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Joint research led by Yutaro Shuto, Ryoya Nakagawa, and Osamu Nureki of the University of Tokyo focused on the spatial structure and functional analysis of a novel gene-editing tool called “prime editor.” This research aimed to understand how the prime editor achieves reverse transcription, synthesizing DNA from RNA, without cutting both strands of the double helix. The findings, published in the journal Nature, provide insights that could help design more accurate gene-editing tools for gene therapy treatments. This is significant because the accuracy of existing gene-editing methods and safety concerns about cutting both strands of DNA have limited their use for therapeutic purposes.

The prime editing system consists of two components: the prime editor, which combines a SpCas9 protein and a reverse transcriptase, and the prime editing guide RNA (pegRNA), which identifies the target sequence within the DNA and encodes the desired edit. This complex acts like a word processor, accurately replacing genomic information. While the tool has already been successfully implemented in living cells of various organisms, the exact mechanism of action was unclear due to the lack of information on its spatial structure. The researchers used cryogenic electron microscopy to observe the prime editor complex at a near-atomic scale, overcoming challenges related to its instability under experimental conditions.

The three-dimensional structures of the prime editor complex revealed that the reverse transcriptase binds to the RNA-DNA complex formed along the Cas9 protein associated with DNA cleavage. As the reverse transcription occurs, the reverse transcriptase maintains its position relative to the Cas9 protein, potentially leading to additional, undesired insertions. These insights into the molecular mechanisms of the prime editor complex have implications for both basic and applied research. The researchers plan to apply their structure determination strategy to develop improved prime editors using different Cas9 proteins and reverse transcriptases, leveraging the newly obtained structural information.

The 2020 Nobel Prize in Chemistry was awarded to Jennifer Doudna and Emmanuelle Charpentier for their pioneering work on CRISPR-Cas gene editing technology, which provided a simple way to edit DNA. While this discovery opened new avenues for research, concerns about the accuracy of the method and the safety of cutting both strands of DNA limited its applications in gene therapy treatments. The development of prime editing as a gene-editing tool addresses these concerns by allowing for precise modifications without the need to cut both strands of DNA, making it a promising tool for therapeutic interventions.

The prime editing system has been successfully implemented in various organisms, demonstrating its potential for precise genetic modifications. The research conducted by Shuto, Nakagawa, and Nureki sheds light on the molecular mechanisms underlying the functioning of the prime editor complex, providing a better understanding of how it achieves reverse transcription without cutting both strands of the DNA double helix. By elucidating these mechanisms, the researchers hope to pave the way for the development of improved prime editors that can be used in a wide range of applications, including gene therapy treatments. Their findings contribute to advancing the field of gene editing and have implications for future research and development in this area.

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