Cryo-EM structure of the ATPase motor, MCM, bound to the DNA double helix.

Alessandro Costa : Macromolecular Machines Laboratory

We are studying the molecular machines that unravel and copy DNA inside our cells, to understand how faults in these processes can lead to cancer.

Every human cell contains more than two metres of DNA, encoding all the genetic instructions required for life. DNA forms a structure known as the double helix – a twisted ladder that is coiled up upon itself with two complementary filaments packaged in dynamic chromosome structures.

Each time a cell divides, it has to copy all its chromosomal DNA and split it equally into two new cells. Not only is the copying process very complicated and prone to mistakes, the thin strands of DNA are easily damaged. If any errors aren’t fixed, then the cell will end up with DNA faults that could disrupt the physical integrity of the double helix, which could lead to uncontrolled cell division and, eventually, cancer.

These events however are very rare, because tiny molecular ‘machines’ that copy DNA and protect the integrity of our chromosomes function very accurately. We are using high-powered microscopes (“cryo-electron microscopes”) and other lab techniques to observe these machines as they work, so that we can understand how they function normally and what goes wrong when they fail.

We are particularly interested in finding out how the machines that open and copy DNA work together, making sure that our genetic information is transmitted correctly as cells proliferate. Knowing more about this process will help us understand how our DNA stays healthy and what might have gone wrong when cancer develops.