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      Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction

      Author(s): , , , , , , , ,
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      Journal: Nature Biotechnology
      Publisher: Springer Nature

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          Abstract

          Base editors enable targeted single-nucleotide conversion in genomic DNA. Here we show that expression levels are a bottleneck in base editing efficiency. We optimize cytidine (BE4) and adenine (ABE7.10) base editors by modification of nuclear localization signals and codon usage, and ancestral reconstruction of the deaminase component. The resulting BE4max, AncBE4max, and ABEmax editors correct pathogenic SNPs with substantially increased efficiency in a variety of mammalian cell types.

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          Basic Local Alignment Search Tool

          S Altschul (1990)
          Article 0 comments Cited 1462 times – based on 0 reviews     Review now
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            Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions

            Y Bill Kim, Alexis Komor, Jonathan Levy … (2017)
            Base editing is a recently developed approach to genome editing that uses a fusion protein containing a catalytically defective Streptococcus pyogenes Cas9, a cytidine deaminase, and an inhibitor of base excision repair to induce programmable, single-nucleotide changes in the DNA of living cells without generating double-strand DNA breaks, without requiring a donor DNA template, and without inducing an excess of stochastic insertions and deletions 1 . Here we report the development of five new C→T (or G→A) base editors that use natural and engineered Cas9 variants with different protospacer-adjacent motif (PAM) specificities to expand the number of sites that can be targeted by base editing by 2.5-fold. Additionally, we engineered new base editors containing mutated cytidine deaminase domains that narrow the width of the apparent editing window from approximately 5 nucleotides to as little as 1 to 2 nucleotides, enabling the discrimination of neighboring C nucleotides that would previously be edited with comparable efficiency, thereby doubling the number of disease-associated target Cs that can be corrected preferentially over nearby non-target Cs. Collectively, these developments substantially increase the targeting scope of base editing and establish the modular nature of base editors.
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              Codon optimality, bias and usage in translation and mRNA decay

              Gavin Hanson, Jeff Coller (2017)
              The advent of ribosome profiling and other tools to probe mRNA translation has revealed that codon bias - the uneven use of synonymous codons in the transcriptome - serves as a secondary genetic code: a code that guides the efficiency of protein production, the fidelity of translation and the metabolism of mRNAs. Recent advancements in our understanding of mRNA decay have revealed a tight coupling between ribosome dynamics and the stability of mRNA transcripts; this coupling integrates codon bias into the concept of codon optimality, or the effects that specific codons and tRNA concentrations have on the efficiency and fidelity of the translation machinery. In this Review, we first discuss the evidence for codon-dependent effects on translation, beginning with the basic mechanisms through which translation perturbation can affect translation efficiency, protein folding and transcript stability. We then discuss how codon effects are leveraged by the cell to tailor the proteome to maintain homeostasis, execute specific gene expression programmes of growth or differentiation and optimize the efficiency of protein production.
              Article 0 comments Cited 262 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Title: Nature Biotechnology
                Abbreviated Title: Nat Biotechnol
                Publisher: Springer Nature
                ISSN (Print): 1087-0156
                ISSN (Electronic): 1546-1696
                Publication date Created: May 29 2018
                Publication date Created: May 29 2018
                Publication date (Electronic): May 29 2018
                Publication date (Electronic): May 29 2018
                Article
                DOI: 10.1038/nbt.4172
                SO-VID: 818c40d7-c240-45a3-92bf-56859b87c348
                Copyright © © 2018
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