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Claire Wyman

‘Looking at DNA repair’

Bio

Bio

Claire Wyman received her PhD in Molecular Biology from The University of California at Berkeley in 1990. In 1996, she joined the Department of Cell Biology and Genetics at the Erasmus MC. In 2005, she was appointed Associate Professor in the Department of Radiation Oncology at Erasmus MC. She has been Professor of Molecular Radiation Biology since August 2008.

POSITION AT:

Erasmus MC: Radiation Oncology
TU Delft: Bionanoscience

‘Feel’ the proteins working

“When I arrived here in Rotterdam about 20 years ago, the fields of physics and biology were just starting to converge. A new kind of science was being developed. I started working on tools to manipulate and study individual biomolecules with researchers at TU Delft. My neighbour in Delft, Cees Dekker, was developing new nanobiology tools in his lab. His instruments could hold and stretch individual molecules. He and Nynke Dekker were already working with DNA. The physical properties they could measure told us a lot about how DNA works. We studied what happens during the repair process of DNA breaks, which can cause cancer and other medical problems. In the cell nucleus, breaks are repaired by teams of different proteins, one of the key ones being RAD51. When this protein binds to a DNA strand to do its repair work, the strand changes shape, length and stiffness – all things we can measure. Nynke’s group developed an instrument to measure twist changes in DNA and the forces involved. Through these instruments, you can ‘feel’ the proteins working!”

Modify to make it faster

“I’m currently working with Martin Depken, a theoretician at TU Delft, on the behaviour of the protein BRCA2. This is a very large and very fascinating protein; first, it detects a DNA break and then leads RAD51 proteins to the site to fix it. In Rotterdam, we developed certain microscopy methods with the Optical Imaging Center and image analysis tools to actually follow BRCA2 in the nucleus of live cells. We can observe a single molecule: how it diffuses in the nucleus and how long it stays in a particular place where it may – or may not – do its job. Together with the theoreticians, we want to develop a mathematical model of this process. In a subsequent phase, we aim to modify the protein to force it to stay in a specific spot for a longer or shorter time and see how this affects DNA repair. If we make the process go ten times faster, it might make no difference; but if we can make it go ten times slower, that could be a big deal. Such changes could determine whether or not a person gets cancer, or responds to a certain treatment.”

“Research into BRCA2 is especially promising because a lot is already known about the variations that exist in human populations. But we still know very little about how these variations correlate with particular diseases. Perhaps we can correlate these known mutations with biophysical data on BRCA2 behaviour. These variants would then have prognostic value to better predict cancer risks, and to improve cancer treatment. We already know, for instance, that certain cancer treatments are very effective in people who have a specific BRCA2 mutation.”

Too good can be dangerous

“People often ask me: ‘Can’t you simply make a highly effective variant of BRCA2 or RAD51 and use that as therapy?’ That’s a very good question, but you have to consider that things that are highly effective can be dangerous too. A healthy cell can repair DNA damage perfectly fine without help. But when that system fails, we want to know what went wrong. Was there not enough protein? Not in the right place? Et cetera. We can produce or isolate different versions of RAD51 that do their job very well. But when you put them into a nucleus, they may hang around for too long and get in the way. Like the cranes that were outside my office window for several years building that new hospital; they were very useful for driving in the foundation pilings but had to get out of the way when construction started. In other words, you can have something very promising in a test tube, but you have to understand the biochemical balance in a living cell. That’s why we work so closely with cell biologists and use various animal models.”

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