Our DNA is damaged each day by radiation, chemicals, or errors during cell division. To safeguard our genetic information, cells have evolved mechanisms to efficiently repair DNA defects. This is especially important during meiosis, in which double strand break formation is necessary to facilitate the exchange of DNA between maternal and paternal chromosomes. Joao Matos’ lab studies how the DNA repair machinery functions in meiosis and mitosis. By investigating the fundamental mechanisms of DNA repair, the researchers also hope to understand what goes wrong in disease.

 

From the very beginning, your research has addressed the topics of meiosis and DNA repair. What fascinates you about these topics?

I started working on meiosis during my PhD many years ago. It didn’t happen because I planned to do so, but rather because a mutant of a kinase I made had an unexpected meiotic phenotype. What I observed is that meiotic cells all of a sudden thought that they were undergoing mitosis. They tried to separate sister chromatids instead of homologous chromosomes. We were not a lab that specialized in meiosis back then, which forced us to learn everything about the process. While learning from scratch, I ended up falling in love with all the intricacies that constitute meiosis. It is a beautiful sequence of tightly coordinated processes - each one of them being almost a field on its own. So, there's really a lot to explore within the field.

 

Your approach uses budding yeast, mouse and human tissue cultures. What is the advantage of using a variety of model systems instead of focusing on one?

Different model organisms are beneficial because they all have unique properties and allow us to ask questions with different levels of depth. We use budding yeast because we can purify meiotic enzymes in their native context which allows us to characterize them. Mouse models are very new in the lab, but we hope to use them to explore conservation in evolution of some of the things we have discovered in yeast. The mammalian tissue culture allows us to explore some angles related to our findings in the context of disease.

 

The discovery of cell division goes back to the 19th century, DNA repair mechanisms were discovered in the 1970s and were acknowledged with the Nobel Prize in Chemistry in 2015. What are the big open questions in the field?

We still have a very poor understanding of how DNA repair really works inside cells. We can reconstitute some reactions in the test tube, but these are simplified versions of what is happening in cells. Furthermore, DNA repair enzymes, such as the DNA nucleases we study, can’t simply be left cutting DNA in an uncontrolled manner in the cells. So there has to be lots of regulation we are also still missing.

 

Given that DNA repair is such an important process in both mitosis and meiosis, what do you hope the impact of your work will be?

We are mostly fascinated by simply understanding how things work. The primary motivation is not to immediately think of ways to cure disease but we also know that when you understand something properly, it is very likely that you can come up with approaches to correct things that go wrong. And when you work in a process such as DNA repair, which is so important in preventing genomic instability, and also fundamental for fertility, it is of course a motivation to think that our work may contribute towards helping people in the future.

 

Why did you decide to become a researcher?

I did not want to be a researcher when I was a kid. I, like every second kid in my country, wanted to be a football player for most of my youth. At the age of ten I wanted to be a guitar player, but sometime in high school I bumped into a very good set of teachers of chemistry and biology. In particular the lab work in the biology classes was supervised by a very curious PhD student. I started to think that it could be interesting to spend my days trying to understand how biological processes function.

 

Why is basic research important?

Basic research typically aims to explore how things work without the need to generate a product at the end of the day. And, as such, it is free to explore areas or topics of research for which we have no immediate application but which might end up revolutionising both our understanding of the world we live in as well as medical research. Just look at CRISPR, for example. I also think that basic research and teaching should go hand-in-hand. Teaching at all stages of university education should be done by people that actively do research, in particular basic or curiosity-driven research. It is important to pass on to the next generation not just what is already written in the textbook, but also a sense of what is still unknown.