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Jul 11, 2014

Look Out CRISPR, BuD-Derived Gene Editing Tools May Be Gaining On You

Look Out CRISPR, BuD-Derived Gene Editing Tools May Be Gaining On You

The structure of the BurrH binding domain, or BuD, before (left) and after (right) recognition of a specific DNA sequence. [Guillermo Montoya, CNIO]

  • While many researchers have focused on refining existing gene editing tools, other researchers have continued to look for new additions to the gene editing toolbox. For example, last January, researchers affiliated with the Cellectis biotechnology group reported the discovery and initial characterization of BurrH, a new modular DNA-binding protein from Burkholderia rhizoxinica. Following up on this result, researchers at the Spanish National Cancer Research Centre (CNIO) detailed the structure of the BurrH binding domain, or BuD. What’s more, the CNIO researchers reprogrammed BuD and directed it toward specific DNA regions.

    The results of the CNIO study appeared July 1 in the journal Acta Crystallographica Section D: Biological Crystallography, in an article entitled, “BuD, a helix-loop-helix DNA-binding domain for genome modification.” The study’s leader, Guillermo Montoya, Ph.D., said that BuD-derived nucleases could “allow us to modify and edit the instructions contained in the genome to treat genetic diseases or to develop genetically modified organisms.”

    The CNIO researchers used X-ray crystallography to resolve the three dimensional structure of BurrH. In particular, they scrutinized BurrH’s apo and DNA-bound crystal structures. This work revealed a central region containing 19 repeats of a helix-loop-helix modular domain, which “identifies the DNA target by a single residue-to-nucleotide code, thus facilitating its redesign for gene targeting.”

    The main advantage of BuDs lies in their high specificity: They are able to distinguish DNA sequences that differ only in two nucleotides. “This high specificity acts as a GPS that allows them to find their destinations within the intricate genome map,” explained Dr. Montoya. “They are very versatile and easy to reprogram in comparison with other proteins used to the same end.”

    “New DNA-binding specificities have been engineered in this template, showing that BuD-derived nucleases (BuDNs) induce high levels of gene targeting in a locus of the human hemoglobin β (HBB) gene close to mutations responsible for sickle cell anemia,” wrote the authors. “Hence, the unique combination of high efficiency and specificity of the BuD arrays can push forward diverse genome-modification approaches for cell or organism redesign, opening new avenues for gene editing.”

    The possibility of making à la carte modifications to the genome of living organisms could have a wide variety of applications, not only in the treatment of human illnesses, but also in the field of synthetic biology—the science that seeks to create new living beings or improve existing ones for their biotechnological use.

    “Our tool, as well as being used to treat genetic disease, could be used to genetically modify micro-organisms targeting metabolite synthesis needed to produce biofuels, for example,” said Dr. Montoya, who added that several companies are already interested in the new gene editing technology.



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