We study the genomics of DNA damage, repair, and mutagenesis. Using a combination of computational biology, machine learning, clinical and experimental data from public sources and collaborating labs, we try to understand the underlying mechanisms despite their complexity, and look for routes to bring this knowledge into clinical use.
Previously, I developed novel techniques to measure oxidative DNA damage genome wide and established the associated data analysis strategies. We found an unappreciated mechanism that leads to lower damage rates in coding sequence, which is reflected in the related mutation profiles of cancer genomes. We also found that the genome context specificity of DNA repair processes impacts on other cellular processes and genome editing.
Mutations accumulate in every cell of our body throughout life. There are processes that come from within, such as those happening by chance and through the cell's metabolic processes. In addition they occur induced by the environment, such as through UV radiation in our skin, through smoking, or also inflammatory processes. Most mutations are of little consequence (blue) and just accumulate in the 3 billion letters of our DNA without affecting a gene. But some may hit important genes (yellow) and disrupt their function. This contributes to ageing, and may also lead for cells to become cancerous. They then develop mechanisms to accumulate more mutations and through deactivating protective genes they may develop a hypermutator phenotype (red). Also most cancer treatments, chemo- and radiotherapy are based on the principle that they damage DNA. They are very efficient in curing cancer and it is very hard to find better alternatives. But, also the treatment is causing additional mutations (pink) - not only in the possibly surviving cancer cells, but in healthy cells as well. As a consequence, the treatments are causing long term side effects, such as contributing to ageing, and they may also cause a different cancer later in life.
Through research, cancer treatment has improved significantly over the last decades, mostly thanks to harsh regimens of chemo-, and radiotherapy. We are interested to better understand the principles behind these treatments to find ways of tailoring treatments to the individual and reducing the long-term side affects and risks for treatment related secondary cancers.
One route to mutagenesis is through oxidative damage to the DNA. This can happen through normal cellular processes that produce oxygen radicals, but also through toxins and ionising radiation, such as radioactivity. It acts through adding an oxygen to mainly Gs in the DNA. This has the risk of causing a mutation from the G to a T, which - dependent on where it happens in the genome - has more or less consequences. To prevent this, all of our cells have a repair system (base excision repair) that functions by cutting out the damaged G with the enzyme OGG1 to leave a gap, an apurinic site (AP-site). This gap is then filled through a longer process by an undamaged G.
We are trying to understand this process and how it happens dependent on the location in the genome, how this differs between tissues, and how oxidative DNA damage in repair leads a cross-talk with other mechanisms that lead to mutations. This is relevant both in response to treatment, and also in the development of many cancer types with mutations that are induced by these processes, such as pediatric brain tumours, and cancer types that are linked to inflammatory processes, such as esophageal adenocarcinoma.
When there is increased DNA damage, DNA damage response pathways are activated, which govern either that the cell safely pulls through or kills itself. DNA damage response is one of the central pathways deregulated in cancer and harbors many possibilities for personallised oncology.
To understand the mechanisms of DNA damage, repair, and mutagenesis, we are collaborating on molecular biological techniques to measure DNA damage and DNA damage response. We are building computational methods and machine learning systems to interrogate the resulting data as well as cancer genome sequencing data to understand the mechanisms that drive these biological processes. In addition, we use these techniques to bring basic science together with clinical application, using mechanisms of mutagenesis and DNA damage response to develop strategies of personalised oncology.