Researchers discover molecular gate that could keep cancer cells locked up

Dividing cancer cell

New research has shed light on how DNA is copied when cells divide, potentially providing a target for cancer treatments.

Researchers from Imperial College London and the Brookhaven National Laboratory (BNL) New York have revealed the location of a molecular gate on a ring-shaped enzyme that opens up to embrace DNA during the process of cell division. Once the DNA is encircled by the enzyme it begins to unwind its double helix to start a copying process which is integral to cell division.

By locating where this gate opens, the work enhances current understanding of an essential biological process and suggests that locking the gate could be a way to block cell division in diseases such as cancer. The study was published in the journal Genes and Development.

Lead researcher from the Medical Research Council (MRC) Clinical Sciences Centre at Imperial College London, Dr Christian Speck said:  “Our work is aimed at understanding the molecular mechanism of DNA replication at a fundamental level, but our findings could have important implications, possibly pointing to new ways to fight cancer, because DNA duplication is a prime target to inhibit cancer cell growth.”

Separated DNA strands

When a cell divides, its genetic information is duplicated in a process known as DNA replication. This involves the unwinding of the two DNA strands that make up its double helix structure. Once the two DNA strands have separated, each of them then acts as a template to generate another complementary DNA strand to produce a new double helix. The replication of DNA in a cell is normally very controlled, but this process can go wrong. Problems in DNA replication are resolved in normal cells, but not in cancer cells, which causes them to grow out of control.

Central to the ‘unwinding’ process is an enzyme called MCM2-7 helicase. It is known that the enzyme has a ring-shaped structure composed of six subunits, but how this ring structure opens to encircle the DNA and start the unwinding process has remained a mystery until now.

Initial theories assumed MCM2-7 helicase existed as an open ring structure, but the research team argued that this would lead to poorly regulated DNA replication with no control. The team used an electron microscope to examine in more detail the MCM2-7 helicase activity in yeast cells, which undergo the same division process as human cells. Contrary to initial theories, this revealed the MCM2-7 helicase actually exists as a closed ring, indicating there must be a gate in the ring to allow the DNA to enter.

Six subunits of the MCM2-7 helicase enzyme and the opening between Mcm2 and Mcm5

To pinpoint the gate’s location, the team used a small molecule called rapamycin which essentially blocked openings at various positions between the six subunits. They found that if they blocked one specific opening, between two subunits called MCM2 and MCM5, the DNA could not enter and start the unwinding process.

“The study shows that the entry gate between MCM2 and MCM5 is essential to the duplication of DNA in cell division,” explained Dr Speck. “If we can find a way to lock the gate shut, it would stop cells from dividing, and therefore could have potential for developing an anti-cancer therapy.”

The collaboration harnessed the electron microscopy expertise at BNL with the chemical biology and genetic expertise at the MRC Clinical Sciences Centre, Imperial College London. This work was supported by the MRC. The first author, Stefan Samel, was supported by a Fellowship from the German Research Foundation (DFG).

Reference: S. Samel et al. ‘A unique DNA entry gate serves for regulated loading of the eukaryotic replicative helicase MCM2-7 onto DNA.’ Genes and Development, 2014.