Dots. Delineating the Regulation of H3K79 Methylation by Dot1. Het promotor is Maarten van Lohuizen and her co-promotor Fred van Leeuwen.  The public defense will take place at March 16 at 14:00h in the Agnietenkapel of the University of Amsterdam, Oudezijds Voorburgwal 229-23, Amsterdam.

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