London: Scientists using large-scale 3D printed models of protein complexes involved in DNA replication have found a protein target that could hold the key to future cancer treatments. When our cells copy their DNA to grow and replicate, they use a complex "machine" made from many hundreds of components.
Researchers have found that one key protein has a far more important role than had been thought. When the team blocked the protein, called Cdc6, DNA copying stopped, breaking down the cellular production line. The findings, may one day help to improve cancer treatments, researchers said. Current chemotherapy drugs kill cancer cells by damaging their DNA, but they can also harm the DNA in healthy cells.
If cellular machinery that copies DNA is targeted, instead of the DNA itself, the risk of secondary tumours could be reduced. Blocking Cdc6 could be the answer, said senior author Christian Speck who leads the DNA Replication group at the Clinical Sciences Centre at Imperial College, London. Our DNA is stored as two strands that are tightly twisted together and joined like a zip.
The most important information sits in the middle of this twisted structure. To copy this information, the strands need to be temporarily pulled apart. To do this, the cell assembles large number of proteins into a complex copying machine. A key component in the machine is a ring-shaped enzyme, called DNA helicase.
The helicase unzips the DNA by binding to a strand but it is not yet known how the helicase binds to the DNA strand. It was thought that Cdc6 acts like a tiny motor to place the helicase on top of the strand. Speck and his collaborators have overturned this theory by showing that the helicase can get into position even when the Cdc6 motor is turned off.
However, without active Cdc6, the cell was unable to proceed to the next stage in the copying process. This showed Cdc6 is vital for the machine to function. The study shows that, once the early stages of copying have begun, the Cdc6 motor is required for removal of the helicase assembly machine. Regulated assembly and disassembly ensures that the machine copies the DNA only once.
"If you replicate the DNA more than once, you end up with gene duplications - and this can cause cancer," said Speck. To study the DNA replication, the researchers first studied proteins, including the helicase and Cdc6, which had been extracted from Saccharomyces cerevisiae (bakers yeast). They explored how these proteins behave in living yeast cells.
The genes that encode these proteins are similar in yeast and people. The team used 3D printers to create large-scale models of these protein complexes. These models help them to visualise how the tiny protein components come together to form the complex copying machine. The study was published in the journal eLife.
