The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Massively parallel assessment of human variants with base editor screens
Open accessPublished version of a preprint
Abstract
Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.
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“It has been utilized for several applications, including single point mutations and targeted mutation induction for therapeutic corrections of diseases (Musunuru et al., 2021), mutational screening, and gene knockout among the genomes (Hanna et al., 2021; Que et al., 2010).”
From Emerging applications of gene editing technologies for the development of climate-resilient crops (2025) · cites this paper as Hanna et al., 2021
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Cites
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
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Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A., & Liu, D. R. (2016) · Nature · doi:10.1038/nature17946 · Cited by 5,437
Self-citationImproved vectors and genome-wide libraries for CRISPR screening
Sanjana, N. E., Shalem, O., & Zhang, F. (2014) · Nature Methods · doi:10.1038/nmeth.3047 · Cited by 5,239
Genome-scale CRISPR-Cas9 knockout screening in human cells
Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelsen, T. S., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., et al. (2014) · Science · doi:10.1126/science.1247005 · Cited by 5,234
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637
ClinVar: improving access to variant interpretations and supporting evidence
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Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage
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Self-citationNext-generation characterization of the Cancer Cell Line Encyclopedia
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CRISPR technology: A decade of genome editing is only the beginning
Wang, J. Y., & Doudna, J. A. (2023) · Science · doi:10.1126/science.add8643 · Cited by 1,105
Prime editing for precise and highly versatile genome manipulation
Chen, P. J., & Liu, D. R. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00541-1 · Cited by 644
Past, present, and future of CRISPR genome editing technologies
Pacesa, M., Pelea, O., & Jinek, M. (2024) · Cell · doi:10.1016/j.cell.2024.01.042 · Cited by 609
Bock, C., Datlinger, P., Chardon, F. M., Coelho, M. A., Dong, M. B., Lawson, K. A., Lu, T., Maroc, L., Norman, T. M., Song, B., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-021-00093-4 · Cited by 641
Base editing: advances and therapeutic opportunities
Porto, E. M., Komor, A. C., Slaymaker, I. M., & Yeo, G. W.-M. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0084-6 · Cited by 499
Metadata
- Authors
- Hanna, R. E., Hegde, M., Fagre, C. R., DeWeirdt, P. C., Sangree, A. K., Szegletes, Z., Griffith, A., Feeley, M. N., Sanson, K. R., Baidi, Y., Koblan, L. W., Liu, D. R., Neal, J. T., & Doench, J. G.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Doench, John G.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 184
- Issue
- 4
- Pages
- 1064-1080.e20
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3132864675
- Cited by
- 316
- References
- 81
- Citations by year
- 2026: 41 · 2025: 65 · 2024: 57 · 2023: 62 · 2022: 57 · 2021: 29
- FWCI
- 16.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- single nucleotide variants, loss-of-function mutations, BRCA1, BRCA2, BH3 mimetics, PARP inhibitors, drug resistance, drug sensitivity, DNA repair genes, cellular stress, single guide RNA library, ClinVar variants
- MeSH terms
- Gene Editing, Loss of Function Mutation, Alleles, Base Sequence, Humans, Poly(ADP-ribose) Polymerases, Selection, Genetic, Genetic Variation, Reproducibility of Results, Mutagenesis, Point Mutation, BRCA1 Protein, Catalytic Domain, BRCA2 Protein, Cell Line, Tumor, bcl-X Protein, High-Throughput Nucleotide Sequencing, Myeloid Cell Leukemia Sequence 1 Protein
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