Helper helicases in human genome replication

The DNA replication machinery (replisome) in human cells is built around a core DNA helicase called CMG, which separates the two strands of the double helix during DNA replication, to generate the single strands of DNA that act as templates for new DNA synthesis. Although CMG is capable of supporting the unwinding of the majority of our genome, it is blocked at numerous protein barriers, and during the final termination stage of DNA replication.

When CMG is blocked, a 2^nd accessory or ‘helper’ helicase is required to support replisome progression, so that genome replication can be completed. We have previously identified a new role for these helper helicases during the final stages of DNA replication (Deegan et al., Mol Cell, 2019), and defined a conserved mechanism for how they are recruited to replisome (Olson et al., EMBO J, 2024). We now intend to interrogate the molecular mechanisms by which these helicases support replisome progression when CMG is blocked, and how these helicases help protect our genomes when DNA replication is perturbed.

This project will combine biochemical reconstitution with purified human proteins with cell biology and genome engineering techniques to investigate a newly discovered, fundamental feature of eukaryotic replisome organisation. Furthermore, this work may shed light on the numerous human diseases in which these helper helicases are mutated.