When cancer strikes, this disturbs the normal and well-controlled mechanisms of cells. To compensate for the many changes, the cancer cells need to slow down the cellular processes. Researchers have a new strategy for treating cancer based on the fact that cancer cells need to keep the speed slow when replicating their genes. If they are forced to keep the speed at maximum, they crash.
Replication plays a central role in life. A fertilized egg undergoes millions of divisions to create a human. And tissue is replaced and renewed throughout life so that the body can function. For every replication – every division – our DNA is copied so that the new cell also gets a copy. The replication process therefore needs to be tightly controlled to avoid numerous errors. Now researchers from the University of Copenhagen have revealed how the replication speed increases and decreases in a normal cell and in a cancer cell.
“This can be compared to a road with potholes. A normal cell has very few potholes, so even a fast-driving car can drive across it without major problems. On the cancer road there will be so many potholes that, if you force a cancer cell to drive across the genome too fast, it will crash. The cancer cell will die, but a normal cell will survive,” explains Jiri Lukas, Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
Like a bricklayer without bricks
The researchers made this spectacular discovery while studying how normal cells divide. Turning one cell into two cells requires duplicating the whole genome in a process called DNA replication. Postdoctoral fellow Kumar Somyajit, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen had a theory that genome replication, which follows a carefully planned cyclical programme that unfolds when the cell replicates and divides, requires a flexible mechanism that can slow down and then increase the replication speed.
“We found some proteins in the laboratory that are always thought to be associated with the ongoing replication. And we discovered that one protein, TIMELESS, accelerates the replication mechanism. TIMELESS actually determines the speed of the replication. The big question therefore was how the cell fine-tunes the motor so that it always runs at the right speed,” explains Kumar Somyajit.
To find out, the researchers developed applied very advanced technologies to map the “molecular engine” that copies our genome and to measure the precise speed at which the cell replicates its DNA in varying situations. This could reveal which signals were transmitted when the speed increased and decreased.
“We found that the TIMELESS accelerator binds to another protein, called PRDX2, which is a very sensitive sensor of an alert signal (called a reactive oxygen) that cells release if they cannot provide enough building blocks for newly synthesized DNA. And, amazingly, we observed that, when PRDX2 detects this alert, it removes the TIMELESS accelerator from DNA and thus slows down the process of genome copying. You can imagine this as similar to PRDX2 taking a foot off the gas pedal in a rapidly moving car.”
The cells are thus able to link the supply of nucleotides with the speed of replication to ensure that the genome is always replicated error free. A shortage of bricks slows the building process – or the house collapses. But if there are plenty of bricks, the speed increases. Conversely, cancer cells need to keep the process slow.
“We compared cancer cells with normal cells and surprisingly found that cancer cells replicate more slowly, even though they proliferate indefinitely and more aggressively,” adds Kumar Somyajit.
Cancer cells pay the price
The slower replication led the researchers to examine whether the difference in speed could be used to specifically target the cancer cells.
“Cancer cells differ from normal cells in many ways. One way is that cancer cells are immortal and can divide indefinitely, unlike normal cells. This is good for a cancer cell, but it pays a price. And one price the cancer cell pays is that it experiences greater stress than a normal cell,” explains Jiri Lukas.
The greater level of stress therefore makes the cancer cells reduce the speed in many cellular processes – including DNA replication. When the researchers removed the ability of the cancer cells to slow down the DNA replication process, the cancer cells crashed.
We could actually see this in many different types of cells from different types of cancer. If we remove the mechanisms so that the cell cannot adjust the replication speed, we can thus destroy specific cancer cells while the normal cells survive.
Although the new stress strategy is still at the experimental stage in the laboratory, Jiri Lukas is convinced that this new knowledge may pave the way for treating different types of cancer and perhaps other diseases in which the replication speed is relevant.
“Finding answers to some of these very basic biological questions can turn out to have enormous influence on understanding how the body functions, and this is often important for developing new drugs. What we plan to do now is to try and investigate other metabolic processes in cells to discover which ones are linked with DNA replication speed,” concludes Jiri Lukas.
“Redox-sensitive alteration of replisome architecture safeguards genome integrity” has been published in Science. Jiri Lukas, Kumar Somyajit and their colleagues who contributed to this article are employees at the Novo Nordisk Foundation Center for Protein Research of the University of Copenhagen.