All cells synthesise a copy of their genome before dividing. Errors in chromosome replication can lead to genome instability, which is a hallmark of cancer cells. Our research aims to understand how macromolecular machines involved in genome duplication function to preserve chromosome integrity. To address these issues, we employ a combination of cryo-electron microscopy (cryo-EM) and biochemistry, to generate mechanistic models that explain genome propagation in eukaryotic cells.
Before chromosome duplication can start, replication origins are ‘licensed’ by initiator factors that recruit a set of two MCM (Minichromosome maintenance) helicases onto duplex DNA. Once activated, MCM unwinds the double helix, providing the single-stranded template for the replicative polymerases. We aim at elucidating the molecular basis of origin licensing, DNA opening and replication fork establishment to understand how any given DNA segment in the genome is replicated only once per cell cycle and how DNA unwinding and synthesis are coupled to maintain genome stability.