Understanding how DNA replication machinery works

DNA replication
Image: 3D helicase structure

Research led by Francis Crick Institute scientists gives important insights into how the machinery that copies DNA functions, heralding further research aimed at intervening when the process goes awry.

Dr Alessandro Costa of the Francis Crick Institute (currently based at Clare Hall laboratories) said: “Making accurate copies of DNA is essential to maintain the physical integrity of our chromosomes and avoid the onset of cancer.”

Dr Costa’s team used high-resolution cryo-electron microscopy to obtain the structure of an enzyme called helicase, imaged as it moves along DNA.

They combined this 3D structure with singlemolecule fluorescence imaging (in collaboration with David Rueda’s group at Imperial College London), to investigate how DNA is manipulated as the helicase engages it.

This showed that the helicase moves on one single DNA filament and pushes away the other filament, hence unzipping the double helix.

Dr Costa said: “Helicases work just like motors, burning fuel to provide motive power. We explain how fuel combustion in the helicase produces movement that makes the replication machinery advance on the DNA during replication. By understanding how this molecular machine works we can learn how to intervene when things go wrong.”

“Our study will enable cancer biologists to ask new important questions. For example, how can the DNA replication machinery halt to facilitate DNA repair when a damaged site is encountered  on the double helix? This is a fundamental process that prevents the accumulation of breakages in our chromosomes, a frequent cause of cancer.”

The paper, Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate, is published in Nature Communications.