CRISPR-like editing protein flexes DNA cargo to lock on to the right match

Designing next-generation CRISPR tools requires a clear understanding of the molecular mechanisms used by these gene-editing systems. Published in Science Advances, scientists at St. Jude Children’s Research Hospital have revealed how transposons — DNA elements that naturally move around the genome — are recognized and prepared for rearrangement by the transposition machinery. By obtaining structures of the transposon ends bound to the transposase TnsB, a key enzyme responsible for the cut-and-paste of DNA, the researchers modeled the early stages of transposition. They showed that the twisting and bending of DNA, with the help of bacterial protein IHF, aligns the transposon ends with high precision. The action is much like turning a puzzle piece until it fits. Once in position, the transposon ends can be cut and the DNA cargo within pasted elsewhere in the genome. The study provides key insights into the early stages of transposition, guiding future engineering efforts toward the design of highly accurate gene therapies. 

“Cut-and-paste transposition is a carefully choreographed process, in which the transposase enzyme pairs the two ends of the DNA segment before making the cut,” said first author Vinh Truong, a St. Jude Graduate School of Biomedical Sciences student working in the lab of Elizabeth Kellogg, PhD, Department of Structural Biology. “We can now see how that pairing happens, and understanding this mechanism gives us a blueprint to engineer gene editing tools that are more precise and more efficient.” 

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