ArcRep · Unravelling the Molecular Specificities of the Archaeal Core Replisome

The ability of cells to copy their genome before cell division is one of the wonders of biology. For DNA replication to succeed, multiple proteins act in concert forming a dynamic molecular engine known as the replisome. Great effort has been made to characterise all the components of the replisome, yet our understanding of how they work together to achieve DNA replication is still very limited. Recent studies have provided initial structural clues on the T7 phage, yeast and human replisomes, yet there is a large knowledge gap around the archaeal one. Furthermore, the archaeal replisome constitutes a living molecular fossil with a blend of bacterial and eukaryotic features that can help us better understand the emergence of eukaryotes.The first aim of ArcRep is to use recent advances in cryo-electron microscopy (cryo-EM) to determine the first structure of the archaeal replisome, revealing the molecular contacts that allow it to function. The second aim is to further understand how the replisome interacts with DNA, and to assess its potential for future development of tools that harness the sophistication of nature’s replisome in a test tube, as novel single-cell genomics biotechnology.With the cryo-EM experience I gained during my PhD, I will join the Sauguet lab to build up on their ample experience in the structure of archaeal replication proteins, and achieve the first aim of ArcRep. During a secondment in the Gardner lab (New England Biolabs, USA), who are experts in archaeal replication enzymology and have an established collaboration with the host lab, I will further characterise the replisome with methods previously developed in their group. This will achieve the second aim of ArcRep backed by a world leader in the production of reagents for life sciences.The distinct expertise that each of the three parties brings to ArcRep is an ideal melting pot for it to succeed and for me to acquire invaluable experience in both academic and industry environments.