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Prime editing – an update on the field

Scholefield, Janine, Harrison, Patrick T.·2021·Gene Therapy
DOI 10.1038/s41434-021-00263-9PMC PMC8376635
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Fig. 1 Prime editing in five steps. Prime editing has just two components, a Cas9 nickase fused to a modified reverse-transcriptase (referred to as PE2) and a multifunctional prime editing guide RNA (pegRNA). 1 The Cas9-H840A/pegRNA complex binds to the desired target region and creates a nick 3 bp upstream of the PAM site. The nick must be upsteam of the first variant site (in this case a TGA stop codon) and occurs on the same strand as the PAM liberating a 3’ flap. 2 This 3’ flap forms a sequence-specific interaction with the 14-16 nt “primer binding site” located at the 3’ end of the pegRNA. This RNA/DNA hybrid serves as the PRIMEr site for new DNA synthesis using the RNA “edit site” as a template; the modified RT polymerase copies the template thereby extending the 3’ flap. 3 The edited 3’ flap displaces the variant unedited 5’ flap, which is removed by a cellular nuclease FEN1. 4 In this example, this leaves two MisMatches to be resolved, one in the edited codon (G ≠ T), and one in the modified PAM (C ≠ C) which can be introduced as an option to prevent further editing to the corrected sequence. 5 MisMatch Repair resolves the DNA resulting in either precisely edited DNA (with no indels), or the original variant sequence. In the latter case where the PAM sequence has not been modified, the Cas9-H840A/pegRNA complex can bind to the variant sequence again and have another attempt at PRIME editing. Key: Cas9-H40A nickase shown in Green, Reverse Transcriptase in yellow. The PAM site is highlighted in a grey box; the pegRNA in blue; the 3’ edit site in red; the edited PAM site in bold; FEN1 in grey. For clarity, only part of the pegRNA is shown in step 1.
Fig. 1 Prime editing in five steps. Prime editing has just two components, a Cas9 nickase fused to a modified reverse-transcriptase (referred to as PE2) and a multifunctional prime editing guide RNA (pegRNA). 1 The Cas9-H840A/pegRNA complex binds to the desired target region and creates a nick 3 bp upstream of the PAM site. The nick must be upsteam of the first variant site (in this case a TGA stop codon) and occurs on the same strand as the PAM liberating a 3’ flap. 2 This 3’ flap forms a sequence-specific interaction with the 14-16 nt “primer binding site” located at the 3’ end of the pegRNA. This RNA/DNA hybrid serves as the PRIMEr site for new DNA synthesis using the RNA “edit site” as a template; the modified RT polymerase copies the template thereby extending the 3’ flap. 3 The edited 3’ flap displaces the variant unedited 5’ flap, which is removed by a cellular nuclease FEN1. 4 In this example, this leaves two MisMatches to be resolved, one in the edited codon (G ≠ T), and one in the modified PAM (C ≠ C) which can be introduced as an option to prevent further editing to the corrected sequence. 5 MisMatch Repair resolves the DNA resulting in either precisely edited DNA (with no indels), or the original variant sequence. In the latter case where the PAM sequence has not been modified, the Cas9-H840A/pegRNA complex can bind to the variant sequence again and have another attempt at PRIME editing. Key: Cas9-H40A nickase shown in Green, Reverse Transcriptase in yellow. The PAM site is highlighted in a grey box; the pegRNA in blue; the 3’ edit site in red; the edited PAM site in bold; FEN1 in grey. For clarity, only part of the pegRNA is shown in step 1.CC BY · PubMed Central

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Research works printed but not linked: 19

  1. Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019. https://doi.org/10.1038/s41586-019-1711-4. · DOI · Paper page
  2. Zhao D, Li J, Li S, Xin X, Hu M, Price MA, et al. Glycosylase base editors enable C-to-A and C-to-G base changes. Nat. Biotechnol. 2021;39:35–40. · DOI
  3. Kurt IC, Zhou R, Iyer S, Garcia SP, Miller BR, Langner LM, et al. CRISPR C-to-G base editors for inducing targeted DNA transversions in human cells. Nat. Biotechnol. 2021;39:41–6. · DOI · Paper page
  4. Chen L, Park JE, Paa P, Rajakumar PD, Prekop H-T, Chew YT, et al. Programmable C:G to G:C genome editing with CRISPR-Cas9-directed base excision repair proteins. Nat. Commun. 2021;12:1384. · DOI
  5. Liu Y, Li X, He S, Huang S, Li C, Chen Y, et al. Efficient generation of mouse models with the prime editing system. Cell Discov. 2020;6:1–4. · DOI
  6. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337:816–21. · DOI · Paper page
  7. Schene IF, Joore IP, Oka R, Mokry M, van Vugt AHM, van Boxtel R, et al. Prime editing for functional repair in patient-derived disease models. Nat. Commun. 2020;11:5352. · DOI
  8. Sürün D, Schneider A, Mircetic J, Neumann K, Lansing F, Paszkowski-Rogacz M, et al. Efficient Generation and Correction of Mutations in Human iPS Cells Utilizing mRNAs of CRISPR Base Editors and Prime Editors. Genes. 2020;11:511. · DOI
  9. Rousseau J, Mbakam CH, Guyon A, Tremblay G, Begin FG, Tremblay JP. Specific mutations in genes responsible for Alzheimer and for Duchenne Muscular Dystrophy introduced by Base editing and PRIME editing. bioRxiv. 2020. https://www.biorxiv.org/content/10.1101/2020.07.31.230565v1. · DOI
  10. Geurts MH, de Poel E, Pleguezuelos-Manzano C, Carrillo L, Andersson-Rolf A, Boretto M et al. Evaluating CRISPR-based Prime Editing for cancer modeling and CFTR repair in intestinal organoids. bioRxiv. 2020. https://www.biorxiv.org/content/10.1101/2020.10.05.325837v1. · DOI
  11. Kim Y, Yu J, Hong S-A, Eom J, Jang K, Lee S-N et al. Ex vivo therapeutic base and prime editing using chemically derived hepatic progenitors in a mouse model of tyrosinemia type 1. bioRxiv. 2020. https://www.biorxiv.org/content/10.1101/2020.09.14.297275v1. · DOI
  12. Aida T, Wilde JJ, Yang L, Hou Y, Li M, Xu D et al. Prime editing primarily induces undesired outcomes in mice. bioRxiv. 2020. https://www.biorxiv.org/content/10.1101/2020.08.06.239723v1. · DOI · Paper page
  13. Gao P, Lyu Q, Ghanam AR, Lazzarotto CR, Newby GA, Zhang W, et al. Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression. Genome Biol. 2021;22:83. · DOI
  14. Kim HK, Yu G, Park J, Min S, Lee S, Yoon S et al. Predicting the efficiency of prime editing guide RNAs in human cells. Nat. Biotechnol. 2020. https://doi.org/10.1038/s41587-020-0677-y. · DOI
  15. Bhagwat AM, Graumann J, Wiegandt R, Bentsen M, Welker J, Kuenne C et al. multicrispr: gRNA design for prime editing and parallel targeting of thousands of targets. Life Sci. Alliance. 2020;3:e202000757. · DOI
  16. Chow RD, Chen JS, Shen J, Chen S. A web tool for the design of prime-editing guide RNAs. Nat. Biomed. Eng. 2020. https://doi.org/10.1038/s41551-020-00622-8. · DOI
  17. Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV, Lam KC, et al. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat. Commun. 2021;12:1034. · DOI
  18. Jiang Y-Y, Chai Y-P, Lu M-H, Han X-L, Lin Q, Zhang Y, et al. Prime editing efficiently generates W542L and S621I double mutations in two ALS genes in maize. Genome Biol. 2020;21:257. · DOI
  19. Kweon J, Kweon J, Yoon J-K, Jang A-H, Shin HR, See J-E, et al. Engineered prime editors with PAM flexibility. Mol. Ther. J. Am. Soc. Gene Ther. 2021. https://doi.org/10.1016/j.ymthe.2021.02.022. · DOI

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Metadata

Authors
Scholefield, J., & Harrison, P. T.
Venue
Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-05-24
Volume
28
Issue
7-8
Pages
396-401
ISSN
  • 0969-7128
  • 1476-5462
DOI
10.1038/s41434-021-00263-9
PMC
PMC8376635
Cited by
135
References
2
Language
en
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Scholefield, J., & Harrison, P. T. (2021). Prime editing – an update on the field. Gene Therapy. https://doi.org/10.1038/s41434-021-00263-9