Molecular mechanisms of DNA replication termination (360G-Wellcome-204678_Z_16_Z)

Eukaryotic cells must duplicate their genome once per cell cycle, to allow genetic information to be accurately propagated during cell division. Defects in genome duplication are a hallmark of the early stages of tumour development, and mature tumours may thus be sensitive to agents that disrupt this process. Chromosome duplication is carried out by a multi-protein assembly termed the replisome, itself a critical determinant of genomic integrity, and a target for current and future anti-cancer therapies. A major focus of the eukaryotic DNA replication field for the past two decades has been understanding the mechanism of replisome assembly during replication initiation. Conversely, almost nothing is known about how the replisome is disassembled once genome duplication is completed. I plan to reconstitute eukaryotic DNA replication from initiation to termination with purified proteins. This reconstitution should facilitate a comprehensive study of the mechanisms and regulation of replisome disassembly, and thus significantly advance our understanding of how the replisome is regulated to preserve genome stability.