PE4 Prime Editor

Prime editor generation 4 combining PE2 with a co-expressed MLH1 dominant-negative fragment to suppress mismatch repair reversion of prime edits. Achieves 2–6× higher editing efficiency than PE2 at many loci with lower indel rates than PE3. Preferred when high efficiency is required without the added complexity of a second nicking guide RNA.

Length: 1 bp(0 aa)

Generation: PE4

Characteristics

Enhanced prime editing via mismatch repair inhibition. MLH1dn co-expression increases editing 2-6× at many sites. Lower indel rates than PE3 while achieving comparable efficiency. Reduces reversion of edited intermediates by cellular repair machinery.

Architecture: PE2 fused to MLH1 dominant-negative (MLH1dn) fragment. Transient co-expression of MLH1dn inhibits mismatch repair pathway that can reverse prime edits.

Capabilities: All PE2 editing capabilities with enhanced efficiency through mismatch repair evasion. Particularly effective for edits creating heteroduplex intermediates.

Efficiency features: Transient MMR inhibition improves editing without permanent cellular changes. Particularly effective for transition mutations and small insertions. Can be combined with PE3 architecture (PE5).

References

  1. Anzalone et al. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature - Anzalone 2019 Prime Editing
  2. Chen et al. (2021). Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell - Chen 2021 PE4 PE5

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