Ross Chapman: Repairing DNA damage
Whilst controlled DNA breaks allow for our vast repertoire of antibodies, DNA damage happening out of context can lead to cancer or predisposition to cancer. Recent developments in personalised medicine exploit the DNA repair weaknesses of cancer cells to selectively kill them. A better understanding of the underlying mechanisms can help develop innovative and targeted therapies.
Q: Can you tell us about your research interests?
Ross Chapman: The focus of my laboratory's research is understanding how cells deal with DNA damage and in particular DNA double strand breaks. DNA breaks happen as a result of the normal functioning of the cell. The cells are usually quite well equipped to deal with these, detect them and make sure that they are repaired. However, we do know that sometimes this repair machinery can malfunction and this can lead to either the mutations that trigger cancer and predisposition of these patients to cancer, and in other cases such malfunctions can lead to defects in the ability of patients to be able to fight infection.
Q: How does DNA damage lead to cancer?
RC: One DNA double strand break can be enough to kill a cell. But it can also in a different context lead to a mutation or loss of a gene that normally functions to protect our cells against cancer. One example being in the context of hereditary breast and ovarian cancer: some patients harbour a faulty copy of a gene of either a BRCA1 or a BRCA2 gene. These BRCA genes encode proteins that are major parts of our DNA repair machinery. In the context of these patients, if they lose their one good copy, this faulty copy takes over, and every time a DNA break is encountered the cells will start incorporating problems such as mutations. These are the mutations which end up driving cancer in these patients.
Q: How does DNA damage lead to immune deficiency?
RC: Immune deficiency at the level of DNA repair is an important and very interesting exception to the rule that we study in the laboratory. In this case in order for your immune system to function normally, it needs to evolve and adapt to the different types of pathogens and different types of viruses that your body is exposed to all the time. In order to do this, a specialised type of immune cell called lymphocytes - essentially white blood cells - use DNA damage in a targeted fashion, introducing breaks into antibody genes. These breaks can be processed into mutations and can enable those antibodies to be different from one another. In which case, you have different lymphocytes that will bring different types of antibodies, and those different antibodies can recognise different targets such as pathogens and viruses. If this machinery breaks down and you can't introduce these mutations, this will lead to an inability to make your full antibody repertoire and this in turn will lead to immune deficiency.
What we have come to know from the research of my laboratory and that of others, is that it is really critical that this machinery, which can be mutagenic, functions in the appropriate context and is limited to a context such as the immune system. If it gets de-compartmentalised it can suddenly wreak havoc in our cells causing mutations in places where they shouldn't do. We now know that it is this pathway functioning out of context which underlies the genome instability which causes cancer in patients that harbour faulty BRCA genes.
Q: How do cells try and repair cell DNA breaks?
RC: Our cells have got two dedicated protein machineries that they use to repair breaks. One side of the machinery is involved in the pathway called homologous recombination. This is a copy and paste mechanism which takes an identical copy of the DNA and uses that as a template to repair a break accurately. If this pathway falls down it is associated with hereditary forms of cancer and spontaneous forms of cancer. The other pathway non homologous end joining is again quite complex but it has a simple principle of taking two ends of a break and putting them together. This is the pathway that is very important for the immune system in generating these programmed mutations. However it is also this pathway functioning out of context that can cause cancer.
Q: What are the most important lines of research that have emerged in this field over the last 5-10 years?
RC: I would say recent developments in personalised medicine. Basic research, specifically in my field, has fuelled the development of new targeted therapies which have been used in the clinic to fight cancers. These therapies, in the case of PARP inhibitors which are used in the UK clinic to fight aggressive forms of ovarian cancer, exploit the DNA repair weaknesses of cancer cells and use this to selectively kill them. Because these weaknesses do not exist in normal cells, they are largely unaffected by these therapies and this translates into improved responses for the patients with less side effects which would lead to the deterioration to their quality of life.
Q: Why does this line of work matter and why should we fund it?
RC: DNA repair is one of our primary cellular defence systems against cancer. Developing a better understanding of the basis of how cells respond to and repair DNA breaks will give us a better insight into how cells protect themselves against mutations and how defects in the repair systems lead to cancer. Developing a further understanding of this area will also give us a better understanding of the DNA repair weaknesses of certain cancer types, and exploit these to develop more targeted therapies to treat and manage cancer.
Q: How does your work fit into translational medicine within the department?
RC: My research is at the basic end of the translational medicine spectrum. We think it is very important to understand the basic processes that functions in a cell to safeguard us against disease. Without this knowledge we won't be able to think of new ways to better diagnose disease earlier. If we understand the basic molecular of human diseases we can exploit this understanding to find weaknesses of cancer cells and exploit these with innovative and targeted therapies.