How DNA gets damaged
Kat - It's not just things in our environment that can damage our DNA - the damage can come from within too. Professor Daniel Durocher, from the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, Canada, explains more about how DNA damage is caused and how it gets repaired.
Daniel - DNA can be damaged as a consequence of our own metabolism. When we age, we'll produce for example reactive oxygen species which are small chemicals that are very reactive and they can interact with DNA and damage DNA. Actually, there's a theory of ageing that suggests that it's this chronic accumulation of damage of DNA that causes ageing.
Kat - But obviously, we need oxygen to be alive, to breathe and to make energy. So presumably, there's nothing we could really do about avoiding this kind of damage.
Daniel - Absolutely. That's why cells have evolved repair pathways to counteract those. They're in effect, the fountain of youth in some ways.
Kat - So, our DNA is always going to get damaged, so we have to repair it. How are some of the ways that cells figure out that they've been damaged and then repair them?
Daniel - That's exactly what my lab is interested in. And we're very interested in actually, the more severe form of damage which is the breakage of DNA. So, when the DNA double-helix is broken, it needs to be detected and then repaired. Just like those alarm signals that gets triggered when DNA is broken, this alarm signal will bring in the repair man. One that's very topical at the moment in the fields is that there are many different ways to repair breaks and the selection of the right repair pathway or the right set of repair men has a profound consequence on survival of the break and also the integrity of the chromosome - the fidelity of the repair.
Kat - So, it's not just recognising that you had a problem and repairing it. It has to be the right kind of repair. So, how many different ways can these breaks be repaired?
Daniel - So, there are two main ways that are mutually exclusives. There are also minor pathways, and they're very fundamentally different. For example, the tumour suppressor BRCA1 which is mutated in the familial breast and ovarian cancer, its function now appears to be to actually direct the repair path which was one type of repair by essentially antagonising the other ones. So, there seems to be a tussle between the different repair pathways that operates and it seems important in breast cells that it's the pathway promoted by BRCA1 that wins.
Kat - So, this is the gene that's faulty in many inherited types of breast and ovarian cancer.
Daniel - Absolutely.
Kat - And then what's the other type of pathway then that's important, maybe in other types of cells?
Daniel - One pathway that's very important is a process that has a very big name called non-homologous end joining (NHEJ). This actually is very simple, conceptually, it's taking the broken DNA molecules and gluing them together.
Kat - So, just any old ends, it'll just stick this together.
Daniel - Exactly, but that's actually the main repair pathway that we have in most of our cells. If you are not proficient in this pathway, you will be very sensitive to DNA damage. But also, you'll be immune-deficient because one thing that's remarkable is that our B-cells and T-cells use DNA repair to generate diversity in our immune system. And defective NHEJ leads to essentially very severe immune deficiency.
Kat - This is a great bit of multitasking then by the cells that the same process that's bad and damaging. Breaking and sticking back together is actually how we generate some of our immune responses. How far are we to actually understanding this process of DNA damage, detection and repair, and how it's involved in diseases like cancer and immune diseases?
Daniel - We've made great inroads in the past 15 years, but we're still a long way to go. I think we've identified the lot of the main players and the main components. Now, it's really trying to understand how this choreography of alert signals and repair factors come in and interact with each other and how all this is integrated in the larger physiology of the cell.
Kat - What's the really big unanswered question for you? What do you really want to know now?
Daniel - Really, I think the really remarkable result recently was, the function of BRCA1 tumour suppressor which is defective in familial breast and ovarian cancer. One of its main functions is to really act almost as a traffic policeman, directing repair in one direction or the other. Exactly, how this works is completely unknown. It's very germane for our understanding of familial breast cancer. I think that is at the moment, the biggest question in the field.
Kat - Do you think this is going to prove to be a really fruitful pathway for these kinds of treatments in the future?
Daniel - I think it will be because at the core, cancer is a disease of genetic alterations. These genetic alterations come from faulty DNA repair. So actually, using our knowledge of DNA repair will allow us to really target the core defect of cancer cells.
Kat - That was Professor Daniel Durocher from the Mount Sinai Hospital in Toronto.