Snapshots of the Reading and Writing of Synthetic Genetic Polymers

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Synthetic genetics aims to expand nucleic acids to new non-natural genetic polymers called ‘xeno nucleic acids (XNA)’ to foster advances in many areas like long-term data storage, biotechnology, diagnostics and medicine. Key for XNA-based applications are enzymatic “machines” for XNA recording (XNA polymerases) and reading (XNA reverse transcriptases). Despite progress in the development of such XNA enzymes, major challenges remain since efficiency and fidelity of the hitherto evolved enzymes with xeno substrates is generally lower than with the natural counterparts. Structural insights into these processes would provide highly valuable insights leading to important advances. However, important structures are lacking. Thus, the aim of this project is the first time elucidation of the structural basis for enzymatic recording and reading of XNA. Thereby we will build on our past success in the structural elucidation of the interplay of DNA polymerases with synthetic substrates. These structures will provide new insights into the chemical boundary conditions of genetic transactions and will guide for further engineering with the goal to obtain very efficient XNA enzymes. Significant momentum for this project will be gained by collaborating with with two world-wide known major protagonists in the field: Philipp Holliger (MRC Cambridge, UK) will provide unique expertise in XNA enzymes and Piet Herdewijn (KU Leuven, Belgium) in the chemical synthesis of XNA components. This line-up will provide a unique setting spurring the progress in this project that lies in a world-wide highly visible and competitive field.