Niek Wit examined damage tolerance mechanisms in DNA damage at the Netherlands Cancer Institute (NKI) and the Swammerdam Institute for Life Sciences (SILS) . He found that in mammals, including humans, this mechanism is more complex than had previously been thought.
What did you research?
‘I looked at damaged DNA. External factors such as UV rays or cigarette smoke, can inflict so much damage on DNA that it can no longer replicate properly, which ultimately can cause cancer. Fortunately, there are special proteins, known as TLS polymerases, which temporarily allow replication to continue. I looked at how the TLS polymerase polĸ works. We already knew that in yeast cells this material is always regulated by the PCNA-Ub protein complex. Our lab bred mice in which that protein complex could no longer be made. You would expect those mutated mice to also be unable to make polĸ. But when damaged by the cancer medication MMS it turned out that they still could, just less efficiently. When the DNA damage came from other sources such as cigarette smoke, they couldn’t produce it anymore. So it seems that polĸ regulation in mammals, including humans, doesn’t just depend on the protein complex, as it does in yeast cells.’
Will those findings help in cancer treatment?
‘Absolutely. The more we find out about how TLS polymerases work, the better we can treat cancer. Radiation treatments and many cancer drugs cause damage to DNA. Because tumours sometimes lack DNA repair mechanisms, medication will kill those cells more quickly than healthy cells. We now know that we can also make potential cancer cells more sensitive to DNA damage by blocking the formation of PCNA-Ub, or specific TLS polymerases, or both. We also know that this only works for certain types of DNA damage. More research is needed into other types of DNA damage.'
Will you be pursuing that research?
‘I’m going to continue in cancer research but in a different area. As of 1 June, I have a post-doc position working with the researcher KJ Patel at the MRC Laboratory of Molecular Biology in Cambridge, on the regulation of DNA repair. Fortunately, my head of department had advised me to start looking for a new job more than a year before I was due to receive my doctorate. When KJ Patel gave a presentation at Leiden University last summer, I gave him my CV. Many months later, I was offered the position. The MRC is a renowned institution and they have their pick of applicants. When I heard just after Christmas that I’d been offered a place, I already had other applications in progress in Copenhagen and a few other cities in the UK such as Birmingham. I cancelled all of those.’
Was it a coincidence that you had applied for so many positions in the UK?
‘No, I’ve always loved it there. We used to go there every year on our family holidays. As a student I didn’t have much money to go on holiday, but as a PhD student I went as often as I could. It’s somewhere I always wanted to live. My new boss said all the Spaniards in his lab complain about the bad weather and the food. I won’t be complaining, as I can’t see any difference to the Netherlands. Another advantage is the high standard of scientific research in the UK, and the MRC is financially robust too. It also has strong links with the University of Cambridge. It will open up so many opportunities for me.’