How to avoid cancer-causing chromosomal car-crashes

Imagine this: you’re speeding along a fast road that runs through the middle of nowhere, stereo on full blast and nothing around for miles. Out of the blue, something goes wrong with your car and you find yourself stalling in the middle of the road, with no chance of being picked up or rescued. To make matters worse, an oncoming lorry’s headed right towards you…

Suddenly things don’t look so good.

Breakdowns and breakups

“Knowing more about this weakness in some cells could open up exciting new possibilities for targeting cancers with this mistake” – Dr Jesper Svejstrup

It may seem like a stretch of the imagination, but this scenario is very similar to what takes place on our DNA when a molecular ‘machine’ known as RNA polymerase II, breaks down while it’s travelling along a long gene inside our cells.

This is important because this particular ‘machine’ is responsible for converting the ‘code’ of our DNA into instructions to make proteins.

When RNA polymerase II stops in these parts of our DNA, there’s very little to help it get started again, putting it at risk of collisions with another ‘machine’ that’s also often travelling along our DNA, that’s responsible for copying DNA when cells replicate to make new cells: DNA polymerase.

Scientists have already discovered that when DNA polymerase runs into a broken-down RNA polymerase II, the resulting collision can cause catastrophic breaks in the DNA.

Much like the destructive effects of a head-on traffic collision, the damage to the DNA can increase the chances of a cell becoming cancerous.

But this week our researchers have published a study that helps us understand a little better how our cells have mechanisms in place to help prevent these ‘car-crash’ events from taking place.

Hitting the brakes

In a paper published in the journal Cell this week, Dr Jesper Svejstrup and his team at our London Research Institute have found a protein that appears to protect RNA polymerase II from breaking down while it’s reading long genes.

Known as RECQL5, it acts like a ‘brake’ on the RNA polymerase II, slowing it down and making it run more smoothly as it travels along our genes, meaning it is much less likely to stall in the middle of a long journey.

As well as preventing RNA polymerase II from stalling as frequently, RECQL5 also appears to help it get started back up again when it does stop, although Svejstrup and his team say they need to carry out more work to understand exactly how RECQL5 actually does this.

Some roads are better than others

Avoiding weak spots in the ‘DNA road’

Even more intriguing is that scientists have also discovered that these breakdowns take place more often on parts of our chromosomes called ‘common fragile sites’.

These are naturally occurring weak points on our chromosomes that are more likely to break when exposed to events such as the DNA-RNA polymerase II collision – to use our motoring analogy, they’re like parts of a road that are particularly susceptible to cracks and potholes.

They also tend to harbour very long genes – exactly the kind that the RNA polymerase II is most likely to catastrophically break down on.

The DNA in all our cells have common fragile sites. Under normal circumstances they are relatively stable and don’t break that often.

But scientists have found that common fragile sites are frequently broken or messed up in cancers, like roads in a terrible state of repair.

This damage appears to be connected to things going wrong with DNA polymerase as it travels along making a copy of the genetic code.

With their new discovery, Svejstrup and his team now believe that by preventing crashes between DNA polymerase and RNA polymerase II on these common fragile sites, RECQL5 could play an important role in protecting our cells from cancer.

Meet the genome mechanics

looking ‘under the hood’ of cancer

The reason cancer researchers are so interested in RECQL5 is that it belongs to an important family of five proteins known collectively as RecQ helicases.

These proteins play a number of different roles as the ‘mechanics’ of our genome, helping the process of copying DNA to run smoothly and fixing any mistakes when things go wrong.

Three of the RecQ helicases, although not RECQL5 itself, are linked to rare genetic diseases that predispose a person to developing cancer.

And although they have yet to find a direct link, scientists have also found that changes to the RECQL5 gene in cells can be seen in many types of cancer including cervical, skin and liver.

All these signs point to the idea that this small group of proteins could be directly involved in some of the events that can lead a cell to becoming cancerous.

The nuts and bolts of cancer

There’s a long road to travel to understand how exactly RECQL5 and RNA polymerase II interact but it seems likely that it does play an important role in keeping our DNA in good working order.

While fundamental biological discoveries like this are still a long way off from being turned into treatments that can benefit patients, they help us look under the bonnet of cancer to understand the ‘engine’ driving the disease.

Lab research is the vital first step in helping us move down the road to new drug discoveries and insights that could help cancer patients in the future.

Flora Malein is a press officer at Cancer Research UK

Reference

• Saponaro M, et al. (2014). RECQL5 Controls Transcript Elongation and Suppresses Genome Instability Associated with Transcription Stress, Cell, DOI: 10.1016/j.cell.2014.03.048

Road image from Wikimedia Commons