Science Interviews


Sat, 8th Mar 2014

DNA repair, and cancer

Professor Steve Jackson

Listen Now    Download as mp3 from the show DNA damage and repair

Kat -   Now itís time to look in more depth at the processes of DNA damage and repair. Professor Steve Jackson, from the Gurdon Institute at the University of Cambridge, told me more about the scale of DNA damage that goes on in our bodies and how researchers are trying to exploit DNA repair mechanisms to come up with new approaches for treating cancer.

Steve -   A very important part of our cells is the DNA in the nucleus of the cell.  That contains all of our genetic information that basically makes us the way we are and makes our cells in our bodies work in the way that they do.  The information in the DNA is very valuable to the cell.  Unfortunately, there's a lot of agents in the environment and made within ourselves and within the body that are continually damaging DNA.  A good example of this is ultraviolet light from sunlight.  That will damage DNA.  It could produce a lot of DNA damage.  But also, even the oxygen in the air at some level will oxidise DNA and then there are other reactions, other processes within ourselves that continually having effect by damaging the DNA. 

If that DNA damage is not repaired, thatís corrupting the genetic information.  If our cells donít repair the DNA damage, theyíll stop functioning correctly.  And so, it turns out that over the course of evolution, our cells and the cells of other organisms have developed ways of detecting DNA damage and repairing it.  In most cases, that makes the genetic information back to its original state so our cells continue functioning.

Kat -   What sort of scale are we talking about this problem?  Is DNA damage very common or is it something thatís very rare in the lifetime of a cell?

Steve -   I think people will all be aware of the fact that if you sit out in the sun too long, you can damage your cells and thatís DNA damage or if you expose yourself to, letís say there's an unprotected radiation source, of course, those things will generate DNA damage.  But there's a large amount of DNA damage taking place in our cells all the time. So, every cell in our body has around 100,000 DNA lesions per day at rest.  So, if you sit in a darkened room away from UV light, away from radiation, still, every one of the cells in your body is having 100,000 breaks or damages to the DNA a day.

Kat -   Thatís an incredible amount of damage.  How do cells cope with this?  How do they even detect that much damage?

Steve -   Well, DNA has a fairly regular structure Ė the DNA double-helix - and most of these damages change that structure.  So, there are certain specialised proteins, molecular policemen if you like, going through our cell, looking at the DNA, and not doing very much when the DNA is normal.  But this surveillance pathway is basically ready to pounce on any bits of damaged DNA.  So, if the structure of the DNA changes through DNA damage, these proteins bind to it and set off the alarm bells.

Kat -   What sort of things are involved in sending these signals to cells?  What calls in the repair men?

Steve -   So, if you like, the damage is recognised by certain proteins that sit on the DNA and basically then serve as landing pads or recruitment pads for other proteins come in, and in some cases, cut out the bad bits of DNA and then fill in the right sequence of the DNA, and then basically ligate the bits back together again.  So basically, like a molecular tool kit which is called in at the right time and at the right place.

Kat -   What are the implications if this process doesnít happen correctly?

Steve -   Well, if it doesnít happen at all, our cells will very, very rapidly die because the DNA would basically be mutated away.  Most DNA damage, maybe all DNA damage is repaired, but sometimes itís repaired in an error-prone way.  So, the original sequence is changed and that can give rise to a mutation.  Thatís what a mutation is Ė the change in the DNA sequence. 

Some of these mutations are fairly innocuous, but other ones will cause a cell to have major problems because heís not now able to do the right thing at the right time.  So, that in some cases could cause a cell to die and other cells, that could stop the cell responding to the environment and that might cause it to grow when it shouldnít grow, and therefore, be one step towards being a cancerous cell.  In fact, we now know that just about every cancer, during the course of its evolution into being a cancer, has got mutations.

Kat -   And now, we know there are some ways that we can use these repair pathways to actually treat cancer.  What's this approach?

Steve -   Yeah.  So normally, DNA repair is a very good thing and you wouldnít want to inhibit DNA repair with for example, a drug.  But in some circumstances, you can imagine how using a DNA repair inhibitor can be very useful to help kill cancer cells.  For example, combining a DNA repair inhibitor with radiotherapy or chemotherapy which are common treatments for cancer.  Radiotherapy and chemotherapy would, by causing DNA damage in cancer cells and if you could slow down the repair in cancer cells, you're going to be able to kill those cancer cells more effectively. 

In addition, there's another way you can use DNA repair inhibitors by taking advantage of some of the key differences that exists between cancer cells and normal cells.  It turns out that most cancer cells are not particularly good at repairing DNA damage because theyíve lost some of their repair mechanisms.  That means that a cancer cell thatís lost one way of repairing DNA damage is very reliant on the other pathways that it still got.  What my colleagues and I, over the last few years, have learned this that if you can come up with a drug targeting that pathway, that the cancer cell is really reliant on, you can kill the cancer cell because it can't repair its DNA whereas normal cells are not affected anywhere near as much because they have multiple ways of repairing the DNA damage. 

So, if you like, weíre trying to use this difference in DNA repair between cancer cells and normal cells as an Achilles heel of the cancer cell to kill the cancer cell without having very much effect in cancer patientsí normal cells. Thatís a concept that we initially established in the test tube, in cell culture in the lab.  This type of approach is now showing great promise as a real treatment for certain subsets of cancers, particularly breast and ovarian cancers.

Kat -   So, in the future, do you think we could be combining treatments like chemotherapy and radio therapy with these DNA damage inhibitors to make a real difference to the effectiveness of treatment?

Steve -   Yes, so of course, these things, particularly when you're combining drugs, donít take place over night.  You have to be very careful how you combine different drugs.  But I think there is a big potential there.  There's a potential for DNA repair inhibitors being used as standalone agents, to kill cancer cells that are deficient in certain repair pathways, and then there are opportunities for combination use.  All of these are now being explored in various clinical trials.

Kat -   That was Professor Steve Jackson from the University of Cambridge.


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