Minichromosome maintenance proteins (MCM) play a critical role in replication and cell cycle progression. Although the MCMs are well known as replicative helicases, their overabundance and distribution patterns on chromatin present a paradox called the “MCM paradox.” Several approaches had been taken to solve the MCM paradox and describe the purpose of excess MCMs distributed beyond the replication origins.

Researchers from the University of Copenhagen have recently reported they discovered how MCM proteins ensure that DNA replication proceeds at the right pace avoiding unnecessary molecular collisions, which could damage their genomes. The new findings also explain how mother cells manage to instruct their daughters to keep the pace of their DNA replication within physiological limits.

Their findings, “Equilibrium between nascent and parental MCM proteins protects replicating genomes,” were published in Nature.

“We have quite many of these MCM proteins inside our cells. We can see them in the microscope, but for decades, scientists did not know what the vast majority of them actually do,” stated Hana Sedlackova, PhD student at the Novo Nordisk Foundation Center for Protein Research. “From an evolutionary standpoint, it did not make sense to maintain a huge surplus of proteins only as back up, with no other important function. We have now solved this ‘MCM paradox’ by finding that all those many MCM proteins in our cells actually have a defined function.”

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

The researchers used CRISPR-Cas9 and HaloTag to map the proteins and find their function. By using 4D imaging, the researchers were able to label native MCM proteins and observe how they are born in the mother cells, how they are inherited by their daughters, and how their functions are changed in the absence of MCMBP.

“During our work, we have also found that the young MCM proteins require a ‘molecular babysitter’ (a protein called MCMBP), which protects them and escorts them to DNA, where they can be useful,” explained Jiri Lukas, executive director at the Novo Nordisk Foundation Center for Protein Research. “Without such protection, molecular roadblocks that slow down DNA replication cannot be made. While DNA in normal cells can be viewed as a nice new highway that allows reasonably fast speed, DNA in cancer cells is riddled by ‘potholes,’ where every fast car (or a molecular motor that replicates DNA) is bound to crash. Based on our new findings, we are currently testing the idea that genetic of pharmacological removal of the MCMBP, and the resulting high speed of DNA replication, can be tolerated by normal cells but lethal to cancer cells.”

“The surplus of MCMs therefore increases the robustness of genome duplication by restraining the speed at which eukaryotic cells replicate their DNA. Alterations in physiological fork speed might thus explain why even a minor reduction in MCM levels destabilizes the genome and predisposes to increased incidence of tumor formation.”

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