Of the CRISPR-Cas9 tools created to date, base editors have gotten lots of attention because of their seemingly simple editing: they neatly replace one nucleic acid with another, in many cases all that should be needed to fix a genetic disease. Scientists have now determined the structure of the latest base editor as it swaps out nucleic acids, showing why it can go off target but also how it can be improved.
Researchers at the University of California, Berkeley, have now obtained the first 3D structure of one of the most promising of these tools: base editors, which bind to DNA and, instead of cutting, precisely replace one nucleotide with another.
First created four years ago, base editors are already being used in attempts to correct single-nucleotide mutations in the human genome. Base editors now available could address about 60% of all known genetic diseases — potentially more than 15,000 inherited disorders — caused by a mutation in only one nucleotide.
The detailed 3D structure, reported in the July 31 issue of the journal Science, provides a roadmap for tweaking base editiors to make them more versatile and controllable for use in patients.
«We were able to observe for the first time a base editor in action,» said UC Berkeley postdoctoral fellow Gavin Knott. «Now we can understand not only when it works and when it doesn’t, but also design the next generation of base editors to make them even better and more clinically appropriate.»
A base editor is a type of Cas9 fusion protein that employs a partially deactivated Cas9 — its snipping shears are disabled so that it cuts only one strand of DNA — and an enzyme that, for example, activates or silences a gene, or modifies adjacent areas of DNA. Because the new study reports the first structure of a Cas9 fusion protein, it could help guide the invention of myriad other Cas9-based gene-editing tools.
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Materials provided by University of California — Berkeley. Original written by Robert Sanders. Note: Content may be edited for style and length.