Non-RVD mutations that enhance the dynamics of the TAL repeat array along the superhelical axis improve TALEN genome editing efficacy

Sci Rep. 2016 Nov 24:6:37887. doi: 10.1038/srep37887.

Abstract

Transcription activator-like effector (TALE) nuclease (TALEN) is widely used as a tool in genome editing. The DNA binding part of TALEN consists of a tandem array of TAL-repeats that form a right-handed superhelix. Each TAL-repeat recognises a specific base by the repeat variable diresidue (RVD) at positions 12 and 13. TALEN comprising the TAL-repeats with periodic mutations to residues at positions 4 and 32 (non-RVD sites) in each repeat (VT-TALE) exhibits increased efficacy in genome editing compared with a counterpart without the mutations (CT-TALE). The molecular basis for the elevated efficacy is unknown. In this report, comparison of the physicochemical properties between CT- and VT-TALEs revealed that VT-TALE has a larger amplitude motion along the superhelical axis (superhelical motion) compared with CT-TALE. The greater superhelical motion in VT-TALE enabled more TAL-repeats to engage in the target sequence recognition compared with CT-TALE. The extended sequence recognition by the TAL-repeats improves site specificity with limiting the spatial distribution of FokI domains to facilitate their dimerization at the desired site. Molecular dynamics simulations revealed that the non-RVD mutations alter inter-repeat hydrogen bonding to amplify the superhelical motion of VT-TALE. The TALEN activity is associated with the inter-repeat hydrogen bonding among the TAL repeats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatography, Gel
  • DNA / metabolism
  • Dynamic Light Scattering
  • Gene Editing*
  • Hydrogen Bonding
  • Molecular Dynamics Simulation
  • Mutation*
  • Repetitive Sequences, Amino Acid
  • Thermodynamics
  • Transcription Activator-Like Effector Nucleases / chemistry
  • Transcription Activator-Like Effector Nucleases / genetics*
  • Transcription Activator-Like Effector Nucleases / metabolism*

Substances

  • DNA
  • Transcription Activator-Like Effector Nucleases