Journal
NATURE GENETICS
Volume 50, Issue 8, Pages 1132-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0174-0
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Funding
- NIH [S10 OD018174]
- Berkeley Macrolab
- Li Ka Shing Foundation
- Heritage Medical Research Institute
- Fanconi Anemia Research Foundation
- SURF Rose Hills Fellowship
- Regents' and Chancellor's Fellowship
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CRISPR-Cas genome editing creates targeted DNA double-strand breaks (DSBs) that are processed by cellular repair pathways, including the incorporation of exogenous DNA via single-strand template repair (SSTR). To determine the genetic basis of SSTR in human cells, we developed a coupled inhibition-cutting system capable of interrogating multiple editing outcomes in the context of thousands of individual gene knockdowns. We found that human Cas9-induced SSTR requires the Fanconi anemia ( FA) pathway, which is normally implicated in interstrand cross-link repair. The FA pathway does not directly impact error-prone, non-homologous end joining, but instead diverts repair toward SSTR. Furthermore, FANCD2 protein localizes to Cas9-induced DSBs, indicating a direct role in regulating genome editing. Since FA is itself a genetic disease, these data imply that patient genotype and/or transcriptome may impact the effectiveness of gene editing treatments and that treatments biased toward FA repair pathways could have therapeutic value.
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