Opher Gileadi: Genome Integrity
Our cells have many proteins that maintain the integrity of the DNA by repairing DNA damage and by preventing cells from dividing until any damage to the DNA is properly repaired. We aim to understand the mechanisms of action and to modify the activity of DNA repair proteins.
Q: How do our cells make sure that DNA is not damaged during their normal life cycle?
OG: Most of us appreciate that the DNA and the genes are responsible for what we look like; the colour of our eyes, our body shape, the shape of our tissues. But DNA is important in every cell of our body throughout our life so a cell has to behave in a particular way; it has to respond to its environment, to be in the right place, to divide just the right number of times and so on. All of this is regulated by the DNA of the cells, so it's very important that the DNA will stay stable and the same in all cells of the body. DNA is constantly under attack from chemical and physical agents that can damage it. We are all aware of things like cigarette smoke or direct sunlight that could damage DNA, but there are also normal processes in the body such as the transport of oxygen and cell-division that can cause damage to DNA and that damage has to be repaired all the time. In fact about 9,999 of every 10,000 events of DNA damage result in complete repair and completely disappear by the repair system of the body. The repair mechanisms involve three elements; one of them is recognising damage to DNA: there are proteins and enzymes in the cell that bind to abnormal sites in DNA. They then raise an alarm system which is the second element, which tells the cells 'stop dividing, wait until the DNA damage is repaired' and also recruits to the site of damage a lot of proteins and other enzymes that repair the damage to DNA – they can stick together the bits that were broken or replace DNA bases that were damaged. All of these elements have to work in concert to ensure the DNA is stable throughout our lifetime.
Q: What happens when this mechanism doesn't work properly anymore?
OG: For the cell the worst thing that can happen is that the cell will die, but the death of individual cells in our body is not a big deal, they can usually be replaced. In terms of health the worst thing that can happen is that the damage is not repaired properly and then the cell has a mutation in one or more of its genes. The mutation could be benign and have no effect, but some mutations disrupt the normal control of the cells. They become released from the number of restraints that keep them in a particular place and with a limited number of divisions, and these cells can run out of control -they can divide indefinitely, they can move around in the body to places where they shouldn't be and these are the hallmarks of cancer. Damage that is not properly corrected can lead to aberrations and can lead a small number of cells to expand, run out of control and cause cancer.
Q: And could this help us in our fight against cancer?
OG: Yes in a way: the cancer cells cannot maintain the stability of their DNA properly. This is an advantage initially in their release from constraints of growth but it also presents a weakness because these cells divide rapidly and are very sensitive to any damage in the DNA; we can enhance the sensitivity by adding drugs that further inhibit DNA repair or by over-loading the cell with DNA damaging agents. This is the basis of a lot of chemo-therapy and radio-therapy. What our research is aimed at is to find more subtle ways to weaken the defences of these cancer cells without hitting other cells in the body.
Q: What are the most important lines of research that have developed over the past 5 or 10 years?
OG: Several decades ago the components of the DNA repair machinery were gradually identified in simpler organisms such as yeast and bacteria. In the last two decades or the last ten years we've seen more and more of these elements identified in human cells and of course in human cells everything is much more elaborate than in yeast cells. We have a much deeper understanding of the different machineries that are involved in DNA repair, the different options for DNA repair, but we also have much better ways to measure this in real human cells in a physiological context. We are not talking about isolated elements working in a test tube but we are watching them in normal and cancer cells and we can really pin-point which are the most important elements in any particular cancer cell line and utilize that.
Q: Why does your research matter, why should we put money into it?
OG: I think almost every development in medicine is linked to a fundamental understanding of mechanisms in the body; we may have a random discovery of a wonder drug that does this or that but without understanding properly what it does and what elements in the body respond to this drug we cannot really make progress, we cannot improve the specificity or reduce side-effects and so on. It's very important to have the fundamental research that delineates all the elements that are involved in the disease process and focus our ability to target the most important elements in that process. Our research is not immediately linked to the clinic but it provides the foundation for further clinical research.
Q: How does your research fit into translational medicine within the department?
OG: Our part of the department, the Structural Genomics Consortium, is focused on learning the properties of proteins that are involved in disease processes and could be targets for drugs and developing small molecules that could interact with these proteins and change their activity. So this fits in this model of looking at the process at the protein level and at the chemical level and expanding them and building gradually up to the cellular level.