At its heart, cancer is a disease that starts when genes go wrong. This can happen when the DNA in your cells gets damaged, for example by tobacco smoke, UV radiation in sunlight, or just the normal chemical reactions of life within our cells.
And, in some rare cases, specific inherited gene faults can also add to the mix.
To try to prevent cancer developing, our cells have evolved sophisticated ways to prevent this damage – collectively called the DNA repair system.
A number of cancer treatments, such as radiotherapy and some chemotherapy, also aim to damage cancer cells’ DNA, but so badly that they die. This leads to a problem – cancer cells can switch on their DNA repair systems to protect themselves against the damage, making these treatments much less effective.
So understanding exactly how cells repair their damaged DNA, both in health and in cancer, is vital for figuring out how this disease starts, as well as finding more effective ways to treat it.
Cancer Research UK’s scientists have a long and distinguished track record in understanding DNA repair. One of the world leaders in this field is Professor Steve Jackson at the Gurdon Institute in Cambridge, whose work we’ve funded for more than a decade. Together with postdoctoral researcher Abderrahmane Kaidi, he’s now managed to join the dots between three previously separate areas of research related to DNA repair
Their discovery, published in the prestigious journal Nature, sheds light on the fundamental mechanisms that detect and repair genetic damage, and points towards important new approaches for treatment.
Let’s look at their work in more detail.
Meet the ‘molecular nurse’
The key player in this story is a protein called ATM. It’s a kind of molecular ‘triage nurse’ that patrols the cell, looking out for signs of DNA damage.
When ATM spots DNA damage, it does one of two things: if the damage is repairable, it tells the cell to stop dividing and calls in emergency crews of repair proteins. But if the damage is too bad to be fixed (for example, in the case of damage caused by radiotherapy or certain cancer drugs) then it tells the cell to die instead.
Because the effects of ATM are so drastic – either halting a cell in its tracks or killing it – it’s very important that it’s only activated exactly when needed. So there are a lot of control mechanisms that help to make sure that ATM is only switched on at the right time and in the right place. But it’s still not entirely clear how all these controls work.
We also know about some other important characters involved in the process of DNA repair. These include two proteins called KAT5 and c-Abl – the latter being the target of the cancer drug imatinib (better known as Glivec). But what’s not been known, until now, is whether and how these two proteins collaborate with ATM to keep our DNA in tip-top shape.
Through detailed experiments with cancer cells grown in the lab, Kaidi discovered a chain of events that links all three proteins together:
- First, he found that, when DNA damage occurs, c-Abl switches on KAT5.
- This ‘activated’ KAT5 then homes in on the cell’s genetic material – particularly proteins called histones that package DNA to make up a structure called chromatin (which is disrupted when DNA gets damaged).
- Finally, the activation and relocation of KAT5 switches on ATM, triggering the cell’s DNA repair machinery.
Having discovered how this pathway works, Kaidi wondered if it could be switched off. So he exposed cancer cells to imatinib, which prevents c-Abl from switching on other proteins. As predicted, the drug blocked the DNA repair process from being activated after the cells were exposed to radiation.
It’s all a bit complicated, so to explain the process we’ve made this handy diagram:
What does it mean?
This discovery is significant because it’s the first time that three distinct molecular pathways – DNA repair, histone proteins and c-Abl – have been linked together.
And, importantly, drugs targeting each of these areas are already available: not just imatinib but other experimental drugs like PARP inhibitors that block DNA repair directly, and chromatin-altering drugs called HDAC inhibitors that change the molecular ‘tags’ on histones.
This research suggests that carefully combining these treatments together could bring new benefits to patients. It also points towards potential gains from trying therapies like imatinib in a wider range of cancer types, in combination with radiotherapy or other chemotherapy agents, or in combination with DNA repair and/or chromatin-changing drugs.
And, of course, there are opportunities for developing entirely new therapies, such as drugs that block KAT5.
This work has only been done using cells growing in the lab, so it comes with all the usual “still early days” warnings. Professor Jackson and his team are now working with colleagues at the Wellcome Trust Sanger Centre and elsewhere to flesh out their new findings, combining cell biology and genetic analyses to work out which kinds of cancers might benefit most from different combinations of agents. He says:
“It’s very satisfying for me to know that basic research like this could lead to clinical benefit for patients. It also highlights the importance of Cancer Research UK funding a broad portfolio of research, enabling us to make these unexpected connections that could help to save lives in the future.”
KAT5 tyrosine phosphorylation couples chromatin sensing to ATM checkpoint signaling. Abderrahmane Kaidi and Stephen P. Jackson. Nature (2013)