Thesis defense Alice Bolner: “Beyond the Fanconi Anemia Pathway”

Our DNA is damaged by environmental factors, chemicals and cellular molecules every day. If these damages are not properly repaired, they can lead to mutations and the development of diseases such as cancer. Fortunately, cells have developed multiple mechanisms that can repair DNA damage and therefore maintain DNA integrity.

Interstrand crosslinks

One particular type of DNA damage that is extremely toxic is the interstrand crosslink (ICL). The ICL binds together the two strands that make up DNA, thereby inhibiting fundamental cellular processes such as the production of proteins and cell division. During her PhD, Alice Bolner and her colleagues studied ICLs caused by acetaldehyde, a molecule that is released when alcohol is broken down. “We used extracts derived from the eggs of the Xenopus laevis frog, which have all the factors necessary to repair DNA. Using these extracts, we were able to study outside of a cell how alcohol-derived ICLs are repaired,” says Bolner.

New DNA-repair mechanism

The researchers found that the Fanconi anemia pathway, which was already known to act on ICLs induced by various factors, is also able to repair alcohol-induced ICLs. But to their surprise, they also found a new repair mechanism, which is much faster than the Fanconi anemia pathway. “This broadens our mechanistic understanding of how ICLs can be repaired. Given their toxicity, ICL-inducing drugs can effectively kill cancer cells and they are therefore often used in chemotherapy. Better understanding of how ICLs can be repaired could provide information needed for the development of better cancer therapies,” Bolner explains.

Nucleosome dynamics

DNA is wrapped around a complex of eight histones, forming a DNA/histones complex called “the nucleosome”. Bolner and colleagues studied how the interactions between DNA and histones change during the repair of an ICL induced by the chemotherapeutic drug cisplatin. Using the Xenopus egg extracts, the researchers found that nucleosomes around the ICL are reorganized during repair, possibly to facilitate the recruitment of DNA-repair proteins. Future research will have to determine which exact proteins are necessary for nucleosome reorganization in order to better define this process.

Publication

When asked to reflect on her PhD trajectory, Bolner says that there were some ups and downs. “Sometimes multiple experiments failed and I just wanted to go home. But when things finally worked out, I could find the excitement and curiosity again.” Especially the publication of her and her colleagues’ paper was very rewarding. “We had a nice celebration with the lab when we heard our manuscript was accepted,” she says. For this, Bolner received the CS&D Best Publication Award earlier this year.

She advises other (future) PhD-candidates to keep in mind that things often do not go as planned in science. “But you can really learn from failed experiments and they can even be part of a successful thesis,” she assures.