A new LUMC study has changed our understanding of how cells work. Researchers have discovered that the CFAP20 protein acts as a kind of 'traffic controller' on DNA. Without this protein, chaos ensues, potentially causing cancer. Their findings have been published in the prestigious journal Nature.
DNA can be seen as a busy railway, whose rails are made up of the four building blocks of DNA. These building blocks always come in pairs known as base pairs. Two types of trains constantly hurtle over the DNA railway: one copies the DNA (replication), allowing cells to divide, while the other reads the DNA (transcription) and creates mRNA, a list of proteins the cell should make.
'The trains, known as polymerases, travel on the DNA railway at one to two thousand base pairs a minute,' says Professor Martijn Luijsterburg. 'The trains can meet within minutes. Things often go wrong at the start of a gene: the transcription train gets off to a slow start, while the replication train behind is already speeding along.'
Traffic controller to prevent collisions
The CFAP20 protein proves to be a traffic controller that prevents collisions. It speeds up the transcription train to ensure it's not hit from behind. Without CFAP20, the traffic comes to a standstill. The transcription train grinds to a halt and blocks the track. Unable to pass, the replication train crashes into it.
'The replication trains set off simultaneously at thousands of places in the DNA,' says Luijsterburg. Without CFAP20, half of them stop, whereas the other half become stressed and try to compensate by speeding up. That sounds smart, but it causes new problems. It's like trying to speed transcribe a book: you miss out lines. The result is a bad copy.'
'If we didn't do fundamental research, we'd never make such discoveries. And then we'd never translate such insights to clinical practice and to patients.'
Bad copies can lead to cancer
Researcher Sidrit Uruci continues: 'The bad copies cause cells to divide in an uncontrolled fashion or follow the wrong instructions, which can lead to cancer over time.' Uruci, Luijsterburg an the other researchers involved in this study in Nature didn't discover CFAP20. 'Researchers already knew the protein existed, but no one had looked for a possible function in the cell nucleus,' says Uruci.
According to Luijsterburg, the discovery that CFAP20 plays an important role as a traffic controller was only possible because two research fields - replication (Uruci) and transcription (Luijsterburg) - met. 'You've got the transcription people who look at the reading from DNA and the replication people who look at the copying, but the two barely spoke. We decided to work together, which is how we saw how replication and transcription affect each other.'
No treatments without fundamental research
They are the first researchers to have discovered CFAP20's important role as a traffic controller. That won't immediately result in treatments, but Luijsterburg believes such discoveries form the basis of future ones. 'If we didn't do fundamental research, we'd never make such discoveries. And then we'd never translate such insights to clinical practice and to patients. That's why it's vital we do both in the LUMC: fundamental research and translating to practice,' he explains.
Study opens new world
The CFAP20 study opens a new world for researchers. For cancer biologists, it's an extra reason why cells derail and cancer arises. For drug developers, it's a new target because tumour cells appear to be dependent on it. 'They misuse the protein to divide more quickly, even if this compromises the quality of their DNA. In the future, this could potentially be a weak spot for fighting tumour cells,' says Uruci.
For fundamental researchers, the study is proof that it's worth continuing to hunt for unknown genes and proteins. 'The human genome consists of 20,000 genes, but 99% of the studies are about the same 10%. Who knows what we might find in the future,' says Uruci.
This research was supported by funding from an ERC Consolidator Grant and a Dutch Research Council Vici grant.
