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- W4307725211 endingPage "4081.e21" @default.
- W4307725211 startingPage "4067" @default.
- W4307725211 abstract "The target DNA specificity of the CRISPR-associated genome editor nuclease Cas9 is determined by complementarity to a 20-nucleotide segment in its guide RNA. However, Cas9 can bind and cleave partially complementary off-target sequences, which raises safety concerns for its use in clinical applications. Here, we report crystallographic structures of Cas9 bound to bona fide off-target substrates, revealing that off-target binding is enabled by a range of noncanonical base-pairing interactions within the guide:off-target heteroduplex. Off-target substrates containing single-nucleotide deletions relative to the guide RNA are accommodated by base skipping or multiple noncanonical base pairs rather than RNA bulge formation. Finally, PAM-distal mismatches result in duplex unpairing and induce a conformational change in the Cas9 REC lobe that perturbs its conformational activation. Together, these insights provide a structural rationale for the off-target activity of Cas9 and contribute to the improved rational design of guide RNAs and off-target prediction algorithms." @default.
- W4307725211 created "2022-11-05" @default.
- W4307725211 creator A5003328243 @default.
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- W4307725211 creator A5082183961 @default.
- W4307725211 creator A5089802474 @default.
- W4307725211 date "2022-10-01" @default.
- W4307725211 modified "2023-10-09" @default.
- W4307725211 title "Structural basis for Cas9 off-target activity" @default.
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