CRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation.

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ID: 40745
2019
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Abstract
The introduction of insertion-deletions (INDELs) by non-homologous end-joining (NHEJ) pathway underlies the mechanistic basis of CRISPR-Cas9-directed genome editing. Selective gene ablation using CRISPR-Cas9 is achieved by installation of a premature termination codon (PTC) from a frameshift-inducing INDEL that elicits nonsense-mediated decay (NMD) of the mutant mRNA. Here, by examining the mRNA and protein products of CRISPR targeted genes in a cell line panel with presumed gene knockouts, we detect the production of foreign mRNAs or proteins in ~50% of the cell lines. We demonstrate that these aberrant protein products stem from the introduction of INDELs that promote internal ribosomal entry, convert pseudo-mRNAs (alternatively spliced mRNAs with a PTC) into protein encoding molecules, or induce exon skipping by disruption of exon splicing enhancers (ESEs). Our results reveal challenges to manipulating gene expression outcomes using INDEL-based mutagenesis and strategies useful in mitigating their impact on intended genome-editing outcomes.
Reference Key
tuladhar2019crisprcas9basednature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Tuladhar, Rubina;Yeu, Yunku;Tyler Piazza, John;Tan, Zhen;Rene Clemenceau, Jean;Wu, Xiaofeng;Barrett, Quinn;Herbert, Jeremiah;Mathews, David H;Kim, James;Hyun Hwang, Tae;Lum, Lawrence;
Journal Nature communications
Year 2019
DOI
10.1038/s41467-019-12028-5
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