By Deborah Oakley

A biological “puppeteer” plays a key role in how our cells make copies of their DNA, show findings published in Nature Structural and Molecular Biology today.

The puppeteer is made up of two proteins, called ORC and Cdc6, and holds “strings” that reach up from an enzyme below. Unlike most protein complexes, which are bound tightly together, these strings connect the proteins and enzyme in a loose and flexible way. This allows them to pull on the enzyme and move it up and onto a DNA strand. Once in position, this enzyme forms the core component of the cellular machinery that copies DNA.

This is the first time that scientists have shown in such detail how this enzyme, called a helicase, is loaded onto the DNA strand. It has been a puzzle, says lead researcher Christian Speck, because the enzyme is shaped like a ring and the DNA strand must sit in its centre, though there is no obvious gap in the ring for the strand to move through.

“It’s like threading a pearl onto a piece of string. But unlike a short piece of string, the DNA strand is incredibly long and so the bead cannot be threaded on at one end. Instead, it must somehow be opened up, slotted around the strand and closed again,” says Speck who leads the DNA Replication group based at the MRC London Institute of Medical Sciences (LMS).

Now the team has shown that the “puppeteer” twists part of the ring and traps the DNA inside. Speck says this twisting is most likely to happen as the helicase is moved into position on the DNA strand.

Speck and team studied how this process happens in yeast cells. The genes that encode these proteins are similar in yeast and people. They extracted the proteins and helicase from the yeast, then collaborated with researchers at the Van Andel Institute in Michigan to use electron microscopy to study in detail how they interact.

This builds on previous work by the Speck group, which showed that the Cdc6 protein plays a crucial role in DNA replication. When they blocked this protein, the DNA copying machinery jammed and stopped – the cellular production line had broken down. Now Speck would like to explore the precise movements of the Orc and Cdc6 proteins.

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Deborah Oakley

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MRC London Institute of Medical Sciences
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