Scientists have developed a mathematical model that describes a key step in human cell division – and an important target for cancer treatment – in unprecedented detail.
Using their model, the researchers were able to unpick the complex network of molecules controlling an early stage of cell division known as the G1/S checkpoint.
Understanding the network in such detail could open up new approaches to treatment aiming to exploit how it operates in particular types of cancer.
Passing the G1/S checkpoint commits a cell to making a copy of its DNA. If a cell’s DNA has been damaged, it won’t be allowed to divide until the damage has been repaired, ensuring potentially lethal DNA errors are not inherited by daughter cells.
Often in cancers, the G1/S checkpoint has become faulty, allowing cells to divide even when they carry errors in their DNA – and that makes it an attractive target for new therapies.
The study, published in the journal Cell Systems and funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC), is the most comprehensive characterisation of the G1/S transition in human cells to date.
Scientists at The Institute of Cancer Research, London, along with collaborators at the University of Oxford, used the latest imaging technology to look at individual cells as they went through cell division.
They used fluorescent ‘labels’ to track the dynamics of molecules already implicated in controlling cell division in yeast cells, so that they could explore what roles they played in human cells.
Researchers developed a mathematical model based on their observations, and performed experiments in human cells grown in the laboratory to validate the model.
The model predicted that low levels of the protein p27Kip1 were required for cells to pass through the G1/S checkpoint. When the researchers investigated further, they found that the enzyme Cdk2 was responsible for maintaining low levels of p27Kip1.
Crucially, a molecule called CyclinE was predicted to control the timing of the G1/S checkpoint, and when the researchers experimentally reduced levels of CyclinE inside cell lines grown in the lab, they found the cell cycle was delayed.
The model also revealed that the molecule Emi1 ensures that the G1/S checkpoint is a ‘point of no return’, so that cells commit to copying their chromosomes only once before dividing.
Dr Chris Bakal, Team Leader in Dynamical Cell Systems at the ICR, said: “Our study has combined mathematical modelling with single cell measurements to produce a dynamic picture of what’s happening during the G1/S checkpoint in human cells.
“Previously, we had a basic understanding of how the cell cycle is regulated from studies in yeast. But human cells are much more complex, and we did not know how the components involved dynamically interact to drive normal or cancerous human cells through cell division.
“We can now use our model to look at what happens in different cell lines and cancer types to reveal changes in cell cycle regulation that can be exploited therapeutically. More work needs to be done, but in future we’d like to see treatment decisions being made based on the dynamics of the cancer’s molecular networks, not just changes in specific genes.”