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) in 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.
Dr Christian Speck of the Medical Research Council (MRC)
Clinical Sciences Centre at Imperial College London 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."
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.
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.
The paper, A
unique DNA entry gate serves for regulated loading of the
eukaryotic replicative helicase MCM2-7 onto DNA, is published
in Genes and Development.