Seat belts, emergency exits and upright tray tables – you’re probably familiar with the roll call of safety checks that accompany a plane journey.
And just as the cabin crew’s priority is the safe transit of their passengers, our cells must also ensure the right checks are in place when they embark on a journey to divide.
While it may seem simple on the surface, the process of cell division – where one cell splits to form two identical new cells – relies on a bewildering set of molecular checklists that make sure nothing goes wrong.
And whether you’re a frequent flyer or a regular divider, safety checking is vital in stopping accidents from happening – accidents that in cells can lead to cancer.
Now, a team of our scientists from the London Research Institute have discovered a new failsafe mechanism in dividing cells. But unlike the mechanisms that help stop normal cells becoming cancerous, their discovery points to something unique to tumour cells that may help them dodge damage to their DNA and keep growing.
Snapshot of a long journey
But first, some crucial information about what happens when cells divide.
The complete journey that sees one cell become two is called the cell cycle.
At the start of the cycle, a cell must grow and process the fuel needed to divide – while also making a complete, and accurate, copy of its DNA.
Once the DNA has been copied, the cell gathers up this crucial genetic material into 23 pairs of sausage-like structures that help the cell split the DNA equally – called chromosomes.
Then, everything in place, the cell splits down the middle – forming two identical new cells, each with 23 chromosomes.
It’s a critical point in the cell cycle, lead researcher Dr Nicola Brownlow tells us. “It’s here that the cell commits to division and the process of splitting the DNA equally begins.”
“Mistakes at this stage can lead to changes in the amount of DNA each cell receives – or damage to the DNA itself, which can lead to a cell becoming cancerous.”
To stop this, healthy cells carry a number of molecular mechanisms that kick in if any potential problems occur before the cell divides – for example, are the chromosomes aligned correctly? Are they connected to the cellular cables that pull the duplicated DNA to opposite sides of the cell?
But it’s the way a cell senses tangled DNA that’s the focus of this latest study.
DNA is an incredibly long molecule, and – like a slinky – tangles easily. When it’s copied, small pieces can get tangled up and looped together. And if the cell tries to divide with these tangles in place, it can snap the DNA – causing potentially harmful genetic damage.
Both cancer cells and healthy cells are really good at avoiding this, Nicola tells us, “but our research, along with others, has shown that some lab-grown cancer cells may have a weakness.”
“When we artificially trigger DNA tangling, the cancer cells stop dividing to give them more time to untangle their DNA,” Nicola says.
But it seems that the delay seen in the cancer cells occurs a little bit later than in healthy cells. They seem to rely on a different mechanism to stop them dividing with tangled DNA because earlier safety checks – that are really efficient in healthy cells – fail.
Nicola and her colleagues wanted to find out what was controlling this. And they had a hunch about where to look.
A molecular ‘safety-net’
But during that work they also spotted some interesting signs of an earlier role for these signals.
When the team switched off the protein during the cell cycle they found that certain cancer cells were still able to divide, despite having tangled DNA.
“This gave us the first clue that the signals controlled by PKC epsilon might be important for checking for DNA tangling,” Nicola says.
Next, as in their initial experiments, they artificially triggered DNA tangling, but this time they also switched off PKC epsilon. The results were striking.
“When we switched off the protein, the cells no longer paused to untangle their DNA,” Nicola said.
Instead, they carried on dividing. And because their DNA was still stuck together, the physical separation of the cell caused the genetic material to be torn apart.
“This sort of genetic damage is catastrophic for the cells,” says Nicola. And shortly after this premature division, the cancer cells die.
A window of opportunity
Crucially, these findings point to a potential weak spot unique to these tumours cells. And if the team can find a way to target PKC epsilon with a drug, this could provide an opportunity to kill the cancer cells.
And given that PKC epsilon is a type of protein that several cancer drugs already target – called a kinase – this could be possible in the future.
But it’s still early days for this research, and it’s not yet clear whether the same safety checks the team have identified in the lab will also be important in patients.
“Our research identifies a window of opportunity,” Nicola tells us. “But we will need to carry out further studies to see which cancers might rely on this safety net and whether there is a marker that could help us identify them.”
Much like the meticulous safety checks on a flight, research like this is vital.
Only with this knowledge can we truly understand how cancer cells bend the rules, ultimately unearthing new ways to stop them.
- Brownlow, N., et al. (2014). Mitotic catenation is monitored and resolved by a PKCε-regulated pathway Nature Communications, 5 DOI: 10.1038/ncomms6685
Cancer cell image courtesy of Dr Nicola Brownlow and Professor Peter Parker from the Cancer Research UK London Research Institute