Characterization of a triad of genes in cyanophage S-2L sufficient to replace adenine by 2-aminoadenine in bacterial DNA

Dariusz Czernecki, Frédéric Bonhomme, Pierre-Alexandre Kaminski and Marc Delarue ()
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Dariusz Czernecki: Unit of Architecture and Dynamics of Biological Macromolecules, CNRS UMR 3528, 25-28 rue du Docteur Roux, Institut Pasteur
Frédéric Bonhomme: Unit of Epigenetic Chemical Biology, CNRS UMR 3523, 25-28 rue du Docteur Roux, Institut Pasteur
Pierre-Alexandre Kaminski: Unit of Biology of Pathogenic Gram-Positive Bacteria, CNRS UMR 2001, 25-28 rue du Docteur Roux, Institut Pasteur
Marc Delarue: Unit of Architecture and Dynamics of Biological Macromolecules, CNRS UMR 3528, 25-28 rue du Docteur Roux, Institut Pasteur

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: Abstract Cyanophage S-2L is known to profoundly alter the biophysical properties of its DNA by replacing all adenines (A) with 2-aminoadenines (Z), which still pair with thymines but with a triple hydrogen bond. It was recently demonstrated that a homologue of adenylosuccinate synthetase (PurZ) and a dATP triphosphohydrolase (DatZ) are two important pieces of the metabolism of 2-aminoadenine, participating in the synthesis of ZTGC-DNA. Here, we determine that S-2L PurZ can use either dATP or ATP as a source of energy, thereby also depleting the pool of nucleotides in dATP. Furthermore, we identify a conserved gene (mazZ) located between purZ and datZ genes in S-2L and related phage genomes. We show that it encodes a (d)GTP-specific diphosphohydrolase, thereby providing the substrate of PurZ in the 2-aminoadenine synthesis pathway. High-resolution crystal structures of S-2L PurZ and MazZ with their respective substrates provide a rationale for their specificities. The Z-cluster made of these three genes – datZ, mazZ and purZ – was expressed in E. coli, resulting in a successful incorporation of 2-aminoadenine in the bacterial chromosomal and plasmidic DNA. This work opens the possibility to study synthetic organisms containing ZTGC-DNA.

Date: 2021
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DOI: 10.1038/s41467-021-25064-x

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