Studying viral protein-primed DNA replication to develop new gene editing technologies

Introduction

There are over 6,000 human genetic diseases, affecting hundreds of millions of people. The vast majority are caused by small mutations in DNA sequences which are potentially correctable, so the development of new gene editing tools will have major benefits for treating human genetic diseases. To tackle this challenge, we will harness the natural protein diversity of viruses to create new gene editing technologies.

Research Focus

We will study an unusual class of viruses that use a unique mechanism to replicate themselves, known as protein-primed DNA replication, which creates the rare feature of a protein-DNA covalent bond. These viruses are very understudied, yet they hold great potential for new biotechnology applications.

Objectives

We will study the protein-primed DNA replication machinery of these viruses, and then exploit this mechanism to develop a novel technology for synthetic biology, specifically:

1. Creating new ways to amplify and deliver DNA into living cells for gene editing.

Major Breakthroughs

Our research represents a major breakthrough on two accounts:

Discovery and Characterization

Firstly, we aim to:

• Discover and characterize large numbers of protein-primed DNA replication proteins from previously unstudied viruses.
• Establish a highly efficient, self-replicating system able to synthesize and amplify large amounts of protein-linked DNA product.
• Study the molecular details of these viral replication proteins for the first time.

Development of New Technology

Secondly, we will develop protein-linked DNA as a new platform technology for gene editing. Our strategy to engineer viral proteins will create protein-linked DNA molecules that are, for the first time:

• Actively nuclear-targeted.
• Self-replicating.

This approach aims to address key limitations in the gene editing field and pioneer a new method for highly efficient homology-directed repair.

Conclusion

Overall, our proposal combines fundamental biological study and applied biotechnology research to transform our understanding of these viral proteins and engineer them for groundbreaking advances in gene editing and DNA delivery.