Researchers Solve the Protein Paradox and Suggest How Cancer Weakness can...

The most important step in this process is DNA replication, in which the DNA in a mother cell is copied into its two daughter cells. Here, many molecules have to work together to put together two new, identical strings of DNA.

Write for the diary natureResearchers at the University of Copenhagen have discovered how MCM proteins ensure that DNA replication occurs at the right rate, thus avoiding unnecessary molecular collisions that could damage their genome.

More importantly, the new findings explain how mother cells manage to instruct their daughters to keep the rate of their DNA replication within physiological limits. In simple terms, the new discoveries discovered nothing less than how an essential skill required for the continuation of life is retained in the cell’s memory.

‘We have quite a few of these MCM proteins in our cells. We can see them under a microscope, but for decades scientists didn’t know what the vast majority of them were actually doing. From an evolutionary point of view, it didn’t make sense to maintain a huge excess of protein just as a backup without any other important function. We have now solved this “MCM paradox” by establishing that all of these many MCM proteins actually have a defined function in our cells, ”says first author Hana Sedlackova, a doctoral student at the Novo Nordisk Foundation Center for Protein Research.

Exploiting cancer weaknesses

To explain the new finding by analogy, the researchers found that the excess of young MCM proteins is used by cells to slow DNA replication by adding “speed bumps” in front of their older siblings, that “power” the DNA replication engine. And while slowing this process down may seem impractical, the body has very good reason to do so.

‘These new results show that most MCM proteins work a bit like speed bumps on a busy street. If they weren’t there, traffic would go too fast and accidents could easily happen. Our study shows that the same thing happens in the cell: if the newborn MCM proteins cannot be passed on from other cells to their daughters, the DNA will replicate too quickly, which can be fatal for the cell. Like a car, the DNA replication machine loses its maneuverability if it drives too fast, ”explains Professor Jiri Lukas, Executive Director at the Novo Nordisk Foundation Center for Protein Research.

The researchers suggest that their findings could potentially help exploit cancer cells’ weaknesses.

“During our work we also discovered that the young MCM proteins need a ‘molecular babysitter’ (a protein called MCMBP) to protect them and guide them to the DNA where they can be useful. Without this protection, molecular roadblocks slow down and DNA replication cannot be performed. While DNA in normal cells can be viewed as a beautiful new highway that allows for relatively high speed, DNA in cancer cells is riddled with potholes where any fast car (or molecular engine that replicates DNA) will test based on our new findings we currently have the idea that the genetic pharmacological removal of the MCMBP and the resulting high speed of DNA replication can be tolerated by normal cells, but are fatal for cancer cells, “says Jiri Lukas.

The researchers succeeded in imaging the proteins using a variety of high-tech devices such as CRISPR-Cas9 and HaloTag and finding their function. With the help of 4D imaging, they were then able to mark native MCM proteins and observe how they are born in the mother cells, how they are inherited from their daughters and how their functions change in the absence of MCMBP, the “MCM babysitter”, to change.

The study was funded by the Danish Cancer Society and the Novo Nordisk Foundation.