Evidence map›Paper›PMID 34653350›Full record

ArticleCell2021

Enhanced prime editing systems by manipulating cellular determinants of editing outcomes.

Peter J Chen, Jeffrey A Hussmann, Jun Yan, Friederike Knipping, Purnima Ravisankar, Pin-Fang Chen, Cidi Chen, James W Nelson, Gregory A Newby, Mustafa Sahin and 4 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 526 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
526citing papers in PubMed, 2 pooled it
42.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

526 citing papers in PubMed, 2 syntheses or guidelines pooled it, 760 citations in OpenAlex.

  1. Pooled it
  2. CRISPR for cystic fibrosis: Advances and insights from a systematic review.Molecular therapy : the journal of the American Society of Gene Therapy · 2025
    Pooled it
  3. Prime Editing: An Overview.Methods in molecular biology (Clifton, N.J.) · 2027
    Review
  4. Article
  5. Article
  6. CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026
    Review
  7. Article
  8. Review
  9. Article
  10. Review
  11. Review
  12. Article
  13. Article
  14. Review
  15. Article
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  18. Article
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  20. Review

466 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors at 5 institutions in 1 country.

Peter J ChenMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Jeffrey A HussmannDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Jun YanDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Friederike KnippingDepartment of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55108, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Purnima RavisankarLewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Pin-Fang ChenHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
Cidi ChenHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
James W NelsonMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Gregory A NewbyMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Mustafa SahinHuman Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Mark J OsbornDepartment of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA; Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55108, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Jonathan S WeissmanDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Britt AdamsonDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA. Electronic address: badamson@princeton.edu.
David R LiuMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: drliu@fas.harvard.edu.
Broad Institute · USPrinceton University · USBoston Children's Hospital · USHoward Hughes Medical Institute · USUniversity of Minnesota · US

Funding

TRANSCRIPTIONAL PROFILINGP30CA072720 · NCI · UNIV OF MED/DENT NJ-R W JOHNSON MED SCH · PI Tracie Saunders · 1997 to 2026
$94.5M
Trial Design and Biostatistical Support CoreP01CA065493 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI J SUNIL RAO · 1995 to 2026
$48.2M
Center for Genomic Editing and Recording: Development and Application of Next-Generation Genome and Epigenome Editing Methods to Advance the Study and Treatment of Human DiseaseRM1HG009490 · NHGRI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI Brittany S. Adamson, Martin Joseph Ankrah Aryee · 2017 to 2026
$22.7M
Toward better characterization and clinical trial readiness for targeting neuropsychiatric manifestations in PTEN pathogenic variantsU54NS092090 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI M. Pilar Trelles · 2014 to 2026
$20.1M
Genetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI SCOTT Loren POMEROY, MUSTAFA SAHIN · 2021 to 2026
$9.4M
Integrating Chemistry and Evolution to Illuminate Biology and Enable Novel TherapeuticsR35GM118062 · NIGMS · HARVARD UNIVERSITY · PI LIU, DAVID R · 2016 to 2025
$6.4M
Mouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2M
PedGeneRx - Admin Supplement to Base Editing and Prime Editing for Sickle Cell Disease R01R01HL156647 · NHLBI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI Agnieszka Czechowicz, DAVID R LIU · 2021 to 2026
$4.8M
Skin-targeted Cell Therapy for Recessive Dystrophic Epidermolysis BullosaR01AR063070 · NIAMS · UNIVERSITY OF MINNESOTA · PI Mark J Osborn, Jakub Tolar · 2013 to 2026
$4.5M
Continuous Evolution of Proteins with Novel Therapeutic PotentialR01EB031172 · NIBIB · BROAD INSTITUTE, INC. · PI LIU, DAVID R · 2021 to 2024
$2.5M
Mapping the DNA damage response in human cells with high-resolution functional genomicsR35GM138167 · NIGMS · PRINCETON UNIVERSITY · PI Brittany S. Adamson · 2020 to 2026
$2.4M
Expanding the Scope of Base EditingU01AI142756 · NIAID · BROAD INSTITUTE, INC. · PI LIU, DAVID R · 2018 to 2022
$2.1M
Howard Hughes Medical InstituteNCI NIH HHS P01 CA065493NCI NIH HHS P30 CA072720NHGRI NIH HHS RM1 HG009490NHLBI NIH HHS R01 HL156647NIAID NIH HHS U01 AI142756NIAMS NIH HHS R01 AR063070NIBIB NIH HHS R01 EB031172NICHD NIH HHS P50 HD105351NICHD NIH HHS U54 HD090255NIGMS NIH HHS R35 GM118062NIGMS NIH HHS R35 GM138167NINDS NIH HHS U54 NS092090
6 · The paper itself

Abstract

While prime editing enables precise sequence changes in DNA, cellular determinants of prime editing remain poorly understood. Using pooled CRISPRi screens, we discovered that DNA mismatch repair (MMR) impedes prime editing and promotes undesired indel byproducts. We developed PE4 and PE5 prime editing systems in which transient expression of an engineered MMR-inhibiting protein enhances the efficiency of substitution, small insertion, and small deletion prime edits by an average 7.7-fold and 2.0-fold compared to PE2 and PE3 systems, respectively, while improving edit/indel ratios by 3.4-fold in MMR-proficient cell types. Strategic installation of silent mutations near the intended edit can enhance prime editing outcomes by evading MMR. Prime editor protein optimization resulted in a PEmax architecture that enhances editing efficacy by 2.8-fold on average in HeLa cells. These findings enrich our understanding of prime editing and establish prime editing systems that show substantial improvement across 191 edits in seven mammalian cell types.

Indexed as

Gene EditingCell LineCRISPR-Cas SystemsDNADNA Mismatch RepairFemaleGenes, DominantGenome, HumanHumansMaleModels, BiologicalMutationMutL Protein Homolog 1Reproducibility of ResultsRNADNAMLH1 protein, humanMutL Protein Homolog 1RNACRISPR-Cas9genome editingmismatch repairprime editingRepair-seq

Identifiers

PMID34653350
PMCPMC8584034
OpenAlexW3206354438

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.