Molecular mechanisms of DNA synthesis by the human replisome

Before mitosis, cells must make two accurate and complete copies of their genome, to ensure genetic stability across cellular generations.

This challenging biochemical task requires complex molecular systems that duplicate chromosomal DNA and repair lesions that stall DNA synthesis.

Sporadic or inherited defects in the cellular apparatus of genomic duplication cause genetic instability, which is responsible for developmental and degenerative pathologies and for cancer predisposition.

Our knowledge of the molecular basis of eukaryotic DNA replication and related repair processes is incomplete, and this is especially true of genomic duplication in human cells, the most relevant to our health.

Our proposal aims to provide a high-resolution view of the molecular mechanisms of DNA replication, using state-of-the-art biochemical and biophysical approaches.

We will focus on components of the human replisome, the multi-protein assembly responsible for DNA synthesis in our cells.

There is intense medical interest in the molecular mechanisms responsible for genomic integrity and the rationale for the consequences of their occasional failure.

In this respect, the work of our proposal is highly significant as it aims to deliver a comprehensive description in atomic detail of the complex and dynamic processes of DNA replication, when our genome is at its most vulnerable.